Pathogenic Mechanisms of HIV Disease: Further

ANNUAL REVIEWS
Further
Pathogenic Mechanisms
∗
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Susan Moir,† Tae-Wook Chun,†
and Anthony S. Fauci
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland, 20892; email: smoir@niaid.nih.gov,
twchun@nih.gov, afauci@niaid.nih.gov
eviews.org by Stanford University - Main Campus - Green Library on 06/21/12. For personal use only.
Annu. Rev. Pathol. Mech. Dis. 2011. 6:223–48

Keywords
First published online as a Review in Advance
on October 25, 2010 persistent infection, immune activation, immune dysfunction, AIDS
The Annual Review of Pathology: Mechanisms
of Disease is online at Abstract
pathol.annualreviews.org
Human immunodeficiency virus (HIV) infection is generally char-
This article’s doi: acterized by inefficient viral transmission; an acute phase of
10.1146/annurev-pathol-011110-130254
intense viral replication and dissemination to lymphoid tissues; a
∗
This is a work of the U.S. Government and is chronic, often asymptomatic phase of sustained immune activation
not subject to copyright protection in the United and viral replication; and an advanced phase of marked depletion
States. +
of CD4 T cells that leads to acquired immune deficiency syndrome.
†
These authors contributed equally.
Major insight into HIV transmission and each phase of infection has
been gained from studies on blood and tissue specimens obtained
from HIV-infected individuals, as well as from animal and ex vivo
models. Not only has the introduction of effective antiretroviral
therapy greatly diminished the morbidity and mortality associated
with HIV disease progression, it has also provided new avenues of
research toward delineating the mechanisms of HIV-induced
pathogenesis. Further advances in therapeutics and in- formative
technologies, combined with a better understanding of the
immunologic and virologic components of HIV disease, hold promise
for new preventative and even curative strategies.
223
+
INTRODUCTION syndrome. Depletion of susceptible CD4 T
In 1983, the isolation of a T lymphotropic cell targets, together with the evolution of an in-
HIV: oid tissue
human retrovirus (1), later
CCR5: C-
immun named human
chemokine
odeficie receptor 5 immunodeficiency
ncy virus (HIV), from a
virus
lymph node (LN) of
LN: an individual with
lymph
node lymphadenopathy
marked the
AIDS:
acquir beginning of
ed almost three
immun decades of intense
e
research into the
deficie
ncy pathogenesis of the
syndro virus that causes
me acquired immune
Antire deficiency syn-

trovira drome (AIDS).
l
Even prior to the
therap
y isolation of HIV,
(ART): other studies
treatm provided the first
ent
glimpses of how
with a
combi HIV induces
nation immune
of dysfunction in-
antiret +
volving CD4 T
roviral
drugs cells (2, 3), as well
from as systemic
differe immune activation
nt and dysregulation,
classes
design as illus- trated by
ed to simultaneous
suppre polyclonal B cell
ss HIV activation and the
replica
tion poor antibody
response to neo-
SIV:
simian and recall antigens
immun (4). Given that HIV
odeficie does not
ncy
productively
virus
replicate in B cells,
GALT:
the last study
gut-
associa (4) also provided the
ted first indications of
lymph the wide array of
224 Moir · Chun ·

deleterio arise during the acute completely effective t smission in LNs, to the
us effects and early phases of HIV-specific immune h the SIV gut-
that HIV infection, as well as over response, leads to e model (7) associated
causes in the course of chronic the establishment of fi described lymphoid
virtually infection; and how a plasma viral set r partially tissue
every antiretroviral therapy point. As discussed in s activated (GALT),
compone (ART) affects disease greater detail below, t CD4
+
T where it
nt of the outcome. both the host
s cells of the induces
host immune system and
t genital massive
immune the nature of the
u mucosa as depletion of
system, HIV rapidly evolving +
d the first memory CD4
predomin TRANSMISSION virus contribute to
i targets of T cells in the
antly this set point.
AND EARLY e productive intestinal
through
INFECTION s viral lamina
the
process of Sexual transmission of Events and t replication propria. As
aberrant HIV following expo- Contributin o less than discussed
immune sure to cell-free or cell- g Factors of one week further below,
activatio associated infectious HIV e after expo- similar cellular
n. This virus in semen or Transmissio x sure depletion
review mucosal surfaces n a (Figure 1); appears to
ad- represents the most m a few days occur in
Because of the
dresses common route of HIV i after this humans (10–
difficulty of
advance transmission globally. n event, lo- 12).
identifying infected
ments in Less frequent routes, e cal The ability
not discussed here, individuals very
our e propagatio of HIV and
include transmission soon after exposure,
understa a n of SIV in related simian
via injection drug use, little is known viruses to
nding of r the less
exposure of blood and regarding the earliest establish
the l abundant
pathogen blood products via events of HIV productive
transmission in the y but more
ic transfusions, and infection is
genital tract or rectal susceptible
mechanis exposure of fetus or dictated by
mucosa. However, e activated the
ms of infant to HIV from an +
infected mother. insight into this v CD4 T availability of
HIV
Following rather inefficient e cells takes +
disease target CD4
transmission, HIV process has been n place. On
by T cells that
disseminates rapidly in gleaned from in vivo t the basis of express the
focusing
on the the absence of models of simian s more chemokine
direct preexisting immune immunodeficiency o recent receptor
and pressures, leading to a virus (SIV) infection f studies of CCR5 (13, 14).
indirect burst of viremia (reviewed in s SIV However, the
effects of manifested in a sub- Reference 5) and e infection in process
virus on stantial proportion of from epidemiological x macaques whereby the
the major patients by an acute u (8, 9), the virus
studies and ex vivo
constitue HIV a virus then penetrates
models that aimed to
nts of the l rapidly mucosal
identify cells and
immune t migrates, barriers to es-
factors affecting the
system; r probably tablish
transmission of HIV
how a via productive
(reviewed in
these n draining infection has
Reference 6). One of been difficult
effects
www.annualreviews.org • Pathogenesis of HIV
to
eval
uat
e in
viv
o,
eve
n in
ani
mal
mo
dels
.
Earl
y
ex
viv
o
mo
dels
bas
ed
on
coc
ultu
res
226 Moir · Chun ·

Infected resting CD4+ T cells Late-responding CTLs
Resting CD4+ T cells

PD-1+CD8+
T cells
Establishment of lymphoid tissue viral reservoirPartial control

HIV
Dissemination of virus
virion Immune activation
DC
Activated CD4+ T cell
Crossing the barrier

Sustained HIV
production
Infected activated CD4+ T cell
DC
InfectedRegulatory
cellT cells
Macrophage
Lamina propriaLymph node
Hours Days Weeks Years
Figure 1
Phases of infection following exposure to human immunodeficiency virus (HIV). Infection begins with transmission across a mucosal
barrier, either by a cell-free virus, infected cell, or virion attached to dendritic cells (DCs) or Langerhans cells (LCs). Early low-
+ +
level propagation probably occurs in partially activated CD4 T cells, followed by massive propagation in activated CD4 T
cells of the gut-associated lymphoid tissue lamina propria. Dissemination of HIV to other secondary lymphoid tissues and
establishment of stable tissue viral reservoirs ensue. Immune response lags behind the burst of viremia and provides only
partial control of viral replication. Adapted from Reference 5. Abbreviations: CTL, cytotoxic T lymphocyte; PD-1, programmed
death 1.
of cells that may be present at the port of Insight into the transmissibility of HIV
entry, including Langerhans cells (LCs) or has also been gained from epidemiologic
other dendritic cells (DCs) or macrophages studies; some estimates of rates of
(Figure 1), demonstrated that productive transmission (19, 20) have been based on
infection occurs following conjugate frequency of coital acts in discordant
+
formation with target CD4 T cells couples, whereas others (6, 21, 22) have
(reviewed in Ref- erence 15). More recently, examined host factors that appear to in-
investigators (16) studied early events of crease or decrease transmission. The
transmission in organ explants where HIV concept that HIV does not transmit easily is
bound to and protected by LCs can cross based on reports that the probability of
the epithelial layers and form complexes transmission ranges from 0.0001 to 0.0040 per
+
with memory CD4 T cells, which then sexual contact (19, 20). Furthermore,
initiate productive viral replication. This circumcision offers a degree of protection
group of investigators as well as others have against HIV infection (21), further
also proposed a concept of virologic suggesting that cells found in foreskin—
synapse, similar to immunologic synapses, including LCs, DCs, macrophages, and
wherein close proximity, additional virus- +
CD4 T cells—may facilitate transmission
attachment molecules such as integrins (17), (6). There are also indications that
and protective transmission is en-
hanced when the mucosal barrier of the genital
endosomal compartments within LCs and tract is perturbed by inflammation or breached LC: Langerhans cell
DCs help HIV establish a productive by the presence of certain genital-ulcerative DC: dendritic cell
infection (18). sexually transmitted diseases (22).
Acute HIV Syndrome and typically peaks at three to four weeks post
Viral Set Point exposure (25, 26), then declines
Approximately two to four weeks following spontaneously for several months before
the transmission of the virus, a majority of reaching a steady state or viral set point
HIV- infected individuals experience an (Figure 2). The level of the viral set point is
acute HIV syndrome (Figure 2), defined as an important determinant of the rate of
flu-like clinical manifestations associated disease progression in HIV-infected
with high plasma viremia and often fever and individuals who are not treated with ART
lymphadenopathy (23). Other reported (27).
symptoms also include myalgias, skin rash, The acute phase of HIV infection is usu-
headache, anorexia, and di- arrhea (23), ally accompanied by a dramatic depletion
although there is a high degree of variability +
of CD4 T cells in the peripheral blood,
in the severity of these clinical symptoms.
which may rebound somewhat after the
During this early phase, HIV often repli-
initial burst of viremia decreases to a set
cates extremely aggressively in the absence
point. This depletion of peripheral-blood

