Download How HIV evades the immune system

2374
Chin Med J 2013;126 (12)
Review article
Tactics used by HIV-1 to evade host innate, adaptive, and intrinsic
immunities
LU Lu, YU Fei, DU Lan-ying, XU Wei and JIANG Shi-bo
Keywords: human immunodeficiency virus; immune evasion; natural killer, antibody; cytotoxic T lymphocytes
Objective To review the mechanisms by which HIV evades different components of the host immune system.
Data sources This review is based on data obtained from published articles from 1991 to 2012. To perform the PubMed
literature search, the following key words were input: HIV and immune evasion.
Study selection Articles containing information related to HIV immune evasion were selected.
Results Although HIV is able to induce vigorous antiviral immune responses, viral replication cannot be fully controlled,
and neither pre-existing infected cells nor latent HIV infection can be completely eradicated. Like many other enveloped
viruses, HIV can escape recognition by the innate and adaptive immune systems. Recent findings have demonstrated that
HIV can also successfully evade host restriction factors, the components of intrinsic immune system, such as APOBEC3G
(apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G), TRIM5α (tripartite motif 5-α), tetherin, and
SAMHD1 (SAM-domain HD-domain containing protein).
Conclusions HIV immune evasion plays an important role in HIV pathogenesis. Fully understanding the tactics deployed
by HIV to evade various components of the host immune systems will allow for the development of novel strategies aimed
toward the prevention and cure of HIV/AIDS.
Chin Med J 2013;126 (12): 2374-2379
A
fter 30 years of research, a vast amount of
information has been amassed to explain the
pathogenesis, structure, and immunobiology of the
human immunodeficiency virus (HIV). Based on this
body of knowledge, great strides have been made in the
development of drug therapies that have dramatically
decreased mortality and prevented transmission. However,
HIV remains an intransigent pandemic threat. More than 60
million people have been infected by HIV with 25 million
deaths since the disease was first identified in the early
1980s, serving as a stark reminder that continued efforts
are required in the search for a cure or a vaccine.1 To date,
however, several efforts to develop an effective vaccine
have failed or shown only low efficacy.2-5 Therefore, it is
worthwhile investigating the mechanisms by which HIV
escapes or evades components of the innate/adaptive/
intrinsic immune systems.
Eukaryotic organisms have been exposed to viral infections
for millions of years. This coevolutionary process has
driven the development of innate and acquired, or adaptive,
immune systems against invading viruses. In turn, viruses
have evolved countermeasures to escape immune control.
A set of different accessory proteins is encoded by HIV
genomes to perform this job so that HIV can readily
replicate in the specific cell environment.6,7
For example, the accessory protein Vpx is found
exclusively in HIV-2 and some simian immunodeficiency
viruses (SIV). Interestingly, Vpx can even enhance HIV-
1 infection in dendritic cells (DCs) and macrophages, and
it is, moreover, able to promote the accumulation of fulllength viral DNA.8-12
In addition to the innate and adaptive immune systems,
humans and other mammal hosts have also developed the
intrinsic immunity or host restriction factors during the
long history of combating pathogenic microbes. Intrinsic
immunity refers to a series of cellular-based antiviral
defense machineries, including those genetically encoded
proteins specifically targeting eukaryotic retroviruses.
