Acquired Immunodeficiency Syndrome

(AIDS)
History
1950s: Blood samples from Africa have HIV antibodies.
1976: First known AIDS patient died.
1980: First human retrovirus isolated (HTLV-1).
1981: First reports of Acquired Immuno-deficiency
Syndrome in Los Angeles.
1983: Virus first isolated in France (LAV).
1984: Virus isolated in the U.S. (called HTLV-III and
AIDS-Related Virus, ARV).
1985: Development and implementation of antibody
test to screen blood donors.
Acquired Immunodeficiency
Syndrome (AIDS)
History (Continued)
1986: Consensus name Human Immunodeficiency
Virus (HIV-1).
Related virus (HIV-2) identified.
1992: AIDS becomes the leading cause of death
among adults ages 25-44 in the U.S.
1997: Mortality rates of AIDS starts to decline due
to the introduction of new drug cocktails.
2001: World Health Organization predicts up to 40
million infected individuals. More than 22 million
have already died.




AIDS: A Leading Cause of Death Among People
Aged 25-44 years in U.S.
0
5
10
15
20
25
30
35
40
1982 1986 1990 1994
AIDS
Accidents
Cancer
Homicide
Deaths per 100,000 people aged 25-44 years
Overview of HIV
-Infect and kills CD4 lymphocytes
- Loss cell mediated immunity opportunistic infect.
- Other (macrofag , monosit) that have protein CD4
on their surface can be infected also
- HIV-1 and HIV-2 cause AID
5
Viral-host Dynamics
About 1010 (10 billion) virions are produced
daily
Average life-span of an HIV virion in plasma
is ~6 hours
Average life-span of an HIV-infected CD4
lymphocytes is ~1.6 days
HIV can lie dormant within a cell for many
years, especially in resting (memory) CD4
cells, unlike other retroviruses
6
Classification of HIV
HIV class: Lentivirus
Retrovirus: single stranded RNA transcribed to double
stranded DNA by reverse transcriptase
Integrates into host genome
High potential for genetic diversity
Can lie dormant within a cell for many years,
especially in resting (memory) CD4+ T4 lymphocytes
HIV type (distinguished genetically)
HIV-1 -> worldwide pandemic (current ~ 40 M
people)
HIV-2 -> isolated in West Africa; causes AIDS much
more slowly than HIV-1 but otherwise clinically
similar
7
HIV at Surface of
CD4 Lymphocyte
Courtesy of CDC
Virulogy of HIV
-Is of one the two HTLV
- Two identical ss (+)RNA surrounded by envelop (lipid
bilayer) containing viirus-specifict glycoprotein
(gp 120 and gp 41)
-Genom complex
1. encode structural protein : gag , pol, env
2. tat , rev (replication) ; nef , vif , vpr and vpu
(as accessory gene)
5
3
LTR
LTR
gag pol env
P24, PROT POL H INT gp120 gp41
VIF TAT VPU REV NEF
gag : internal core protein as group-specifict antigen
pol : polymerase protein ( riverse transriptase)
env : envelope glycoprotein
VIF : viral infectivity factor
TAT : transactivating protein
VPU : viral protein U
REV : regulator of expression of virion protein
NEF : negtive regulatory factor
LTR : long terminal repeat

gene protein encode by gene Fungtion of protein
gag p24 , p7 nucleocapsid
p17 matrix protein
pol riverse trancriptase transcribec RNA DNA
protease (PROT) cleaves precursor polipeptide
integrase (INT) integrates viral DNA host DNA
env gp 120 attachment to CD4 protein
gp 41 fussion with host cell
tat TAT activation of transcription v. gene
rev REV transport mRNA from nucleus
to cytplama
nef Nef decrease CD4 & MHC I protein
on surface infected cellls, induce
death of uninfected CTL, I impor-
tand for pathogenesis SIV




gene protein encode by gene Fungtion of protein

vif Vif Enhance infectivity by inhibit
APOBEC3G ,enzyme that
cause hypermutation of
retroviral DNA
vpr Vpr transport viral core from
cytplasma in nondividing cells
Vpu Vpu enhance virion release from
cells


Notes : - Apolipoprotein B RNA editing enzymes

Structure of the Human Immunodeficiency Virus
HIV is a Retrovirus
gp120
gp 41
gp24
Lipid bilayer
P17 Matrix
protein
Several important antigen of HIV

1. gp 120 and gp 41 (type specific glycoprotein)
gp120 interact with CD4 protein second protein
chemokine reseptors. gp 41 mediates fussion of
viral envelope and cell membrane.
Ab against gp120 neutralize innfectivity of HIV

