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HIV Life Cycle: Overview

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Encyclopedia of AIDS
DOI 10.1007/978-1-4614-9610-6_60-1
# Springer Science+Business Media New York 2013

HIV Life Cycle: Overview

Frank Kirchhoff*
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany

Definition
The HIV life cycle defines the steps and changes the virus undergoes from its first contact with a
target cell to the production of new infectious viral particles that can initiate the next round of
replication. The combination of reverse transcription of viral RNA into DNA and integration of the
latter into the host cell genome is a key feature of the retroviral replication cycle.

Introduction
The goal of this chapter is to provide a brief overview on the “life” cycle of HIV, which should
perhaps be better referred to as the viral “replication” cycle, since viruses do not have their own
metabolism and are thus usually not considered living organisms. Viruses can be considered as
intracellular parasites that are strictly dependent on living host cells for reproduction. Understanding
how HIV interacts with its target cells in order to replicate is of great interest because it may provide
important clues for the generation of improved antiretroviral drugs and the development of novel
strategies to control or even eliminate the virus.
The main targets of HIV are CD4+ helper T cells, which are key regulators of the humoral and
cellular immune responses. Thus, their destruction and depletion by mechanisms that are not fully
understood render the body unable to defend itself against opportunistic pathogens. When HIV
infects an activated CD4+ T cell, it hijacks and manipulates its transcriptional and translational
machinery to reproduce itself. As briefly outlined below and specified in the following chapters, HIV
has to utilize a multitude of cellular factors and to counteract the antiretroviral activity of others in
order to complete its replication cycle. Theoretically, each interaction with cellular factors that are
essential for virus replication (termed “virus-dependency” factors) or strengthening of antiretroviral
(or “host restriction”) factors provides a potential means to interfere with the HIV life cycle.
Although activated CD4+ helper T cells represent the main target cells for HIV replication, the
virus can also infect other cell types, such as macrophages, immature dendritic cells, and more
resting T cell subsets. The latter cell types are not important for the bulk of virus replication but most
likely play important roles in innate and adaptive antiviral immune responses. Furthermore, they
may harbor the virus in a silent integrated proviral form and thus contribute to the establishment and
maintenance of viral reservoirs that prevent the eradication of HIV from the human body, even under
optimized antiretroviral therapy (ART). Finding ways to activate these latent proviruses to eliminate
the infected cells and to cure HIV infection is a main challenge in AIDS research. A better
understanding of the steps in the viral life cycle, especially the regulation of proviral transcription,
may help to achieve this.

*Email: frank.kirchhoff@uni-ulm.de

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HIV-1 provirus
vif tat2
LTR gag tat1 vpu rev2 nef
pol env LTR
vpr rev1

RNA genome
PBS (tRNALys primer binding site) PPT (Polypurine tract)

TAR RRE
(Tat responsive element) (Rev responsive element) polyadenylation signal

Representative transcripts tat1 tat2

Tat *
rev1
*
rev2
* nef Early:
RRE-Rev
Rev, Nef
Nef * nef independent

Gag-Pol * gag
prot RT int

Vif
* vif Late
vpr
Vpr
* RRE -Rev
dependent
vpu ** env
Vpu, Env

Fig. 1 Overview of the organization and expression of the HIV-1 genome. Some cis-regulatory elements in the viral
RNA genome and representative early and late RNAs are presented. Stars indicate splice sites