The intrinsic immune proteins, such as host restriction
factors, can be expressed at a constant level to halt
viral infection promptly. Thus far, four major classes of
retroviral restriction factors have been identified, including
the apolipoprotein B mRNA-editing enzyme, catalytic
polypeptide-like 3G (APOBEC3G), the first host gene
identified as an inhibitor of HIV-1 infection;13,14 tripartite
motif 5-α (TRIM5α);15 tetherin, also known as BST-2,
DOI: 10.3760/cma.j.issn.0366-6999.20122551
Key Laboratory of Medical Molecular Virology of Ministries of
Education and Health, Shanghai Medical College and Institute of
Medical Microbiology, Fudan University, Shanghai 200032, China
(Lu L, Xu W and Jiang SB)
Lindsley F. Kimball Research Institute, New York Blood Center, New
York, NY 10065, USA (Yu F, Du LY and Jiang SB)
School of Pharmaceutical Sciences, Southern Medical University,
Guangzhou 510515, China (Yu F)
Correspondence to: Dr. JIANG Shi-bo, Key Laboratory of Medical
Molecular Virology of Ministries of Education and Health, Shanghai
Medical College and Institute of Medical Microbiology, Fudan
University, Shanghai 200032, China (Email: [email protected])
Chinese Medical Journal 2013;126 (12)
CD317, or HM1.24;16,17 and SAM-domain HD-domain
containing protein 1 (SAMHD1).18,19
At the same time, HIV has also developed tactics to
antagonize these antiviral host restriction factors through
its accessory proteins, including, for example, the HIV Vif
and Vpu proteins as the antagonists of APOBEC3G and
tetherin, respectively.16
In this review, we summarize and discuss the advancements
made in the study of the host immune system and the
mechanisms used by HIV to evade it.
HIV ESCAPES FROM THE INNATE IMMUNE
SYSTEM
Innate immunity is a first-line defense against HIV infection
and contributes to the control of early viral pathogenesis.
Natural killer (NK) cells and complement immunity are
vital components of the innate immune system, and they
provide very different methods to defend against HIV
infection. NK cells respond to HIV infection by cytolytic
and noncytolytic mechanisms. Although HIV-infected
target cells lack expression of major histocompatibility
complex (MHC) molecules, activated NK cells can lyse
them by perforin and granzymes. It is notable that NK cells
also secrete several chemokines, such as CC-chemokine
ligand3 (CCL3), CCL4 and CCL5, or cytokines, such as
interferon-γ, to antagonize HIV infection via noncytolytic
control. As a part of innate immunity, the complement
system promotes the ability of antibodies and phagocytes to
clear pathogens from an organism. However, its activation
is multifaceted, involving a number of blood-borne small
proteins.
NATURAL KILLER (NK) CELLS
NK cells play an important role in controlling HIV1 infections through different mechanisms. It has been
reported that a slow progression of AIDS is associated with
the combined expression of the killer immunoglobulinlike receptor (KIR) 3DS1, which is an activating natural
killer (NK) cell receptor, and human leukocyte antigen
(HLA)-B Bw4-80I, as its presumed ligand. Notably, the
KIR3DS1-expressing NK cells exhibited strong inhibition
of HIV-1 replication in target cells that express HLA-B
Bw4-80I, indicating that variation at the KIR locus
affects the effectiveness of NK cell activity against HIV-1
infection.20 Most recently, Alter et al20 reported the presence
of KIR-associated amino acid polymorphisms in HIV-1
sequences isolated from chronically infected individuals
and demonstrated their ability to enhance the binding of
inhibitory KIRs to HIV-1-infected CD4+ T cells, resulting
in a reduction of antiviral activity in KIR-positive NK
cells. These findings suggest that HIV-1 can evade NK cell
recognition by selecting sequence polymorphisms within
regions targeted by KIRs.
2375
Viruses use multiple strategies to evade the response of NK
cells, and HIV is no exception. To implement its evasive
strategy, HIV uses negative factor (Nef) protein to downregulate the expression of MHC and non-MHC ligands for
NKRs, resulting in the reduction of the NK cell-mediated
anti-HIV activity.21 Furthermore, HIV can modulate NK
cell differentiation and maturation, promote apoptosis of
NK cells, as well as dysregulate the expression of NKRs
and the production of NK cell-activating cytokines.
COMPLEMENTS
As suggested above, activation of the complement system,
which is a component of innate/adaptive immunity, with
a powerful capacity to lyse pathogens, including HIV,
can basically be divided into four pathways: the classical
pathway, the mannose-binding lectin (MBL) pathway, the
alternative pathway and the membrane lytic pathway. The
binding of antigen to antibody can trigger the complement
system via the classical pathway, while cleavage of C3 and
C5 proteins is an alternative pathway for activation. The
end result of activation by both the classical and alternative
pathways is the formation of the membrane-attack complex
(MAC), which forms transmembrane channels, resulting
in the lysis of virions or virus-infected cells. Extensive
evidence demonstrates that the complement system deploys
antibody- mediated, complement-dependent lysis against
challenge by HIV. However, such deployment in the
defense against HIV infection is a sword with two edges.