of an immune response, reaching levels of +
plasma viremia as high as 10 million copies CD4 T cells may be associated with the
+ +
per milliliter (24, 25). In the abence of ART, massive depletion of CCR5 memory CD4
plasma viremia T cells in the GALT (Figure 3). In SIV
infection, this depletion is a
Acute phase Early chronic phase

8
10
Acute HIV syndrome
Wide dissemination of virus Seeding of lymphoid tissues
Destruction of gut-associated lymphoid tissue Establishment of HIV reservoirs
107
HIV-specific CD8+ T cells
Plasma viremia (copies of HIV RNA per ml)
Viral
106 escape from CD8+ T cells
105
Virus-specific neutralizing antibody
Viral escape from neutralizing antibody
104
HIV-specific antibody+ (Western blot) HIV-specific antibody+/- (Western blot)

HIV-specific antibody+ (ELISA)
103
HIV p24+ (ELISA)
Viral set point
2
10
Limit of detection
101 HIV RNA+ (PCR)
100
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Days
Figure 2
Kinetics of immunologic and virologic events associated with human immunodeficiency (HIV) infection during acute and early
chronic phases. The schematic represents the sequence of events, including the appearance of viral antigens, HIV-specific
antibodies, and
+
HIV-specific CD8 T cells during the acute and early chronic phases of infection. HIV reservoirs are established during the acute
phase of infection soon after emergence of plasma viremia. Throughout the acute phase of infection, characterized by
massive virus replication and high levels of plasma viremia, an acute HIV syndrome develops in the majority of infected
+
individuals, and the virus rapidly spreads to various lymphoid organs, causing extensive depletion of CD4 T cells. Although
anti-HIV immunity, including
+
virus-specific CD8 T cells and antibodies, develops during the acute phase of infection, escape viral mutants rapidly emerge.
Abbreviations: ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction. Adapted from Reference 36.
Chronic HIV
Massive HIV infection
infection in GALT
High levels of plasma

Primary viremia and wide
infection dissemination of virus to
lymphoid organs
Lymph
node
Establishment of
persistent viral reservoir
Massive and progressive

depletion of
CD4+ T cells
HIV-mediated chronic
Destruction of Accelerated virus immune activation
immune system replication via direct and indirect
and disease mechanisms
progression
Rapid CD4+ T cell

turnover
Figure 3
Key events associated with human immunodeficiency virus (HIV) disease progression. During acute
+
HIV infection, profound depletion of CD4 T cells occurs primarily in the gut-associated lymphoid
tissue (GALT), which is accompanied by high levels of plasma viremia and dissemination of the virus
to other lymphoid organs. During this period, persistent viral reservoirs—such as latently infected,
+
resting CD4 T cells—are established. During the chronic phase of infection, HIV replication also
occurs in all secondary lymphoid tissues, resulting in generalized immune activation, sustained viral
production, increased cell turnover, and ultimately destruction of the host immune system and rapid
disease progression.
consequence of infection and direct killing Studies in SIV and HIV infection have demonstrated that initial
+
associated with the high abundance of depletion of CD4 T cells is less pronounced in peripheral LN
susceptible target cells present in the GALT compared with GALT (11, 28); however, additional studies are
(9), in addition to extensive bystander needed to further delineate the mechanisms of depletion in the
killing by apoptosis (8). The early and high GALT and LNs in humans. The ultimate consequences of mas-
+
level of replication of HIV and SIV in the sive CD4 T cell depletion during the early stages of infection in
GALT is followed by dissemination of the the GALT on HIV disease
virus to peripheral lymphoid tissue,
especially LNs, and the establishment of
persistent lymphoid tissue viral reservoirs
(see the section entitled Establishment and
Maintenance of HIV Reservoirs, below).
progression also remain individuals, acute HIV infection gives rise
somewhat speculative, to persistent viral replication, and in the
given the lack of absence of ART, plasma viremia remains
longitudinal data and detectable throughout the course of disease
compar- ison between (Figure 2). Several recent studies that aimed
slow and rapid to characterize the trans- mitting virus have
progressors. used single-genome ampli- fication and
mathematical modeling to suggest
(a) that a single “founder” virus (or infected
Failure of cell) is transmitted in a majority of
the individuals and
Immune (b) that HIV begins to evolve or diverge
System to from the founder virus only once a cellular
Clear HIV immune response arises several weeks after
In the vast majority of exposure
+
(29–31). A number of studies have peak of the early HIV-specific CD8 T cell
suggested that transmission represents a response and is characterized by mutations in
+
genetic bottle- neck for the virus, in that
Latently infected epitopes recognized by CD8 T cells (30). Similar