2. Group specific antigen gp24
located in the core is not know. Ab against this
antigent not neutralize of HIV infectivity
Life Cycle of HIV
1. Attachment: Virus binds to surface
molecule (CD4) of T helper cells and
macrophages.
Coreceptors: Required for HIV infection.
CXCR4 and CCR5 mutants are resistant to
infection.
2. Fusion: Viral envelope fuses with cell
membrane, releasing contents into the
cell.
HIV Life Cycle: Attachment Requires CD4
Receptor plus a Coreceptor
Life Cycle of HIV
3. Reverse Transcription: Viral RNA is
converted into DNA by unique enzyme reverse
transcriptase.
Reverse transcriptase
RNA ---------------------> DNA
Reverse transcriptase is the target of several
HIV drugs: AZT, ddI, and ddC.
HIV Life Cycle: Reverse Transcriptase
Converts RNA into DNA
Life Cycle of HIV
4. Integration: Viral DNA is inserted into host cell
chromosome by unique enzyme integrase.
Integrated viral DNA may remain latent for years
and is called a provirus.
5. Replication: Viral DNA is transcribed and RNA
is translated, making viral proteins.
Viral genome is replicated.
6. Assembly: New viruses are made.
7. Release: New viruses bud through the cell
membrane.
HIV Life Cycle: Latent versus Active Infection
HIV Life Cycle: Latent versus Active Infection
in Macrophages
HIV Immunology
22
Intracellular
infection
Nave B-
Cell
Nave T8 cell
Nave T4
helper cell
MHC I presentation
of endogenous
antigen
MHC II presentation
of exogenous antigen
Cell-mediated (CTLs)
Humoral (plasma
cells / antibodies)
Free antigen
Th1 Th2
Overview of Adaptive Immune
Response Extracellular
infection
APC
Diagram courtesy of Dr. Samuel Anderson
23
Cellular Immune Responses to HIV
CD8 Cytotoxic T lymphocyte (CTL)
Critical for containment of HIV
Derived from nave T8 cells, which recognize viral
antigens in context of MHC class I presentation
Directly destroy infected cell
Activity augmented by Th1 response
24
Cellular Immune Responses to HIV
CD4 Helper T Lymphocyte (Th)
Plays an important role in cell-mediated response
Recognizes viral antigens by an antigen presenting
cell (APC)
Utilizes major histocompatibility complex (MHC) class II
Differentiated according to the type of help
Th1 - activate Tc (CD8) lymphocytes, promoting cell-
mediated immunity
Th2 - activate B lymphocytes, promoting antibody
mediated immunity

25
Humoral Immune Response to HIV
Neutralization
Antibodies bind to surface of virus to prevent
attachment to target cell
Antibody-dependent cell-mediated
cytotoxicity (ADCC)
Fc portion of antibody binds to NK cell
Stimulates NK cell to destroy infected cell

26
HIV Evasion Methods
Makes 10 billion copies/day -> rapid mutation
of HIV antigens
Integrates into host DNA
Depletes CD4 lymphocytes
Down-regulation of MHC-I process
Impairs Th1 response of CD4 helper T
lymphocyte
Infects cells in regions of the body where
antibodies penetrate poorly, e.g., the central
nervous system



Pathogenesis of HIV
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Cells Infected by HIV
Numerous organ systems are infected by HIV:
Brain: macrophages and glial cells
Lymph nodes and thymus: lymphocytes and
dendritic cells
Blood, semen, vaginal fluids: macrophages
Bone marrow: lymphocytes
Skin: langerhans cells
Colon, duodenum, rectum: chromaffin cells
Lung: alveolar macriphages
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General Mechanisms of HIV
Pathogenesis
Direct injury
Nervous (encephalopathy and peripheral neuropathy)
Kidney (HIVAN = HIV-associated nephropathy)
Cardiac (HIV cardiomyopathy)
Endocrine (hypogonadism in both sexes)
GI tract (dysmotility and malabsorption)
Indirect injury
Opportunistic infections and tumors as a consequence
of immunosuppression


30
General Principles of
Immune Dysfunction in HIV
All elements of immune system are affected
Advanced stages of HIV are associated with
substantial disruption of lymphoid tissue
Impaired ability to mount immune response to
new antigen
Impaired ability to maintain memory responses
Loss of containment of HIV replication
Susceptibility to opportunistic infections

31
Role of Cytokine Dysregulation in
Pathogenesis of HIV
HIV is associated with increased expression of
pro-inflammatory cytokines
TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma
Associated with up-regulation of HIV replication
HIV results in disruption and loss of
immunoregulatory cytokines
IL-2, IL-12
Necessary for modulating effective cell-mediated
immune responses (CTLs and NK cells)
32
Role of Cytokine Dysregulation in
Pathogenesis of HIV
HIV is associated with increased expression of
pro-inflammatory cytokines
TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma
Associated with up-regulation of HIV replication
HIV results in disruption and loss of
immunoregulatory cytokines
IL-2, IL-12
Necessary for modulating effective cell-mediated
immune responses (CTLs and NK cells)
33
Consequence of Cell-mediated
Immune Dysfunction
Inability to respond to intracellular infections
and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama, Cryptosporidium,
Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
34
Consequence of Cell-mediated
Immune Dysfunction
Inability to respond to intracellular infections
and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama, Cryptosporidium,
Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
35
Consequence of Cell-mediated
Immune Dysfunction
Inability to respond to intracellular infections
and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama, Cryptosporidium,
Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
36
Transmission
Modes of infection
Sexual transmission at genital or colonic mucosa
Blood transfusion
Mother to infant
Accidental occupational exposure
Viral tropism
Transmitted viruses is usually macrophage-tropic
Typically utilizes the chemokine receptor CCR5 to gain
cell entry
Patients homozygous for the CCR5 mutation are
relatively resistant to transmission
37
Cell free
HIV
Skin or mucosa
24 hours 48 hours
1. HIV co-receptors, CD4
+ chemokine receptor
CC5