On the one hand, complement can promote the removal
of HIV virus and neutralization of HIV-1 particles. On the
other hand, it can enhance HIV infectivity by mediating the
attachment of virus to specific cells, such as macrophages
or dendritic cells, which express complement receptor CR3
and CR4, in turn resulting in expanding the source of HIVinfected cells and facilitating the spread of the virus. Thus,
as a strategy to evade complement-mediated destruction,
HIV can, in fact, enhance its coverage by complement
receptor, further incorporating complement receptors CD55,
CD59 and CD46 into its membrane to resist complementmediated lysis.22
HIV ESCAPES FROM THE ADAPTIVE IMMUNE
SYSTEMS
Neutralizing antibodies
HIV infection elicits multiple antibodies. Some of them are
broadly neutralizing antibodies which have the potential
to protect against AIDS virus infection. Although the
underlying mechanism remains unclear, the humoral
immune response is still responsible for controlling HIV
infection. Accordingly, binding with neutralizing antibodies
may interrupt the interaction between HIV and receptors on
the susceptible cell surface, permitting the engagement of
Fc receptor-mediated phagocytosis. Thus far, a number of
broadly neutralizing monoclonal antibodies (mAbs) have
2376
been identified. For instance, b12 and VRC01 bind to the
CD4-binding site on gp120, and 2G12 binds to the glycan
configuration on the outer domain of gp120.23 2F5, Z13e1,
4E10 and 10E824 bind at the membrane-proximal external
region (MPER) on gp41, which is a very conserved site in
gp41, while PG9 and PGT128 bind to the V3 regions of
gp120.
Two strategies are commonly used by HIV to evade
neutralizing antibodies.25 One is rapid mutation. Because
it takes time to produce antibodies against HIV, rapid
mutation makes it impossible for the immune system
to immediately produce a corresponding antibody, thus
enabling HIV to successfully evade antibody response.
Second, the viral envelope (Env) is heavily glycosylated. In
fact, almost 50% of the mass of gp120, the surface moiety
of the HIV-1 Env, is carbohydrate. This modification
results in masking critical epitopes.26 Moreover, numbers of
neutralizing antibodies target the regions of the Env that are
only transiently exposed at the time of viral entry, just when
the glycoprotein is ready to mediate the fusion between
viral and cellular membranes.27-30 Thus, once again, HIV
has configured a tactic that successfully evades risk to its
replication.
Cytotoxic T lymphocytes (CTLs)
CTLs play a critical role in the host’s anti-HIV immune
response. CTLs interact with the MHCI molecules
present on the surface of infected cells. CTLs depend on
the granule-independent pathway involving Fas/FasL
interaction and the perforin pathway to kill the infected
cells. Again, however, viral mutation is the major HIV
evasive stratagem. By its tolerance for sequence variability
and lack of fidelity of viral reverse transcriptase, the HIV
antigenic repertoire can form polymorphisms, particularly
in the viral Env. On average, each time the 10 kb HIV
genome is replicated and one nucleotide substitution
is introduced,31 the potential for variation is enormous,
particularly when millions of viruses are produced each
day, and viral generation time is short.32,33 Similarly, as
observed in an SIV-infected monkey, progressive variation
in dominant epitopes of the Env and Nef viral proteins
resulted in successful evasion of CTL-specific recognition.34
Furthermore, CTL killing efficiency has been significantly
decreased by the mutation of these viral epitopes.35 During
the process of infection, the immunoselection of escape
variants lead to an increased fitness for replication in the
infected animal.36 Another study also demonstrated that
CTL escape variants occur in HIV-infected individuals.37
HIV can also avoid CTL attack by latency whereby HIV
can hide in at least two sites: glial cells in the central
nervous system and resting T lymphocytes. In the latter
case, the latent reservoir may be generated through
activated T cells, with integration of viral DNA into the
host genome. During this time, viral gene expression can
Chin Med J 2013;126 (12)
be limited by anti-retroviral drugs or immune response
because latent infection allows the virus to survive freely.