+
cells: resting CD4 T
certain traits, especially those of the viral to the phenomenon of escape from neutralizing
cells carrying envelope, appear to be preferentially antibodies, selection of sequential viral variants
unintegrated or selected. Such early viruses tend to be +
with mutations in CD8 T cell epitopes has been
integrated HIV DNA characterized by an increased sensitiv- ity to
described in HIV-infected individuals (31). This
that can give rise to neutralization and a paucity of glycosy-
infectious virus upon
evolution occurs very early in the course of
lation sites in the exposed areas of the HIV infection, before the appearance of neutralizing
cellular stimulation
envelope gp120 (32). Approximately 12 weeks antibodies, and continues throughout the course
after transmission, neutralizing antibodies be- of disease, thus also contributing to viral
gin to arise and evolve (Figure 2); however, persistence. There is
this response appears to be too little, too also recent evidence from animal models that,
late, as well as too narrow, as although the timing of the HIV-specific T cell
neutralization- sensitive virus is quickly response is important, other factors such as the
replaced in succes- sion by neutralization- location and magnitude of the response are also
resistant variants (33, 34). The envelopes of likely to contribute to disease outcome (37).
the escaping populations of HIV tend to be
more highly glycosylated; this finding has led
to the notion of a so-called gly- can shield
that prevents binding of neutralizing
antibodies and promotes viral persistence (33).
Several other mechanisms regarding the
failure of antibodies to neutralize the virus
have been proposed, but they are beyond
the scope of this discussion (see Reference
35 for a review).
There is reasonable evidence, albeit cir-
+
cumstantial, that early HIV-specific CD8
T cell responses contribute to the decline in
HIV plasma viremia during the acute phase
of infection (Figure 2) (see Reference 36
for a review). Rapid evolution of the
initially homogeneous virus begins at the
E CE OF HIV As discussed in the previous section, the
S RESERVOIRS GALT provides HIV with its first abundant
T The rapid establishment and persistence source of targets for intensive replication
A of various HIV reservoirs remain two (Figure 3). The massive depletion of GALT-
+ +
B of the most important impediments to associated CCR5 memory CD4 T cells in
L early HIV infection is often cited as
achieving complete eradication of the
I evidence for high levels of HIV replication;
virus in infected individuals, even in
S however, bystander cytopathic effects also
an era of clinically effective ART.
H contribute to cell death (8), and there is
Nonetheless, strategies to eradicate the +
M evidence that CD4 T cells in the GALT
virus and cure HIV infection in at least
E disappear before peak viremia (39).
some individuals remain a topic of
N Nonethe- less, on the basis of the detection
considerable interest within the HIV
T of virus in tissue sections and single cells
scientific community (38). HIV
reservoirs can be divided into two isolated from biopsied tissue, the GALT
A remains a major early site for active HIV
main categories: (a) lymphoid tissues
N and SIV replication (8, 9, 40). In addition,
that provide HIV with an abundance
D the GALT remains a major reservoir for
of target cells, close con- tacts for
efficient cell-to-cell propagation, and HIV throughout the course of disease, again
M on the basis of virus detection either in
A reduced drug penetration; and (b)
cellular reservoirs that consist mainly tissue sections or in isolated single cells (41,
I + 42). Several of these studies, among others,
N of CD4 T cells that are highly
susceptible to HIV replication when also demonstrate the presence of HIV in
T
activated but can also carry latent GALT after several years of ART (41, 43),
E
virus. suggesting that the GALT is a persistent
N
HIV reservoir. It is unclear what accounts
A
for the persistence of the virus. Long-lived
N
latently infected cells
Lymphoid Tissue Reservoirs
+
and/or CD4 T cells undergoing low levels ART ted in tissue sections
Induce viral replication Stimulate cellular immunityIL-7/IL-15Toxicity
of viral propagation through cell-to-cell and isolated from peripheral
spread could contribute to persistent HIV sensi LNs of clinically
infection in the GALT (see the section - tive asymptomatic HIV-
+ assay infected individuals (44,
entitled Persis- tent CD4 T Cell Reservoirs, Suppress virus Increase CD4+ T cells
s for 45). These studies
below). The latter scenario is feasible, CD8 CD4
meas revealed HIV in close
given the abundance of activated and
+ uring proximity to the follicular
proliferating CD4 T cells in the GALT even Fusion/entry inhibitors HIV dendritic cell (FDC)
after several years of ART (41, 42). In HIV- plas network, which was later
infected individuals, the level of HIV Integrase inhibitors ma shown to har- bor
+
proviral DNA in tissue-derived CD4 T cells vire infectious virus (46). Such
has been directly correlated to the level of ReverseCD4 mia, FDC reservoirs are
+ transcriptase
activation on GALT-derived CD8 T cells, inhibitors large established early in HIV-
an indication that the level of immune Protease inhibitors amo infected individuals and
activation plays a role in the persistence of unts show resistance to the
HIV in the GALT (43). of effects of ART (47, 48).
The GALT is not the only lymphoid virus However, the level of
tissue to serve as a site for active HIV and can persistence of HIV in
Side effects
SIV replication (Figure 3). As described be
Drug-resistant virus IRIS
peripheral LNs following
several years ago before the era of effective Incomplete immunologic detec
restoration several years
of effective ART remains
to be determined.
CD4
HDACi
Purge latent virus SAHA
IL-7
Cell death
Inhibition Benefit Risk
+
Persistent CD4 T Cell Reservoirs Figure 4
In 1995, with the availability of protease in- Therapeutic strategies in human immunodeficiency virus (HIV) infection.
hibitors as a third class of ART (Figure 4), Risks (red boxes) and benefits ( green boxes) associated with antiretroviral and
immune-modulating therapies in HIV-infected individuals are shown.
two important studies on viral dynamics Risks uncertain at present
Abbreviations: HDACi, histone deacetylase inhibitor; IL, interleukin;
demonstrated that potent ART could IRIS, immune reconstitution inflammatory syndrome; SAHA,
suppress plasma viremia to below the limits suberoylanilide hydroxamic acid.
of detection within a few weeks of initiation
of therapy (49, 50). These studies also
demonstrated the existence of a biphasic first evidence of HIV latency at the cellular
+
decay in plasma viremia, beginning with a level was described in resting CD4 T cells
rapid decay that reduced the majority of of infected individuals (Figure 5) (51). This
replicating virus in short-lived cells and study was followed a few years later by a
followed by a second, slower phase of de- detailed analysis of the frequency of
cay thought to involve a minor population infectious virus in such latently infected cells
of longer-lived infected cells. That same in lymphoid tissues (154). The latter study
year, the estimated the pool of latently
HIV
infection
Unintegrated HIV DNA
Resting CD4+ T cell
HIV Activation
virion
Integration of HIV DNA
Cell death
Productively infected CD4+ T cell
Lymph nodeGALT
Latently infected
CD4+ T cell
Figure 5
+
Establishment and maintenance of the resting CD4 T cell reservoir in human immunodeficiency
+
virus (HIV)-infected individuals. HIV infects resting CD4 T cells and completes reverse
transcription. In the absence of cellular activation and prior to the integration of a provirus into the
+
nuclear DNA of the cell, infected resting CD4 T cells “cure” themselves of virus as a result of the
short half-life of the HIV preintegration complex. Following activation of the infected cells, the vast
majority of these cells die from HIV-induced cytopathic effects and the host immune response.
However, a very small fraction of productively infected cells revert to a resting memory state. In the
+
presence of effective antiretroviral therapy, these latently infected, resting CD4 T cells can persist for
prolonged periods of time in infected individuals. Some of these cells reactivate in lymphoid tissues and
may further contribute to the persistence of viral reservoirs in infected individuals by cell-to-cell spread
of virus, even in the absence of detectable viremia. Abbreviation: GALT, gut-associated lymphoid
tissue.
+
infected CD4 T cells carrying infectious for a minimum of 12 months
virus to be small: fewer than 10 million cells and up to three years
in the body. However, three subsequent interrupted their therapy
studies (52– and experienced rapid viral
54) demonstrated that this latent HIV rebound (56). In
reservoir was resistant to the ART regimens
that were employed at that time, which cast
doubt on the implication that HIV could be
eradicated after two to three years of
effective ART (55). These studies did,
however, indicate that its estimate was based
on the two aforementioned slopes of decay
and did not take stable reservoirs into ac-
count (55). The importance of stable
reservoirs and other mechanisms of
persistence was further demonstrated when
HIV-infected individuals whose plasma
viremia had been fully suppressed by ART
the majority of individuals studied, HIV plasma viremia In addition to the persistence of HIV in
returned to detectable levels within two weeks of the the latent viral reservoir, there is also
interruption of their drug regimen. Although there is no evidence for low levels of ongoing viral
consensus in the field on the precise half-life of latently replication in HIV-infected individuals
+ whose viremia was otherwise well
infected, resting CD4 T cells, a number of studies have pro-
jected that it will take 7 to more than 60 years to eliminate suppressed by ART (57, 59, 60). One source
HIV in this viral reservoir (57, 58), which has led to the of viral replication was identified
+
prediction that eradication based on these numbers and in the activated CD4 T cells of HIV-infected
current treatment strategies may not be feasible (38).
individuals whose plasma viremia had been either purging the latent reservoir or References 38 and
suppressed below the limits of detection preventing its establishment (38, 64). For 64). Furthermore,
for up to nine years; this finding suggests example, if intensification of ART with a given the early
that virologic cross talk occurs between new class of drugs can further reduce establishment of the
+ the residual pool of infectious virus, it latently
activated and resting CD4 T cells in the infected,
absence of detectable viremia (61). The would indicate that low levels of +
resting CD4 T cell
trigger of such events could be the ongoing viral replication in the absence
reservoir (65),
of detectable viremia contribute to viral
occasional activation of the immune system adding a drug that
persistence (64). In addition, several strate-
by (a) random triggering events and blocks cellular