HIV Structure
The HIV genome contains the typical retroviral genes gag, pol, and env flanked by long terminal
repeats (LTRs), which contain the viral promoter (Fig. 1, upper). Gag codes for the structural
proteins capsid (CA), matrix (MA), and nucleocapsid (NC); pol encodes the enzymes reverse
transcriptase (RT), protease (PR), and integrase (IN); and env encodes the glycoproteins gp120
and gp41 (Swanson and Malim 2008). In addition, HIV has six regulatory genes (tat, rev, nef, vif,
vpr, and vpu) and is thus considered a “complex” retrovirus. Tat enhances proviral transcription, and
Rev is essential for the export of incompletely or unspliced viral mRNAs into the cytoplasm. The
remaining genes were named “accessory” because they are not absolutely required for replication in
some cell culture systems (Kirchhoff 2010). However, they perform a multitude of activities
facilitating viral immune evasion and antagonize a variety of specific antiretroviral cellular (host
restriction) factors and are thus essential for viral spread in vivo (▶ Viral Auxiliary Proteins).
HIV-1 belongs to the Lentivirus genus (lentis = slow) of the Retroviridae family. The virion has a
spherical shape and a diameter of 100–130 nm (or 1/10,000 mm) (▶ HIV-1 Virion Structure). The
viral envelope is composed of a lipid membrane, which is derived from the host cell and contains
cellular proteins, as well as about 7–12 trimeric complexes of viral envelope (Env) protein (Fig. 2).
Env consists of the external glycoprotein 120 (gp120) that mediates viral attachment and the
transmembrane glycoprotein 41 (gp41) that is critical for viral fusion. Gp41 is associated with the
viral p17 matrix protein and encompasses a conical capsid that consists of the viral Gag protein, p24.
The capsid contains two single strands of viral RNA with positive polarity and a length of close to
10,000 nucleotides. The RNA is associated with the nucleocapsid proteins, as well as the RT and
IN. The virions also contain some copies of the viral protease and the accessory Vif, Vpr, and Nef
proteins, as well as some cellular factors, such as tRNAlys3 which is used as primer for reverse
transcription.

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HIV-1 provirus
vif tat1 tat2
LTR gag vpu rev2 nef
pol vpr env LTR
rev1

p17 p24 p9 p6 p11 p51/66 p32 gp120 gp41

MA CA NC PR RT IN Vif Vpr SU TM

nucleocapsid, NC, p6 transmembrane-

protein, TM, gp41
Lys
tRNA
surface envelope
matrix, MA, p17 glycoprotein
SU, gp120
reverse transcriptase
RT, p66, p51
membrane
capsid, CA, p24
protease, PR, p10 viral RNA
Cyclophylin A
integrase, IN, p32 cellular
p6 protein
Vpr Vif

Fig. 2 Schematic presentation of the expression of viral proteins that are found in the viral particle (upper) and of the
mature HIV virion (lower)

Overview on the HIV Replication Cycle

The HIV-1 life cycle is complex and can roughly be divided in an early and a late phase of
replication. The early phase begins with the attachment of the virion at the cell surface and ends
with the integration of the proviral DNA into the host genome (Fig. 3). The late phase of replication
starts with the initiation of proviral transcription and ends with the release of fully infectious progeny
virions. In highly activated CD4+ T cells, the HIV life cycle lasts just one to two days and is
associated with the programmed death of both virally infected cells and uninfected bystander cells.
The viral life cycle illustrates some of the challenges associated with HIV infection. The viral RT has
a very high mutation rate (1 error per 10,000 nucleotides), and the viral populations in an infected
individual are not uniform but rather a collection of the so-called quasispecies. Together with the
short generation time and massive virus production (up to 2  109 virions per day), this allows HIV
to rapidly adapt to its host environment and to develop resistance against antiretroviral drugs or
immune responses. To generate a higher barrier for the evolution of resistances, combination
therapies are currently used to treat HIV. Furthermore, proviral integration into the host genome
allows the virus to hide in long-living cells. Finally, HIV infects and kills CD4+ helper T cells that
are crucial for the maintenance of a functional immune system. It is important to consider, however,
that other cell types can also be infected and that the time frame of viral replication and the fate of the
infected cells vary. Macrophages, for example, may produce HIV over several weeks and store
infectious virions intracellularly (▶ Macrophage-Specific Aspects of HIV-1 Infection). Although a
lot of exciting progress has been made, we are still just beginning to understand the multitude of
interactions of HIV with its host cell.