Evidence for this model comes from the studies of viral
persistence in patients on highly active anti-retroviral
therapy (HAART) who exhibit exceedingly low levels
of viremia or have undetectable free virus.38 However,
along with the stimulation of T cell receptors (TCR),
viruses can be easily recovered from their peripheral blood
mononuclear cells (PBMCs).39 A similar examination of
nonstimulated PBMCs was conducted among HAART
patients, and it revealed the presence of episomal HIV1 DNA intermediates, a strong indicator of ongoing viral
replication.40,41
HIV EVADES AGAINST INTRINSIC IMMUNE
SYSTEM
Starting from the early 2000s, more and more evidence has
demonstrated that HIV-1 infection can be affected by host
restriction factors and that some viral accessory proteins
function as their antagonists. For example, APOBEC3G
was identified as the first host restriction factor that potently
inhibits HIV-1 infection, but its antiviral activity was found
to be suppressed by the Vif protein. 14 Subsequently, a
variety of anti-HIV restriction factors and their antagonists
have been discovered.42-44
APOBEC3G
APOBEC3G (apolipoprotein B mRNA-editing enzyme,
catalytic polypeptide-like 3G) is the first host restriction
factor against HIV discovered by Sheehy et al in 2002.
They found that APOBEC3G could inhibit HIV DNA
synthesis in the absence of Vif.45 As a cytidine deaminase,
APOBEC3G suppresses HIV transcription by substituting
G to A in the HIV genome. Upon contact with the GG
dinucleotides, APOBEC3G changes TGG (coding for
Trp) to TAA (stop codon), stopping the translation of the
viral protein. However, HIV can recruit Vif to induce
the ubiquitin-dependent degradation of APOBEC3G
by linking a cullin 5-based E3 ubiquitin ligase complex
to APOBEC3G proteins, resulting in the degradation
of APOBEC3G in proteasomes and preventing the
encapsidation of APOBEC3G into viral particles. In
addition, the virus makes use of the special characteristic
of APOBEC3G to promote mutations when APOBEC3Gmediated mutations are at a low level.
TRIM5α
TRIM5α (tripartite motif 5-α) is an important determinant
of resistance first found in monkey cells. 46 TRIM5a
controls viral replication by binding to viral capsids in the
cytoplasm and interrupting their coating procedure, which
is important because capsid uncoating time is critical for
retroviruses. Hence, if the process is delayed or blocked, the
preintegrated complex will not enter the nucleus of target
cells, and if the process is accelerated, the virus capsid
Chinese Medical Journal 2013;126 (12)
protein will be degraded, and the reverse transcription
process will be terminated. However, HIV can escape from
attack by TRIM5α by mutating the sequence of the viral
capsid protein so that the viral capsid cannot be bound by
TRIM5α.47
Tetherin
Tetherin, also named BST-2 (bone marrow stromal antigen
2), CD317, or HM1.24, is the newest host restriction factor
identified by Neil and Bieniasz.48 In the absence of HIV1 viral protein U (Vpu), tetherin is a host cellular protein
which inhibits HIV infection by preventing the virus from
releasing mature virions to the cell surface.49 While tetherin
is not expressed in primary CD4+ T cells, it can be highly
induced by type I interferons.50 However, Vpu plays an
important role as an antagonist to tetherin. Vpu is a 16
kDa protein which is produced together with Env. Vpu
functions to recruit ubiquitin ligase complex to mediate
polyubiquitinylation and proteasomal degradation and
help release mature viral particles.51 While we also now
know that Vpu helps to keep tetherin away from the virion
budding sites, the exact mechanism of antagonism still
needs further study. In addition, recent study showed that
HIV replication is hypersensitive to IFN-α if Vpu is absent,
and effective replication is dependent on Vpu for both in
vivo- and ex vivo-infected human lymphoid tissues.52
SAMHD1
HIV-1 and the related primate lentiviruses HIV-2 and SIV
infect cells that express CD4 and an appropriate chemokine
receptor, CCR5 or CXCR4. However, the magnitude of
infection with HIV-1 is cell type-specific. The activated
human CD4+ T cells are much more susceptible to infection