gies have been proposed for purging activation, such as cy-
(b) specific events such as secondary infections
HIV from latently infected reservoirs closporin A, to ART
or vaccination; the latter induces HIV
replication (62). Continual replenishment (Figure 4). Such ap- proaches include the may reduce the
+ use of inhibitors of histone deacetylases, a initial burst of
of CD4 T cell viral reservoirs could also be group of chromatin-remodeling enzymes viremia in activated
associated that restrict HIV expression in latently +
with trafficking of cells between the CD4 T cells and
infected cells, to decrease the latent viral
peripheral blood and tissues, such as the thereby limit the
reservoir through purging (reviewed in
GALT, where (as described in the previous establishment of a
section) there are an abundance of activated latent viral reservoir
+ (66).
CD4 T cells and a persistent HIV reservoir
(Figure 5). In addition to occasionally
+
activated CD4 T cells contributing to the IMMUNE
low level of persistence of virus, the latent DYSFUNCT
+
CD4 T cell viral reservoir may be ION
expanded by homeostatic proliferation of CAUSED
+
these latently infected cells in CD4 T cell BY HIV
lymphopenic HIV-aviremic individuals INFECTIO
(63). The findings of this latest study also N
suggest that in healthier HIV-aviremic The previous
individuals, the size of the HIV reservoir is sections described
+
increased by subsets of CD4 T cells that are how HIV rapidly
expanded during the immune establishes a
reconstituting effects of ART. persistent infection
There is increasing belief, although amid that is accompanied
some controversy, that new insight into by high levels of viral
residual viral replication and long-lived replication in
persistent reservoirs will come from new lymphoid tissues,
therapeutic strategies, including new classes
together with massive
of antiretroviral drugs and drugs aimed at
depletion of
+
memory CD4 T cells in the GALT. By infected individuals, with an emphasis on
targeting a major constituent of the immune individuals whose plasma viremia is not
+
system, HIV destroys and dysregulates CD4 T controlled by ART.
Increased cell
cells. However, HIV also induces immuno- turnover: an in vivo
+
logic dysfunction of CD8 T cells, B cells, process whereby cells
Lymphoid Tissue Dysfunction
natural killer (NK) cells, and nonlymphoid cells respond to activating
+
through mechanisms that include increased Massive CD4 T cell depletion in the GALT stimuli by undergoing
occurs soon after transmission of HIV in hu- increased proliferation
cell turnover, activation, differentiation, and and cell death
homeostatic responses. Together, these vari- mans and pathogenic SIV in the nonhuman
ous factors lead to qualitative changes within primate model by cytopathic effects that
each immune cell population that ultimately probably include both direct and indirect
affect overall immunologic competence. As in mechanisms (8–12). In nonpathogenic
the previous section, immune dysfunction and natural SIV infections, similar levels of
+
dysregulation are considered in terms of both CD4 T cell depletion occur early after
the major lymphoid organs and the cellular infection but are followed by a period of
compartments that are affected in HIV- recovery that is not observed in HIV and
pathogenic SIV infections
(reviewed in Reference 67). It is unclear

+
why recovery of CD4 T cells in the GALT Stimulation
occurs in nonpathogenic natural SIV but of innate and adaptive immune cells
not in HIV and pathogenic SIV infections,
although differences in levels of chronic im-
mune activation may be an important Release of proinflammatory cytokines, increased cell turnover,
determinant of pathogenicity (see the
section entitled Role of Immune Activation
in the Pathogene- sis of HIV, below).
Although it is also unclear whether early Chronic immune activation
+
depletion of CD4 T cells in the GALT of Enhan
HIV-infected individuals leads to ir- ced
HIV
reversible damage to the immune system, sim- replica
+ tion
ilar levels of early CD4 T cell depletion in and
destru
ction
HIV infection of
immu
ne
syste
m
Figure 6
Factors associated with human immunodeficiency virus
(HIV)-induced immune activation. During the
establishment of persistent HIV viremia, cells from both
the innate and adaptive arms of the immune system
become activated by factors such as viral proteins,
HIV replication Microbial translocation microbial products translocated from the gut-associated
and viral proteins in GALT lymphoid tissue (GALT), and host responses. Activated
Host immune responses cells produce a swarm of proinflammatory cytokines,
to HIV infection such as tumor necrosis factor α, interferon-α, and
interleukin-1 and -6, which in turn cause chronic immune
activation. In addition, ongoing HIV replication and
host immune responses to infection contribute to
immune activation. These events promote enhanced
levels of HIV replication and ultimately lead to the exhaustion and
nonpathogenic and pathogenic SIV
destruction of immune system.
infections suggest that these events may not
necessarily predict disease outcome (68).
Early reports on GALT depletion and
gastrointestinal damage in HIV and SIV
infection were based largely on histological
findings at necropsy (reviewed in Reference
69), with little emphasis on the functional
consequences of these alterations. More
recently, loss of mucosal integrity in HIV and
SIV infection has been reported to be
associated with translocation of microbial
products (70) from the intestinal mucosa
into the circulation, thus contributing to
HIV-induced systemic immune activation
and dysregulation, as discussed below
(Figure 6). Gene-expression profiles of
GALT-derived cells from HIV-infected indi-
viduals are also consistent with a disruption
of the mucosal epithelial barrier and of the
metabolic and digestive functions (71). Specific
losses in mucosal immune function have
also been associated with (a) the preferential
+
depletion of IL-17-secreting (Th17) CD4 T
cells, which are a subset of T helper cells
that are involved in mucosal host defense
against extracellular bacteria, and (b) the
consequent
inability to control systemic dissemination
of Salmonella in pathogenic SIV infection
(72). Preferential depletion of Th17 cells in
the GALT has also been reported in HIV-
infected individuals (73), although the
functional implications remain unknown.
As first described over 25 years ago (re-
viewed in Reference 74), HIV infection has
a profoundly deleterious effect on
peripheral lymphoid tissues, causing
extensive follicular and germinal-center
hyperplasia during the clinically early
stages of infection and invo- lution during
the advanced stage of disease (Figure 3).
These alterations begin to occur soon after
initial infection (47, 48) and are associated
with ongoing viral replication in the
untreated patient. However, both direct and
indirect effects of the virus are probably
responsible for the changes described
above, especially given that germinal-center
B cells, which are not targets for productive HIV replication, are largely responsible for
the hyperplasia observed in these lymphoid + +
question why CD8 T cell numbers increase, whereas CD4 T cell
tissues (75). As with the GALT, it remains numbers decrease in HIV-viremic individuals, leading to only
difficult to establish the precise partial normalization of their ratios in ART-treated individuals
immunologic consequences of HIV-induced (83). Explanations
alterations in peripheral lymphoid tissues.
However, given the critical role of these
tissues in mounting effective cellular and
humoral immune responses, any disruption
probably has deleterious consequences. In
this regard, recent studies suggested that
collagen deposition in T cell zones of LNs of
HIV-infected individuals (76), possibly
resulting from HIV-induced immune
activation and inflammation, may disrupt
normal lymphocyte trafficking and contribute
to decreased immunologic function (77).
HIV-Induced Immune Dysfunction

at the Cellular Level
+
The massive depletion of CD4 T cells that
occurs early after HIV infection in the
GALT, and to a lesser extent in the
peripheral blood and LNs, is offset by
+
increased CD4 T cell turnover (Figure 3)
(78). Given that other cell populations,
+
including CD8 T cells, B cells, and NK
cells, also exhibit increased turnover during
HIV viremia (79), immune activation (see
the section entitled Role of Immune
Activation in the Pathogenesis of HIV)
+
rather than homeostatic responses to CD4
T cell depletion may explain increased
lymphocyte turnover (Figure 3) (77).
Regardless of the mechanism, increased cell
turnover is induced soon after HIV and
pathogenic SIV infection and, in the absence
of control of virus replication, persists
throughout the chronic phase of infection
(31, 80). The initiation of ART leads to a
significant decrease in the rate of turnover
+ +
in CD4 and CD8 T cells (81), and similar
changes are thought to occur for B cells and
NK cells on the basis of cross-sectional
studies in SIV infection (82). The similarly
+
high turnover rates for both CD4 and
+
CD8 T cells have led investigators to
of these observations The consequences of ongoing HIV repli-
include the suggestion cation on lymphocyte dynamics include
that there is an qualitative alterations within each
increased relative population that probably contribute to the
proportion of activated
progressive loss of cellular and humoral
+ +
CD8 to CD4 T cells responses. Lymphocytes of the B cell and T
due to a higher death cell lineage can be divided into two main
rate in the latter categories: na¨ıve (antigen-na¨ıve) and memory
population (77, 84). (antigen-experienced) cells. Both memory
There is also evidence + +
CD4 cells and memory CD8 T cells can be
that residual ongoing
divided further into central memory and
viral replication in
infected individuals effector memory cells, in addition to several
receiving ART is additional subpopulations on the basis of
associated with an the expression of various phenotypic markers
+ (reviewed in Reference 86). Whereas acute
inverted ratio of CD4
+
HIV infection is associated with preferential
to CD8 T cells (83). infection and depletion of effector memory
Interestingly, B cells, +
CD4 T cells at mucosal sites (12), the