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11. Maturation
1. Entry Protease, p10
Env proteins, gp120, gp41
10. Budding
Gag

9. Assembly
Gag

2. Reverse Transcription
Reverse Transpriptase, p66, p51 3. Uncoating 8. Translation
Capsid, p24

4. Nuclear Import 7. RNA Export

Capsid, p24 Rev
5. Integration 6. Transcription
Integrase, p32 Provirus Tat

Fig. 3 Overview of the viral replication cycle

Viral Attachment
Cell-free HIV virions usually have a half-life of just about 20–30 min in infected individuals. Thus, the
virus must find and infect a new target cell within a very short time frame. As described below, CD4 is
the primary receptor, and the chemokine receptors CCR5 and CXCR4 are the main co-receptors of
HIV entry (▶ Fusion). These receptors are sufficient to render cells susceptible to HIV entry and thus
determine the viral cell tropism. However, the densities of the Env trimers on the virions and of the
CD4 receptor on the target cells are frequently low. Thus, viral attachment is often inefficient and a
limiting step for HIV infection. Several receptors, such as poly-glycans, lectins, and others, can bind
HIV virions in a more unspecific manner and may thereby greatly increase viral infection rates
(▶ Attachment/Binding). On the one hand, they concentrate virions at the cell surface and facilitate
their interaction with CD4 and a co-receptor to allow virion fusion. Furthermore, they may trap viral
particles at the cell surface to stabilize them and to mediate trans infection of susceptible T cells. For
example, it has been suggested that dendritic cells (DCs) bind HIV virions at the site of genital
exposure and transport them to the lymph nodes where they mediate both trans infection and
stimulation of T cells that results in massive virus production (van Kooyk and Geijtenbeek 2003).

Binding and Fusion

Viral entry is a complex multi-step process that offers multiple possibilities for therapeutic inter-
vention (Didigu and Doms 2012). Either directly or following unspecific binding of HIV to its target
cell, the infection process is initiated by the interaction of the external viral glycoprotein gp120 with
the cellular CD4 receptor (▶ Fusion). CD4 binding induces conformational changes in the Env

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trimer that allow the interaction of gp120 with either the CXCR4 (X4) or CCR5 (R5) co-receptor.
Usually, only R5 viruses are sexually transmitted and found during chronic infection. In comparison,
X4 HIV strains emerge late during the course of infection and are associated with rapid progression
to AIDS in the absence of antiretroviral therapy. Co-receptor interaction induces additional confor-
mational changes that allow the gp41 transmembrane protein, which is usually hidden by the gp120,
to insert its hydrophobic fusion peptide into the cell membrane to make the first direct contact
between the virus and its target cell. Thereafter, the trimeric gp41 complex forms a helical bundle
structure which pulls the cellular and viral membranes together, thus allowing virion fusion and the
release of the contents of the virus particle into the cell. Drugs that block the CCR5 co-receptor or
prevent viral fusion are already used to treat HIV infection in the clinic, and other HIV entry
inhibitors are in preclinical development.

Reverse Transcription
Once fusion is completed, the genetic information of the virus can enter into the cell. The HIV genome
consists of two plus-stranded RNAs that are protected by the nucleocapsid. After fusion, the single-
stranded viral RNAs are transcribed into linear double-stranded DNAs by a process called reverse
transcription (▶ RT). It is called “reverse” transcription because it reverses the order of events that take
place during the regular transcription process, i.e., generation of messenger RNA from nuclear DNA
followed by export into the cytoplasm and protein synthesis. It is performed by an enzyme called
reverse transcriptase that is characteristic – although not unique – to retroviruses and involves a very
complex series of events that are outlined in chapter ▶ Reverse Transcriptase-Catalyzed HIV-1 DNA
Synthesis. The very first drugs against HIV inhibited reverse transcription. Currently, there are two
different classes: nucleoside and nucleotide analog reverse transcriptase inhibitors (NRTIs), which
prevent further elongation of the DNA chain, and non-nucleoside reverse transcriptase inhibitors
(NNRTIs) that bind to the enzyme and render it inactive (cross-link to ART section).