with HIV-1 than human myeloid-lineage cells, such as
macrophages and dendritic cells (DCs).53 However, DCs
have a unique capacity to take up intact viral particles and
hand them off to susceptible T cells, thus enhancing T cell
infection in trans. This phenomenon of trans enhancement
highlights the ability of HIV-1 to potentially exploit the
cellular trafficking machinery of DCs, while, at the same
time, avoiding activation of the innate immune recognition
pathways in these cells.54 Recent studies have demonstrated
that a myeloid cell-specific dominant restriction factor, the
SAM-domain HD-domain containing protein 1 (SAMHD1),
is able to limit the extent of reverse transcription following
viral entry. The restriction also limited infection with HIV2 and SIVmac as long as these viruses were defective for
the accessory protein viral protein X (Vpx), which is not
encoded by HIV-1. The Vpx proteins from HIV-2 and SIV
render human myeloid-lineage cells permissive to HIV-1
infection through proteasomal degradation of SAMHD1.55,56
Delivery of Vpx by virus-like particles (VLPs) resulted in
the reversal of HIV-1 infection of DCs. In addition, Vpx
could also reverse the inhibition of HIV-1 infection in
macrophages, as mediated by SAMHD1. The inhibition
of HIV-1 infection in macrophages could be overcome by
2377
coinfection with Vpx containing SIVsm VLP.57
Hrecka et al 58 used a Flag HA-tagged Vpx protein as
bait to pull down potential binding proteins for Vpx.
Using a combination of tandem affinity purification and
electrophoresis followed by mass spectrometry, they have
found that SAMHD1 is the major interacting protein.
They then showed that SAMHD1 is highly expressed
in HIV-1 nonpermissive cells, whereas it is absent in a
range of HIV-1-sensitive cell lines, such as Jurkat and
SupT1. They further proved the mechanism by which
Vpx induces SAMHD1 degradation, namely that Vpx
causes relocalization of SAMHD1 to the cytoplasm prior
to routing toward the proteasomal machinery. Using
overexpression and RNAi approaches, Laguette et al59
showed that SAMHD1 is required in differentiated THP-1
cells, macrophages, and monocyte-derived dendritic cells
for restriction of HIV-1 infection. The restriction does not
occur in SAMHD1-expressing THP-1 cells when they are
cycling; instead, it requires differentiation-induced cellcycle arrest. This observation suggests that the restriction
may apply to a broader category of noncycling cells, such
as resting CD4+ T lymphocytes.
Like human myeloid-lineage cells, resting CD4+ T cells are
also refractory to HIV-1 infection, while activated CD4+
T cells are permissive to HIV-1 infection. Most recently,
two groups compared the dNTP levels in the resting
and activated CD4 + T cells and found that the resting
CD4+ T cells exhibit much lower levels of dNTPs than
the activated CD4+ T cells. However, in the presence of
dNTPase SAMHD1, which has been identified as a HIV-1
restriction factor to limit HIV-1 reverse transcription, HIV1 replication in the resting CD4+ T cells is significantly
suppressed, suggesting that SAMHD1 acts as a HIV-1
restriction factor against HIV-1 in noncycling cells.60,61
CONCLUSIONS
HIV has evolved a diverse array of strategies to evade host
immune responses, including those presented by the innate,
adaptive, and intrinsic immune systems. NK cells, as the
main component of the innate system, play an important
role in combating HIV infection through cytolytic and
noncytolytic mechanisms. However, HIV-1 employs
different strategies to antagonize NK-mediated anti-HIV-1
activity, including selecting sequence polymorphisms
within regions targeted by KIRs, using its Nef protein
to down-regulate the expression of NKR ligands, or
modulating NK cell differentiation and maturation.
Complement is another component of innate immunity
against HIV by mediating viral lysis. However, HIV can
also use complement to attach to macrophages or dendritic
cells that express complement receptors, thus enhancing
HIV infection.
The humoral and cellular immune systems are the main
Chin Med J 2013;126 (12)
2378
components of the acquired/adaptive immune systems.