which are not targets
chronic phase of HIV infection in untreated
for HIV replication,
individuals is associated with a relative
behave more similarly
+ + expansion of short-lived effector memory
to CD4 than to CD8 + +
CD4 and CD8 T cells (87). Possible
T cells before and after
reasons for such skewing of T cell sub-
initiation of ART in
populations include loss of regenerative
terms of cellular
potential resulting from reduced thymic
dynamics (85). These
observations further function, excessive differentiation, and
support the concept progressive destruction of LN architecture
that HIV- induced (see Reference 77 for a review). Similar
+ skewing of NK cell and B cell subpopulations
changes in CD4 T cell
has also been reported and probably
dynamics are more
likely to be driven by contributes to dysfunction in both the innate
indirect rather than (reviewed in Reference 88), and adaptive
direct effects of (humoral) arms (reviewed in Reference 89),
ongoing viral respectively, of the immune system in HIV-
replication (77). infected individuals. Overall, the alterations in
various lymphocyte populations observed sponse against HIV itself. Although several
in persistent viral infections such as HIV are earlier studies suggested that there is no differ-
most likely associated with chronic antigenic ence in the frequency of HIV-specific T cells
IFN: interferon across various groups of HIV-infected individuals
stimulation that induces increased
Exhaustion: elusive (91, 92), recent findings suggest that certain
turnover and differentiation, ultimately
consequence of functional capabilities of responding cells
immune activation
culminating in progressive loss of the
are more important than the number of cells that
whereby effector potential to regenerate, which is key to
are available. In untreated patients, the HIV-
immune cells lose maintaining a competent immune system (90). + +
their proliferative and In addition to contributing to overall im- specific CD4 and CD8 T cells of infected
functional capacities + individuals who control HIV replication and
mune competence, the quality of CD4 and
disease progression tend to proliferate bet-
+
CD8 T cells also appears to be important ter ex vivo than do those of infected individuals
for mounting and sustaining an effective re- who experience disease progression (93, 94).
Furthermore, IN THE PATHOGENESIS OF HIV described for B cells well over 25 years ago
defective HIV- (4). Although the underlying causes of HIV-
+
One of the most widely recognized
specific CD8 T cell hallmarks of the chronic phase of HIV induced cellular hyperactivity remain some-
responses against infection is generalized immune activation, what obscure and a source of intense
HIV have been which was first debate, the pathogenic consequences of
associated with such activity are fairly well understood.
decreased function, These consequences include increased cell
including cytolytic turnover; the skewing of lymphocytes
capacity (95) and toward more activated and dif- ferentiated
the capacity to subpopulations; and the induction of cellular
secrete multiple exhaustion, senescence, and low re- newal
cytokines (96). The potential. In addition, several recent avenues
paucity of
of research on the GALT and animal models
multifunctional
+
have provided important insight into the
CD4 T cells also pathogenesis of chronic HIV infection.
appears to
correlate with
HIV disease Role of Soluble Factors in
progression; HIV- HIV-Induced Immune Activation
infected indi- Modulators of the immune system that
viduals with are thought to play a significant role in HIV-
advancing disease
induced immune activation include
have an increasing
proinflammatory cytokines (e.g., TNF-α,
proportion of HIV-
+
IL-1, IL-12, IL-6) and chemokines (e.g.,
specific CD4 T CXCL10), lipopolysaccharide (LPS), and
cells that secrete type I IFN (IFN-α). Many of these factors
only interferon arise during acute infection, and several are
(IFN)-γ, whereas maintained during the chronic phase of
those of infection (Figure 6) (see Reference 36 for a
individuals who review). Increased levels of LPS, a
control HIV particularly potent activator of the immune
disease with or system because of its ability to bind to and
without ART trigger the release of proinflammatory
secrete IL-2 along factors from macrophages and DCs, have
with IFN-γ (97, been associated with certain changes that
98). Thus, occur during acute HIV infection. These
polyfunctionality changes include disruption of the intestinal
and proliferative mucosal barrier, which causes microbial
capacity of T cells translocation in the form of LPS into
are probably two
circulation (70), and periods of intense
important
secretion of cytokines and chemokines (36).
correlates of the
Levels of LPS in the plasma are maintained
control of HIV
at increased levels throughout the chronic
disease
phases of both HIV and pathogenic SIV
progression.
infection (70), leading to the speculation that
virus-induced destruction of the GALT and
ROLE OF the associated leaking of microbial products
IMMUNE are central to the induction and
ACTIVATION maintenance of the immune activation
observed throughout the course of disease
(99). However, several other potential
(and probably multifactorial and intercon- prominent role for pDCs and IFN-α recent indications
nected) mechanisms of HIV-induced responses in determining outcome during that TLR triggering
immune activation have been proposed (36, the chronic phase of SIV and, by of pDCs modulates
67). extension, HIV infection. There are also levels of cellular
A role for IFN-α in the pathogenesis activation (see the
of HIV infection was first suggested over section entitled
20 years ago on the basis of ultrastructural Consequences of HIV-
analyses of lymphoid tissue sections (100). Induced Immune
More recently, DNA microarray analyses have
Activation at the
demonstrated that induction of a wide
Cellular Level, be-
array of IFN-α-stimulated genes (ISGs) low) in HIV-infected
occurs in all major lymphocyte populations individuals (105).
isolated from chronically viremic
individuals (reviewed in Reference 101).
Although a direct association between ISGs Consequence
and HIV-induced immune activation has s of HIV-
been difficult to establish in humans, recent Induced
data from animal models have provided a Immune

possible link. The absence of immune acti- Activation at
vation in the setting of natural the Cellular
nonpathogenic SIV infection in sooty Level
mangabeys despite chronic high levels of
plasma viremia provided one of the earliest One of the most
concrete indications of a role for immune widely reported
activation in pathogenic HIV and SIV correlates of HIV
infections (102). More recent studies have disease progression
pursued this line of investigation by is the increased fre-
focusing on the differences between quency of activated
pathogenic and nonpathogenic SIV lymphocytes, which is
infections. One such difference is in the manifested
triggering of two Toll-like receptors (TLRs), especially by
TLR7 and TLR9, and the induction of upregulation of the
downstream adaptor molecules and ISGs. activation marker
IFN-α is secreted in copious amounts by CD38 on CD8 T
+
plasmacytoid dendritic cells (pDCs), which cells (106). Increased

express TLR7 and TLR9 and appear to be
expression of
differentially regulated in pathogenic versus
activation markers has
nonpathogenic SIV infections (103). When
also been described
the two types of infections were compared,
for all major
pDC activation was muted in the acute
phase of nonpathogenic but not pathogenic lymphocyte
SIV infection, and the latter setting led to populations and is
strong induction of IFN-α via TLR7- and largely associated
TLR9-mediated signaling in pDCs. Although with ongoing HIV
these findings have raised questions about replication (77, 88,
the role of TLR signaling and whether acute 89). Further- more,
events are important in determining dis- HIV-induced immune
ease outcome in SIV infection (67, 104), activation that oc-
there remains a strong consensus for a curs during ongoing
viral replication has been associated with other apoptosis-inducing ligand and its receptor, as
manifestations, including increased turnover well as Fas (reviewed in References 107 and
of lymphocytes, as described in the previous 109).
One of the numerous oddities associated ISG: IFN-α-
section (Figure 6); hypergammaglobulinemia,
stimulated gene
which probably results from increased terminal with HIV infection and chronic immune ac-
tivation is the appearance of HIV-specific T Toll-like receptors
differentiation of B cells (89); increased activation- (TLRs): a family of
+ + cells and B cells that show signs of exhaustion
induced apoptosis of CD4 and CD8 T cells receptors that
as well as B cells (107); and increased or senescence (Figure 6) (see References 89 recognize conserved
susceptibility to the development of HIV-related and 110 for reviews). These cells arise from molecular patterns
the induction of inhibitory pathways, expressed by
malignancies, especially of the B cell type pathogens and play an
which would be expected to attenuate the
(108). Notably, the increased susceptibility to important role in
state of systemic hyperactivation, as has
apoptosis is probably induced by several innate immunity
been proposed (68) as a potential
factors, including the induction of ISGs involved pDC: plasmacytoid
mechanism for the lack of pathogenesis in
in cellular death pathways, namely TNF-related dendritic cell
natural SIV infections. However,
functional immune cell exhaustion is a phe- be more important than that
nomenon that has been observed in the set- of any one receptor (117).
ting of numerous persistent viral infections In addition, although the
(90), including HIV infection. Furthermore, effects of blocking PD-1