Uncoating and Nuclear Entry

Uncoating refers to the disassembly of the viral capsid before import of the viral genome into the
nucleus. Untimely uncoating due to point mutations in the capsid protein or interactions with the
tripartite motif 5-alpha protein (TRIM5a) impairs viral infectivity (▶ Uncoating and Nuclear Entry).
Early studies suggested that uncoating may occur immediately after viral entry. More recent data,
however, suggest that capsids may remain intact for several hours and that this stability is critical for
HIV-1 infection. Furthermore, it seems that uncoating is tightly associated with reverse transcription
and accompanies the transition of the reverse transcription complex (RTCs) to the pre-integration
complex (PIC) that is competent for integration into the host cell genome (Arhel 2010). However,
the exact timing of uncoating is still poorly understood and subject to intense research. Lentiviruses
have the unique ability to infect nondividing terminally differentiated cells, such as macrophages;
thus, the viral genome must be transported through an intact nuclear membrane. HIV-1 PICs must be
actively transported through the nuclear pore since they are too large to cross them by passive
diffusion. Originally, the viral matrix protein, Vpr, and integrase have been implicated in nuclear
entry. However, recent studies suggest that none of them are essential for infection of nondividing
cells and that the HIV-1 capsid protein may play a key role in this process, although the underlying
mechanisms remain to be fully elucidated.

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Integration
After successful generation of linear ds DNA and its transport across the nuclear membrane, HIV
must insert its genome into that of the host cell for gene expression and productive infection (Fig. 3).
Once the viral DNA is inserted into the cellular DNA by an enzyme called integrase (▶ Integration),
the cell is usually infected for the remainder of its life span. As part of the host cell chromosome, the
proviral DNA is replicated along with the host DNA. Thus, spread of infection can be achieved
either by infection of new cells or by multiplication of cells already containing proviral
DNA. Notably, several compounds that inhibit viral integration are now successfully used in the
clinic (cross-link to ART section). In some long-living cells such as memory T cells, the integrated
viral genome, which is referred to as a provirus, may remain silent for many years. This constitutes a
main problem for viral eradication because as long as the provirus remains inactive, these cells are
not recognized by the immune system and thus not eliminated. Sometimes the proviruses may
become activated and produce infectious HIV that damages the immune system if ART is
discontinued after many years. Whether or not a cell becomes latently or productively infected
depends on the type and state of activation of the infected target cells during infection as well as
subsequent exogenous stimulation (Colin and Van Lint 2009). The viral reservoirs are not fully
defined, but quiescent CD4+ T cells seem to constitute an important part of them.

Transcription
In productively infected cells, the integrated HIV provirus serves as a template for the transcription
of both viral messengers and genomic RNA by the cellular Pol II polymerase (▶ Transcription
(Initiation, Regulation, Elongation)). Proviral transcription is initiated by the viral promoter, which
is located in the U3 region of the 5’ LTR and active in many cell types. Viral gene expression is
strictly dependent on cellular transcription factors, such as NF-kB and NFAT. Initially, the tran-
scriptional output is low because elongation of viral transcripts is very inefficient and the viral
transactivator protein Tat is required for effective viral gene expression (▶ Tat Expression and
Function). Tat binds to a specific sequence in the R region of the 5’ LTR, named the trans-acting
response (TAR) element, to increase transcriptional processivity (Fig. 1). This effect is dependent on
the cellular factor pTEFb. Tat allows the efficient synthesis of full-length HIV transcripts, and more
than 25 different mRNAs in three size classes are generated by alternative splicing: (i) unspliced
RNA (9 kb) serving as genomic RNA or to produce the Gag and Gag-Pol precursors; (ii) singly
spliced (4 kb) RNA encoding Vif, Vpr, Vpu, and Env; or (iii) fully spliced (2 kb) RNA expressing
Tat, Rev, and Nef (Fig. 1). Transport of unspliced and partially spliced mRNAs from the nucleus to
the cytoplasm is mediated by the viral Rev protein which interacts with the rev responsive element
(RRE) in the viral RNA and the cellular export factor Crm1 to connect these viral RNAs to the export
machinery (▶ Rev Expression and Function).