Immature Dendritic
cell
3. Mature Dendritic cell in
regional LN undergoes
a single replication,
which transfers HIV to
T-cell
Via lymphatics or
circulation
T-cell
PEP
Burst of HIV
replication
2. Selective of
macrophage-
tropic HIV
Early Phases of HIV Infection of
Mucosal Surfaces
38
Laboratory Markers of HIV Infection
Viral load
Marker of HIV replication rate
Number of HIV RNA copies/mm3 plasma
CD4 count
Marker of immunologic damage
Number of CD4 T-lymphocytes cells/mm3 plasma


AIDS Associated Disease Categories
1. Gastrointestinal: Cause most of illness and death
of late AIDS.
Symptoms:
Diarrhea
Wasting (extreme weight loss)
Abdominal pain
Infections of the mouth and esophagus.
Pathogens: Candida albicans, cytomegalovirus,
Microsporidia, and Cryptosporidia.

AIDS Associated Disease Categories
2. Respiratory: 70% of AIDS patients develop
serious respiratory problems.
Partial list of respiratory problems associated with AIDS:
Bronchitis
Pneumonia
Tuberculosis
Lung cancer
Sinusitis
Pneumonitis
AIDS Associated Disease Categories

3. Neurological: Opportunistic diseases and
tumors of central nervous system.
Symptoms many include: Headaches, peripheral
nerve problems, and AI DS dementia complex
(Memory loss, motor problems, difficulty
concentration, and paralysis).
AIDS Associated Disease Categories
4. Skin Disorders: 90% of AIDS patients develop
skin or mucous membrane disorders.
Kaposis sarcoma
1/3 male AIDS patients develop KS
Most common type of cancer in AIDS patients
Herpes zoster (shingles)
Herpes simplex
Thrush
Invasive cervical carcinoma
5. Eye Infections: 50-75% patients develop eye
conditions.
CMV retinitis
Conjunctivitis
Dry eye syndrome

Drugs Against HIV
Reverse Transcriptase Inhibitors: Competitive
enzyme inhibitors. Example: AZT, ddI, ddC.
Protease Inhibitors: Inhibit the viral proteases.
Prevent viral maturation.
Problem with individual drug treatments:
Resistance.
Drug Cocktails: A combination of:
One or two reverse transcriptase inhibitors
One or two protease inhibitors.
Drug cocktails have been very effective in
suppressing HIV replication and prolonging the
life of HIV infected individuals, but long term
effectiveness is not clear.
Transmission of AIDS (Worldwide)
1. Sexual contact with infected individual: All
forms of sexual intercourse (homosexual and
heterosexual). 75% of transmission.
2. Sharing of unsterilized needles by intravenous
drug users and unsafe medical practices: 5-
10% of transmission.
3. Transfusions and Blood Products:
Hemophiliac population was decimated in
1980s. Risk is low today. 3-5% of
transmission.
4. Mother to Infant (Perinatal): 25% of
children become infected in utero, during
delivery, or by breast-feeding (with AZT only
3%). 5-10% of transmission.
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Key Points
HIV is a retrovirus, capable of integrating into host genome
and establishing chronic infection
HIV can be classified into subgroups (clades) which have
characteristic geographic distribution
The important steps in the lifecycle of HIV include cell entry,
reverse transcription, integration, and maturation/assembly
Cell-mediated immunity is critical for containment of HIV
infection and other intracellular infections
HIV evades host immunity by a variety of mechanisms
46
Key Points (2)
HIV activates the immune system to increase
its own replication
CD4 count declines by both direct and indirect
mechanisms
HIV RNA set point predicts rate of progression
to AIDS
CD4 count decline is associated with a
predictable sequence of opportunistic
infections



47
Key Points (2)
HIV activates the immune system to increase
its own replication
CD4 count declines by both direct and indirect
mechanisms
HIV RNA set point predicts rate of progression
to AIDS
CD4 count decline is associated with a
predictable sequence of opportunistic
infections



48
Key Points (2)
HIV activates the immune system to increase
its own replication
CD4 count declines by both direct and indirect
mechanisms
HIV RNA set point predicts rate of progression
to AIDS
CD4 count decline is associated with a
predictable sequence of opportunistic
infections