several animal studies have demonstrated have been proposed to
that blocking the interaction between relieve its inhibitory effects
programmed death 1 (PD-1), one of the (114, 115), there is also ev-
major inhibitory receptors associated with idence that the triggering of
+ +
virus-specific exhausted T cells, and its ligand PD-1 CD8 T
(PDL-1) reverses the exhaustion and cells induces apoptosis of
improves cellular and humoral responses cells expressing high levels of
against the persisting virus (111, 112). PD-1 (118). Thus, blocking
Although it may appear difficult to reconcile the triggering of PD-1 on
the nega- tive effects of PD-1 in HIV and these cells leads to enhanced
pathogenic SIV infections with its proposed survival and effector
positive effects in nonpathogenic SIV responses against HIV.
infection, early induction of PD-1 in the In addition to the
latter setting may contribute to the increased expression of in-
favorable outcome (113). hibitory receptors,
Much emphasis has been placed on the + +
exhausted CD4 and CD8
+
role of PD-1 in virus-specific CD8 , and to a T cells, as well as B cells that
+ arise during chronic immune
lesser extent, CD4 T cell exhaustion in HIV
activation in the setting of
and SIV infections. However, there are
per-
indications that other inhibitory receptors
sistent viral infections, are
may be involved in virus-induced immune
cell exhaustion. This hypothesis is based on characterized by loss of
(a) the relatively mod- est effects of blocking proliferative capacity and
PD-1 ex vivo (114, 115), effector functions (reviewed
(b) the involvement of the inhibitory in References 89 and 110).
receptor CTLA-4 (cytotoxic T lymphocyte– These cells also tend to
+ express distinct receptor
associated antigen 4) in HIV-specific CD4
profiles (119, 120), including
T cell exhaustion (116), and (c) evidence
decreased expression
that the combined
effect of multiple inhibitory receptors may
of receptors associated with homing to and within LNs individuals experience progressive loss of
+
(e.g., CD62L, CCR7, CXCR4, CD4 T cells and increased
CXCR5) and increased expression of receptors associated immunodeficiency that ultimately lead to
with homing to inflammatory extralymphoid tissues (e.g., the opportunistic diseases characteristic of
CXCR3, CCR6, CD11c). Given the importance of the LN en- AIDS (reviewed in Reference 121). With
vironment for generating optimal cellular and humoral the increasing availability of ART, there has
immune responses (Figure 3), these findings suggest that been a dramatic reduction in the number of
the dysregulated homing to extralymphoid tissues may
people who progress to AIDS and
contribute to the ineffective immune responses against HIV
subsequently die from AIDS-defining
observed in chronically viremic individuals. Finally, recent
illnesses. However, long-term pathogenic
gene-expression analyses suggest that inflammatory markers
consequences of living with HIV persist in
contribute to the hyperactivation profile associated with
most infected individuals who receive ART,
pathogenic but not nonpathogenic outcomes of SIV infection
(104). These findings further suggest that the inflamed- although the effects are, for the most part,
tissue homing receptor profiles observed on exhausted far less severe than those arising in
lymphocytes in chronic HIV–infected individuals represent a untreated individuals. Some of these effects
consequence of HIV-induced immune activation and that may arise from incomplete immunologic
these dysregulated cells contribute to HIV pathogenesis. recovery that is manifested by persistently low
+
CD4 T cell counts and that may be

associated with incomplete suppression by
LONG-TERM CONSEQUENCES OF HIV ART of low levels of cell-to-cell spread of
INFECTION virus, even in the absence of detectable
In the absence of ART, the vast majority of HIV-infected viremia.
+ response to HIV as measured by suppression of plasma viremia
Consequences of Low CD4
(125). As discussed above, other potential reasons for incomplete
T Cell Counts +
+
restoration of CD4 T cells may include loss of regenerative
A progressive depletion of CD4 T cells oc- potential, senescence, exhaustion, and destruction of lymphoid
curs in the majority of HIV-infected tissue architecture and mucosal integrity of the GALT. In addi-
individuals who remain untreated and can tion, thymic dysfunction may also contribute to incomplete
also occur in individuals receiving ART. +
restoration of CD4 T cells in HIV-infected individuals (77, 84).
Although the initiation of effective ART
+
typically leads to a dramatic increase in During the early stages of HIV infection, CD4 T cell
+ depletion is balanced by increased immune activation, whereas
CD4 T cell counts, there are individuals
+
during the advanced stages of infection, the immune system
whose CD4 T cell counts remain low gradually loses the ability to replenish itself. During the latter
despite long-term and virologically +
phase of progressive CD4 T cell lymphopenia, homeostatic
suppressive ART (Figure 4). A very low
+
pressures rise, as evidenced by increased serum levels of the T
CD4 T cell count at initiation of ART is one cell homeostatic cytokine IL-7. Several studies have demonstrated
of the most important predictors of +
+
a strong inverse correlation between CD4 T cell counts and serum
incomplete CD4 T cell restoration following +
levels of IL-7 in HIV infection and other settings in CD4 T cell
ART (122). This observation, among others,
lymphopenia (126, 127). These observations were initially
has led to a reassess- ment of
interpreted as resulting from an increased homeostatic produc-
recommendations on when to initiate ART
tion of IL-7 in response to the lymphopenia.
(123, 124). The incomplete restoration of
+
CD4 T cell counts in individuals who delay
therapy may result from incomplete
virologic suppression, as evidenced by
ongoing immune activation, even in
individuals with a sustained virologic
However, more recent another cytokine with important T cell
findings (128) suggest immunomodulating features (Figure 4) (see
that levels of IL-7 Reference 129 for a review).
increase in
lymphopenic in- Consequences of Initiating Therapy in
dividuals as a result of the Setting of Advanced HIV Disease
reduced utilization of Individuals who initiate ART when their
the cytokine stemming +
CD4 T cells counts are low and/or who
from the loss of cells have an underlying opportunistic infection
expressing the IL-7 are at increased risk of developing a
receptor CD127, which potentially dev- astating complication
serves as regulator of referred to as immune reconstitution
IL-7 production under inflammatory syndrome (IRIS) (reviewed in
normal physiologic References 132 and 133). This syndrome has
conditions. Given the been particularly prevalent in resource-poor
importance of IL-7 in countries, where ART is generally started
the expansion and late in the course of HIV disease in
maintenance of T patients who usually present with one or