Translation and Assembly

As mentioned above, the fully spliced viral RNAs that are initially generated encode for Tat, Rev,
and Nef. Tat boosts viral transcription and RNA elongation, and Rev mediates the transport of
unspliced and partially spliced viral RNAs to the cytoplasm. Nef performs a large number of
functions and basically seems to make the infected cell less visible to the immune system by

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down-modulation of several surface receptors, such as CD4 and class I MHC, and manipulates the
cells in a way that they become more effective producers of fully infectious viral particles. Synthesis
of Tat and Rev allows the generation of full-length unspliced mRNA that expresses the Gag and
Gag-Pol precursors which are then processed to major structural and enzymatic proteins. In parallel,
the Vif, Vpr, Vpu, and Env proteins are synthesized from single spliced viral RNAs (Fig. 1).
Viral assembly is a complex and highly ordered process (▶ Virus Assembly). In brief, the Gag and
Gag-Pol precursors multimerize via interactions between Gag proteins. Furthermore, both pre-
cursors are N-terminally myristoylated in the matrix domain and thus concentrated in lipid rafts at
the inner leaflet of the plasma membrane (Ganser-Pornillos et al. 2008). The viral Env glycoproteins
are recruited to these building platforms through interactions with the matrix protein. Finally, two
copies of genomic viral RNA are recruited to this complex through interactions of their stem loops
packaging signal with the zinc fingers present in the NC domain of Gag (Fig. 3). Furthermore, the
viral Vif protein, which antagonizes the restriction factor APOBEC3G, as well as some cellular
factors, are also recruited to the sites of virion assembly and incorporated into viral particles. The
accumulation of viral proteins and RNA at the plasma membrane induces first its curvature and
subsequently the formation of a membrane-coated spherical particle.

Budding
The release of progeny virions from the infected cells is called budding. The late domain of the p6
part of Gag and the cellular Tsg101 protein are involved in this step which allows newly formed HIV
to pinch off and enter into the circulation (▶ Budding). Notably, also this late step of the viral
replication cycle is targeted by a restriction factor: tetherin (BST-2) tethers mature and infectious
viruses to the cell surface and is counteracted by the HIV-1 Vpu and the Nef or Env proteins of other
primate lentiviruses (Martin-Serrano and Neil 2011).

Maturation
The HIV particles are released in an immature and noninfectious form that is morphologically
characterized by a thick layer of radially arranged Gag and Gag-Pol precursors (▶ Maturation).
During or shortly after budding, the viral protease becomes activated and cleaves the Gag and
Gag-Pol precursors into their mature final components. As a consequence, the configuration of the
proteins is reorganized to generate the characteristic electron-dense conical inner core and to render
the virus infectious (Briggs and Kr€ausslich 2011). Drugs that block this last essential step of the viral
life cycle by inhibiting the viral protease are a main component of effective ART.

Viral Dependency and Host Restriction Factors

It has long been known that viruses are strictly dependent on live host cells in order to replicate. Only
recently, however, it has become clear that these interactions may be far more complex than
previously appreciated. Several studies have used genome-wide knockout strategies in order to
better assess the cellular factors that may be critical for effective replication of HIV. All of them
found that HIV may utilize hundreds of cellular proteins in order to complete its life cycle. Similarly,
a recent study performed elegant broad-based screens to clarify how many cellular proteins interact