cells (reviewed in more opportunistic infections. The clinical
Reference 129), as well manifestations of IRIS are diverse, and the
as evidence of underlying causes are not completely
incomplete restoration understood; however, the phenomenon
+ involves a strong inflammatory response after
of CD4 T cells and
immune competence initiation of ART. IRIS typically reflects a
of both CD4
+
and dysregulated response to a pathogen that
+
CD8 T cells in HIV- was present prior to ART, such as
tuberculosis, herpes zoster, cryp- tococcus,
infected individuals,
toxoplasmosis, or bacterial pneumonia (132,
several studies have
133). Initiation of ART in severely im-
explored the
munosuppressed individuals may cause a
therapeutic potential
rapid activation of the immune response
of IL-7 in HIV
against the secondary pathogen as the
infection (130, 131). immune system is partially reconstituted,
Similar attention is leading to an inflammatory response that is
being paid to IL-15, specific to the pathogen but
that can cause substantial tissue damage risk of cardiovascular manifestations. There
+ is evidence for a role of HIV-induced IFN-α
(134). In addition to low CD4 T cell counts,
conditions that favor IRIS include a rapid on one of the main risk factors for cardio-
NADM: non-AIDS-
defining malignancy decrease in HIV plasma viremia upon vascular disease, namely increased
initiation of ART and triglycerides
a high antigenic burden of secondary initiate therapy against the
pathogen, opportunistic infection(s) is
which serves as trigger of the dysregulated almost always more life-
immune response (134). Treatment options threatening than the clinical
for cases of IRIS are complicated and manifestations of IRIS (132–
controversial, although most experts agree 134).
that deferring the initiation of ART for more
than the short inter- val that is required to
Consequences of Long-
Term Antiretroviral Therapy and (135). In addition, a landmark study
Living Longer with HIV compar- ing the effects of continuous and
intermittent ART on HIV disease outcome
The increasing availability and use of ART
(138) identified cardiovascular disease as
have greatly reduced the incidence of
one of the significant events associated with
opportunistic infections and AIDS-related
individuals who interrupted ART
malignancies. The increasing availability of
intermittently, which led to increased
different classes of antiretroviral drugs to
exposure to replicating virus. Fur- ther
treat HIV-infected individuals has also
analyses from this study found an asso-
reduced concerns regarding the emergence
ciation between cardiovascular events in the
of viral resistance and has provided
ART interruption arm and inflammatory
physicians with more options to min- imize
markers (139), which have been proposed
drug-related toxicities and complications
as important factors in HIV-induced
(Figure 4). Nonetheless, several areas of
immune activation (see previous section).
con- cern remain; some are associated with
One area that has received considerable
the ART regimens themselves, and others are
attention and controversy is the incidence
associated with the fact that people are living
of malignancies in the era of ART.
longer with HIV. Within the latter category,
Although ART has dramatically reduced
there are conditions that suggest
the incidence of AIDS- defining malignancies
premature aging and conditions that are
such as Kaposi’s sarcoma and non-Hodgkin
exacerbated by the fact that most HIV-
lymphoma, the effect of ART on the incidence
infected individuals never achieve complete
of non-AIDS-defining malignancies
immunologic reconstitution; in addition,
(NADMs) has been more difficult to
there are conditions that combine elements
evaluate. Confounding factors in assessing
of both aging and HIV infection. Cardio-
changes in NADMs in the era of ART
vascular disease represents one such
include longer survival time, age and other
condition; it also involves risks associated
risk factors, and variables associated with
with prolonged use of ART itself (reviewed
HIV status (108, 140, 141). There has been
in Reference 135). Both nonnucleoside
little agreement on whether HIV-infected
reverse transcriptase inhibitors and
individuals continue to experience diminished
protease inhibitors have been associated with
immune surveillance that would affect the
increased risk of cardiovascular disease (136,
incidence of NADMs, despite effective
137), part of which can be explained by
immunologic and virologic responses to
effects of the drugs on lipid metabolism.
ART. However, HIV-infected individuals
However, HIV infection itself increases the
may be more likely than HIV- uninfected
individuals to develop NADMs that are
caused by infectious agents, including hu-
man papillomavirus and hepatitis B and C
viruses (142). It remains unclear whether an
impaired ability to suppress coinfecting
onco- genic viruses explains the increased
incidence of corresponding cancers,
although coinfections themselves continue
to be highly prevalent in HIV-infected
individuals in the era of ART (143). These
observations underscore the need to find
better therapeutic strategies for treating
coinfections such as hepatitis B and C (144),
as
well as to develop vaccines against these control HIV infection through innate,
viruses. These are important considerations, cellular, and humoral immunity.
given that both age and HIV infection (with
or without ART) are associated with reduced LTNP: long-term
nonprogressor
responsive- ness to immunization (145).
Insight from Long-Term
Nonprogressors and Elite Controllers
EFFECTS OF HOST AND VIRAL
FACTORS IN HIV INFECTION LTNPs were first described in the 1990s,
when sensitive testing for HIV plasma
Both host and viral factors are thought to in- viremia made it possible to begin to identify
fluence the natural course of HIV infection the approximately 5–15% of HIV-infected
and disease progression. Considerable individuals who fall into the broader
insight has been gained over the past 25 years nonprogressor category (146). The subgroup
from studies of HIV-infected individuals who of elite controllers com- prises less than 1% of
maintain low to undetectable HIV plasma HIV-infected individuals (146). In this group,
+
viremia and stable CD4 T cell counts in the certain human leukocyte antigen (HLA)
absence of ART. As a group, these class I haplotypes, particularly HLA-B57–01,
individuals are referred to as long- term are overrepresented (Table 1). Although
nonprogressors (LTNPs), and within this there has been much debate and some
group, patients who maintain a viral burden evidence that low viral fitness may contribute
below the limits of detection are referred to to the suppression of HIV replication in a
as elite controllers. Studies on the natural certain percentage of LTNPs (147), there are
control of HIV disease progression in strong indications that host factors also play
LTNPs and other HIV-infected individuals an important role in restricting HIV
have focused on cellular restriction factors replication and disease progression (Tables
1 and 2). Among the host genetic factors
and viral fitness, as well as host genetics and
most consistently
its impact on the ability to
Table 1 Characteristics of long-term nonprogressors (LTNPs)a

Key characteristics
Infected >10 years
Maintain low (LTNP) to undetectable plasma viremia (elite LTNP, <50 copies per
+
milliliter) Maintain normal and stable CD4 T cell counts
+
Maintain high levels of human immunodeficiency (HIV)-specific and functional CD4 T
cells Maintain strong innate immunity against HIV
+
Maintain strong anti-HIV immunity, particularly CD8 CTLs
Carry certain genetic traits
Genetic features
∗
HLA B 5701
∗
HLA B 5703
∗
HLA B 2705
Heterozygosity for CCR5O32
Antiviral CD8+ T cell immunity
+
High frequency of polyfunctional HIV-specific CD8 T cells
High capacity to produce perforin upon exposure to HIV
antigens High capacity to proliferate upon exposure to HIV
antigens Secretion of antiviral factors (C-chemokines)
a
Abbreviations: CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen.
Table 2 Host restriction factors of human immunodeftciency virus a

Replication of HIV and
other retroviruses may be
Host restriction factors restricted at the
CCR5O32 intracellular level by intrin-
CCL3L1-CCR5 genotypes sic host factors that
APOBEC3G function in a virus-specific
Trim-5α and, in many cases,
Tetherin species-specific manner
MicroRNA
Coexpression of KIR3DS1 (on natural killer cells) and HLA Bw4–08I
Coexpression of KIR3DL1 (on natural killer cells) and HLA Bw4
a
Abbreviations: APOBEC3G, apolipoprotein B editing complex
3G; CCR5, C-chemokine receptor 5; HLA, human leukocyte
antigen.
associated with LTNP status are certain alle-

les within the HLA class I loci that are
thought to help control viral replication via
+
CD8 T cell–mediated immunity. Given that
HLA class I molecules present processed viral
antigens on the surface of infected cells to
+
CD8 T cells, it is assumed, although not
proven, that HLA molecules associated with
nonprogression are the most effective at
+
enabling CD8 T cells to recognize and lyse
infected cells and/or secrete antiviral
+
cytokines. Also, CD8 T cells of LTNPs may
be superior to those of HIV- infected
progressors in terms of proliferation (93),
cytolytic capacity (148), ability to secrete
multiple cytokines (see previous section)
(96), and capacity to respond to viral
variants (149). Other mechanisms of immune-
mediated viral control in LTNPs include a
role for HLA molecules that recognize certain
regulatory receptors on NK cells, which kill
infected cells via innate mechanisms;
enhanced survival and effector functions of
+
CD4 T cells; and a possible role for
neutralizing antibodies and antibodies that
facilitate cell-mediated killing (reviewed in
Reference 150).
Cellular Restriction Factors