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with viral proteins and identified about 500 of them (J€ager et al. 2011). Altogether, these studies
provide an exciting first glimpse at the enormous complexity of interactions between HIV and the
host cell. However, there are some caveats. For example, the overlap between the potential viral
dependency factors in the genome-wide knockout studies was minimal (Bushman et al. 2009) most
likely because of variations in the cell types, viral strains, and experimental conditions used.
Furthermore, it is difficult to assess how many other cellular proteins may be affected by each
individual knockdown. Similarly, most interaction studies cannot distinguish between direct inter-
actions between viral and host cell proteins or interactions with larger protein complexes. Nonethe-
less, these studies have provided exciting first insights into the enormous complexity of interactions
between the virus and the host cell and may help to identify additional key factors involved in HIV
replication.
Although HIV hijacks the host cell and takes advantage of many cellular proteins and pathways, it
has become clear that the cell is not a very friendly environment for the virus, because it encodes
specific antiviral factors that may inhibit HIVat various steps of its life cycle and are counteracted by
the viral accessory proteins (▶ Cellular Restriction Factors). In brief, the best characterized antiviral
or host restriction factors are APOBEC3G which induces lethal hyper-mutation of the retroviral
genome and affects reverse transcription, TRIM5a protein that induces untimely uncoating of
incoming retroviral capsids, and tetherin that inhibits virion release. Unfortunately, HIV-1 evolved
effective strategies to evade or counteract these antiviral host factors (Kirchhoff 2010).

Target Cell Dependency

The main target cells for viral replication in vivo are activated CD4+ T cells, and the viral life cycle
illustrated in Fig. 3 provides a rough overview of the events in this cell type. Similarly, almost all
studies on the HIV replication cycle have been performed using immortalized cell lines or fully
activated T cells. In vivo, however, many T cells are minimally activated. This may not be very
important for the bulk of virus replication but most likely highly relevant for the establishment of
latent viral reservoirs and for the pathogenesis of AIDS. For example, some long-living memory
T cells may return to a quiescent stage upon HIV infection and not show any gene expression for
several years before they finally become activated and start to produce infectious HIV particles.
Cells that carry the provirus but do not produce viral proteins cannot be recognized and eliminated
by the immune system and constitute a major obstacle to virus elimination. Furthermore, it is
important to consider that HIV does not only infect T cells and that the viral replication cycle may
be somewhat different in other cell types. Macrophages, for example, are also productively infected
by HIV and may contribute to the viral reservoirs and facilitate viral evasion of the blood-brain
barrier (▶ Macrophage-Specific Aspects of HIV-1 Infection). Furthermore, HIV may also infect
immature dendritic cells, microglial cells, and (possibly) stem cells although the relevance of these
and other potential target cells of HIV for viral spread and pathogenesis in vivo is currently largely
unclear.

Conclusions and Perspectives

Although enormous progress has been made in understanding the complex events and interactions
that are critical for the life cycle of HIV, a lot remains to be learned. It will be essential to further
clarify which host dependency factors are really critical for viral replication in the human host.

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Currently, only a single cellular factor (CCR5) is targeted for antiviral treatment. Preventing the use
of other host cell proteins that are obligatory for viral replication may lead to the development of
novel antiretroviral strategies that make it more difficult for HIV to develop resistance. Furthermore,
it seems likely that additional restriction factors will be discovered and strengthening them or
weakening the viral antagonists may also allow to impair the viral replication cycle at different
steps. It will also be important to further clarify why some T cells get stuck after the early stage of
infection and become latently infected and how to stimulate them in order to eliminate the viral
reservoirs. Furthermore, recent studies suggest that the protection of specific T cell subsets may play
a major role in the lack of disease progression in some monkey species that are naturally infected
with simian immunodeficiency viruses. Since the fate and type of the viral target cell determine the
damage for the individual, it seems important to further study target cell-dependent differences in the
viral replication cycle. Finally, it is important to consider that in vivo HIV is mainly replicating in
lymphoid organs that are densely packed with different cell types and may spread through direct
cell-cell contact.

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