(Table 2) (see Reference 151 for a review). One such modified to allow HIV replication, it could
restriction factor is APOBEC3G, a member of the lead the way to better animal models for
apolipoprotein B editing complex (APOBEC) cellular HIV infection.
deaminase family that modifies cytidine and restricts HIV Both APOBEC3G and Trim-5α are consid-
replication by at least two different mechanisms. ered to be part of the innate immune
APOBEC3G is packaged within viral particles and, upon response, which could be harnessed in order
subsequent entry into a new target cell, induces dG-to-dA to restrict the early deleterious effects of HIV
hypermutations in the nascent proviral DNA. The potentially infection (see above) and enable a more
crip- pling effect of APOBEC3G on HIV DNA is greatly effect adaptive immune response against
diminished by the action of the HIV ac- cessory protein Vif. HIV to develop. Among other elements of
In addition, APOBEC3G may be active in resting but not innate immunity that have been implicated
+
activated CD4 T cells and may restrict HIV postentry events in slower disease progression are (a)
in a deaminase-independent mechanism (152). A second receptors and HLA molecules associated
intrinsic cellular restriction factor is Trim-5α, a member of with NK cell function and (b) members of
the tripartite protein family that targets the retrovirus capsid the TLR family of pattern-recognition re-
protein for degradation (reviewed in Reference 151). The ceptors expressed on pDCs and associated
activity of Trim-5α is highly dependent on species-specific with the myriad of antiviral IFN-α-based
compatibility, such that HIV Gag escapes the effects of human pathways. However, any strategy aimed at
Trim-5α and SIV Gag escapes the effects of most simian enhancing innate immune responses must
Trim-5α, whereas the inability of HIV to infect nonhuman be balanced with the potential deleterious
primates is at least in part due to the inhibitory effects of effects of inducing excessive immune
simian Trim-5α on HIV. If simian Trim-5α could be activation, as can occur with
IFN-α and ISGs in chronically HIV-infected innate immunity are considered important for
individuals (see the section entitled Immune stimulating adaptive responses against HIV
Activation). Nonetheless, efforts to improve for both infected and vaccinated individuals
(153).
SUMMARY POINTS
1. HIV transmission occurs primarily at mucosal sites during sexual contact and is
followed by a period of intense viral replication, first in the GALT and then
systemically in all lymphoid tissues.
2. The consequence of acute HIV infection is massive depletion in the GALT of
+
CCR5- expressing memory CD4 T cells, which are the major targets of HIV
replication.
3. The early events of intense HIV replication and dissemination lead to the
establishment of stable viral reservoirs in lymphoid tissues and, at the cellular
+
level, in the form of latently infected resting CD4 T cells. These stable reservoirs
are major impediments to eradication of the virus.
4. Cellular and humoral immune responses are generated against HIV during the
acute and early phases of infection, yet they fail to restrict HIV replication in the
majority of infected individuals. There is strong evidence for selection of viral
mutants that escape these cellular and humoral responses.
5. Immune cell dysfunction, manifested by poor immune responses against HIV and
other pathogens, is observed in the majority of untreated HIV-infected individuals.
Chronic HIV viremia leads to increased cell turnover and changes in cellular
phenotype and function that are consistent with increased immune activation,
differentiation, and exhaustion.
6. There is strong evidence from animal models and human studies that HIV-
induced immune activation is a major determinant of HIV pathogenesis that is
likely to be driven by multiple factors.
7. Effective ART has greatly reduced HIV-related morbidity and mortality by
+
dramatically reducing HIV plasma viremia, which results in increased CD4 T cell
counts. How- ever, incomplete immune restoration persists to varying degrees in
most HIV-infected individuals.
8. Studies on host genetic determinants, as well as on adaptive and innate immune
responses and restriction factors associated with HIV disease progression, are
providing insight into new avenues of treatment and prevention.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings
that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This work was funded by the Intramural Research Program of the National Institute of
Allergy and Infectious Diseases at the National Institutes of Health.
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Annual Review of
Pathology:
Mechanisms of
Contents Disease
Volume 6, 2011
Starting in Immunology by Way of Immunopathology

Emil R. Unanue................................................................................................................1
The Pathogenesis of Sepsis
Deborah J. Stearns-Kurosawa, Marcin F. Osuchowski, Catherine Valentine,
Shinichiro Kurosawa, and Daniel G. Remick . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

EGFR Mutations and Lung Cancer
Gilda da Cunha Santos, Frances A. Shepherd, and Ming Sound Tsao. . . . . . . . . . . . . . . . . . . . 49
Zebrafish Models for Cancer
Shu Liu and Steven D. Leach..........................................................................................71
Mouse Models of Cancer
Dong-Joo Cheon and Sandra Orsulic.............................................................................95
Disorders of Bone Remodeling
Xu Feng and Jay M. McDonald...................................................................................121
The Acute Respiratory Distress Syndrome: Pathogenesis
and Treatment
Michael A. Matthay and Rachel L. Zemans.................................................................147
The HIF Pathway and
Frank S. Lee and Melanie J. Percy................................................................................165
Erythrocytosis
Parkinson’s Disease: Genetics and
Joshua M. Shulman, Philip L. De Jager, and Mel B. Feany . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pathogenesis 193
Pathogenic Mechanisms of HIV
Disease
Susan Moir, Tae-Wook Chun, and Anthony S. Fauci.....................................................223
Pathogenesis of
Kenneth C. Anderson and Ruben D. Carrasco.............................................................249
Myeloma
Alternative Macrophage Activation and
Justin I. Odegaard and Ajay Chawla............................................................................275
Metabolism
v
The Pathobiology of Arrhythmogenic Cardiomyopathy
Jeffrey E. Saffitz............................................................................................................299
Mechanisms of Leukocyte Transendothelial Migration
William A. Muller........................................................................................................323
Retinoids, Retinoic Acid Receptors, and Cancer
Xiao-Han Tang and Lorraine J. Gudas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Biomedical Differences Between Human and Nonhuman Hominids:
Potential Roles for Uniquely Human Aspects of Sialic Acid Biology
Nissi M. Varki, Elizabeth Strobert, Edward J. Dick Jr., Kurt
Benirschke,
and Ajit Varki............................................................................................................365
A Glimpse of Various Pathogenetic Mechanisms
of Diabetic Nephropathy
Yashpal S. Kanwar, Lin Sun, Ping Xie, Fu-you Liu, and Sheldon Chen. . . . . . . . . . . . . . . 395
Pathogenesis of Liver Fibrosis
Virginia Hernandez-Gea and Scott L. Friedman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
Mesenchymal Stem Cells: Mechanisms of
w.annualreviews.org by Stanford University - Main Campus - Green Library on 06/21/12. For personal use only.
Nora G. Singer and Arnold I. Caplan..........................................................................457

Inflammation
Molecular Genetics of Colorectal Cancer
Eric R. Fearon...............................................................................................................479
The Pathogenesis of Systemic Sclerosis
Tamiko R. Katsumoto, Michael L. Whitfield, and M. Kari Connolly...........................509
Indexes
Cumulative Index of Contributing Authors, Volumes 1–6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539

Cumulative Index of Chapter Titles, Volumes 1–6...................................................542
Errata
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ANNUAL REVIEWS

Annu. Rev. Pathol. Mech. Dis. 2011. 6:223–48

Antire deﬁciency syn-

224 Moir · Chun ·

226 Moir · Chun ·

Resting CD4+ T cells

Establishment of lymphoid tissue viral reservoirPartial control

Crossing the barrier

Hours Days Weeks Years

point. This de- pletion of peripheral-blood

Acute phase Early chronic phase

HIV-specific antibody+ (Western blot) HIV-specific antibody+/- (Western blot)

101 HIV RNA+ (PCR)

High levels of plasma

Massive and progressive

Rapid CD4+ T cell

Latently infected epitopes recognized by CD8 T cells (30). Similar

Productively infected CD4+ T cell

by (a) random triggering events and blocks cellular

(reviewed in Reference 67). It is unclear

HIV-Induced Immune Dysfunction

CD4 T cells at mucosal sites (12), the

data from animal models have provided a Immune

plasmacytoid dendritic cells (pDCs), which cells (106). Increased

(90), including HIV infection. Furthermore, effects of blocking PD-1

CD4 T cell counts and that may be

mainte- nance of T patients who usually present with one or

Table 1 Characteristics of long-term nonprogressors (LTNPs)a

Table 2 Host restriction factors of human immunodeftciency virus a

associated with LTNP status are certain alle-

Cellular Restriction Factors

1. Identiftes the virus

early HIV-1 infection. J. Exp. Med. 206:1273–89

immunodeftciency virus type 1 infection. Nature 373:117–22

spread of the human immunodeﬁciency virus. Lymphology 21:28–35

Starting in Immunology by Way of Immunopathology

Shinichiro Kurosawa, and Daniel G. Remick . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Nora G. Singer and Arnold I. Caplan..........................................................................457

Cumulative Index of Contributing Authors, Volumes 1–6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539

An online log of corrections to Annual Review of Pathology: Mechanisms of Disease articles

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