After infection, HIV can induce neutralizing antibody and
CTL responses against the invading virus. However, the
virus can quickly change its Env glycoprotein’s sequences
to prevent recognition by neutralizing antibodies and
CTLs. In addition, HIV can use its glycan shield to protect
itself from antibody attack. HIV can also hide in the latent
reservoir so that CTLs are unable to kill it.
The recent discovery of a series of anti-HIV restriction
factors, such as APOBEC3G, TRIM5α, tetherin, and
SAMHD1, gives some hope of developing these proteins as
therapeutics for treatment of HIV infection. However, it has
been quickly demonstrated that HIV has, again, evolved
a variety of strategies to fight against intrinsic immunity,
most notably by using some viral accessory proteins,
such as Vif, Vpu, Nef, or Vpx, as antagonists of the above
restriction factors.
Understanding the mechanisms of HIV immune evasion
will allow us to develop novel strategies to prevent and
cure HIV/AIDS. For example, we may design and develop
artificial restriction factors with broader antiviral activity
and higher resistance to the viral antagonists. These
artificial host restriction factors may also be effective
against viral pathogens.
REFERENCES
1. Steffen I, Pohlmann S. Peptide-based inhibitors of the hiv
envelope protein and other class I viral fusion proteins. Curr
Pharm Des 2010; 16: 1143-1158.
2. Iaccino E, Schiavone M, Fiume G, Quinto I, Scala G. The aftermath
of the Merck’s HIV vaccine trial. Retrovirology 2008; 5: 56.
3. Kim JH, Rerks-Ngarm S, Excler JL, Michael NL. HIV vaccines:
lessons learned and the way forward. Curr Opin HIV AIDS
2010; 5: 428-434.
4. Wilson NA, Watkins DI. Is an HIV vaccine possible? Braz J
Infect Dis 2009; 13: 304-310.
5. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J,
Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX
to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361:
2209-2220.
6. Malim MH, Emerman M. HIV-1 Accessory proteins, ensuring
viral survival in a hostile environment. Cell Host Microbe 2008;
3: 388-398.
7. Gramberg T, Sunseri N, Landau NR. Accessories to the crime:
recent advances in HIV accessory protein biology. Curr HIV /
AIDS Rep 2009; 6: 36-42.
8. Gramberg T, Sunseri N, Landau NR. Accessories to the crime:
recent advances in HIV accessory protein biology. Curr HIV /
AIDS Rep 2009; 6: 36-42.
9. Wolfrum N, Muhlebach MD, Schule S, Kaiser JK, Kloke
BP, Cichutek K, et al. Impact of viral accessory proteins of
sivsmmpbj on early steps of infection of quiescent cells.
Virology 2007; 364: 330-341.
10. Goujon C, Arfi V, Pertel T, Luban J, Lienard J, Rigal D, Et al.
Characterization of simian immunodeficiency virus sivsm/
human immunodeficiency virus type 2 Vpx function in human
myeloid cells. J Virol 2008; 82: 12335-12345.
11. Ayinde D, Maudet C, Transy C, Margottin-Goguet F. Limelight
on two HIV/SIV accessory proteins in macrophage infection: is
Vpx overshadowing Vpr? Retrovirology 2010; 7: 35.
12. Sharova N, Wu Y, Zhu X, Stranska R, Kaushik R, Sharkey M, et
al. Primate lentiviral Vpx commandeers DDB1 to counteract a
macrophage restriction. Plos Pathog 2008; 4: E1000057.
13. Sheehy AM, Gaddis NC, Malim MH. The antiretroviral enzyme
APOBEC3G is degraded by the proteasome in response to HIV1 Vif. Nat Med 2003; 9: 1404-1407.
14. Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a
human gene that inhibits HIV-1 infection and is suppressed by
the viral Vif protein. Nature 2002; 418: 646-650.
15. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier
P, Sodroski J. The cytoplasmic body component TRIM5alpha
restricts HIV-1 infection in old world monkeys. Nature 2004;
427: 848-853.
16. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release
and is antagonized by HIV-1 Vpu. Nature 2008; 451: 425-430.
17. Van DN, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson
MC, et al. The interferon-induced protein BST-2 restricts HIV1 release and is downregulated from the cell surface by the viral
Vpu protein. Cell Host Microbe 2008; 3: 245-252.
18. Hrecka K, Hao C, Gierszewska M, Swanson SK, KesikBrodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV1 infection of macrophages mediated by the SAMHD1 protein.
Nature 2011; 474: 658-661.
19. Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia
C, Segeral E, Et Al. SAMHD1 is the dendritic- and myeloid-cellspecific HIV-1 restriction factor counteracted by Vpx. Nature
2011; 474: 654-657.
20. Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ,
Schneidewind A, et al. Differential natural killer cell-mediated
inhibition of HIV-1 replication based on distinct KIR/HLA
subtypes. J Exp Med 2007; 204: 3027-3036.
21. Iannello A, Debbeche O, Samarani S, Ahmad A. Antiviral NK
cell responses in HIV infection: II. viral strategies for evasion
and lessons for immunotherapy and vaccination. J Leukoc Biol
2008; 84: 27-49.
22. Favoreel HW, Van De Walle GR, Nauwynck HJ, Pensaert MB.
Virus complement evasion strategies. J Gen Virol 2003; 84: 1-15.
23. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, et al.
Structural basis for broad and potent neutralization of HIV-1 by
antibody VRC01. Science 2010; 329: 811-817.
24. Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, Longo
NS, et al. Broad and potent neutralization of HIV-1 by a Gp41specific human antibody. Nature 2012; 491: 406-412.
25. Burton DR, Poignard P, Stanfield RL, Wilson IA. Broadly
neutralizing antibodies present new prospects to counter highly
antigenically diverse viruses. Science 2012; 337: 183-186.
26. Reitter JN, Means RE, Desrosiers RC. A role for carbohydrates
in immune evasion in AIDS. Nat Med 1998; 4: 679-684.
27. Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC.
Atomic structure of the ectodomain from HIV-1 Gp41. Nature
1997; 387: 426-430.
28. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J,
Hendrickson WA. Structure of an HIV Gp120 envelope
glycoprotein in complex with the CD4 receptor and a
neutralizing human antibody. Nature 1998; 393: 648-659.
Chinese Medical Journal 2013;126 (12)
29. Wyatt R, Kwong PD, Desjardins E, Sweet RW, Robinson J,
Hendrickson WA, et al. The antigenic structure of the HIV
Gp120 envelope glycoprotein. Nature 1998; 393: 705-711.
30. Sullivan N, Sun Y, Sattentau Q, Thali M, Wu D, Denisova
G, Et Al. CD4-induced conformational changes in the
human immunodeficiency virus type 1 Gp120 glycoprotein:
consequences for virus entry and neutralization. J Virol 1998;
72: 4694-4703.
31. Mansky LM, Temin HM. Lower in vivo mutation rate of human
immunodeficiency virus type 1 than that predicted from the
fidelity of purified reverse transcriptase. J Virol 1995; 69: 50875094.
32. Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch
P, et al. Viral dynamics in human immunodeficiency virus type 1
infection. Nature 1995; 373: 117-122.
33. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM,
Markowitz M. Rapid turnover of plasma virions and CD4
lymphocytes In HIV-1 infection. Nature 1995; 373:123-126.
34. Evans DT, O'Connor DH, Jing P, Dzuris JL, Sidney J, Da SJ, et
al. Virus-specific cytotoxic T-lymphocyte responses select for
amino-acid variation in simian immunodeficiency virus Env and
Nef. Nat Med 1999; 5: 1270-1276.
35. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA,
Lifton MA, et al. Control of viremia in simian immunodeficiency
virus infection by CD8+ lymphocytes. Science 1999; 283: 857-860.
36. Kimata JT, Kuller L, Anderson DB, Dailey P, Overbaugh J.
Emerging Cytopathic and antigenic simian immunodeficiency
virus variants influence AIDS Progression. Nat Med 1999;
5:535-541.
37. Borrow P, Lewicki H, Wei X, Horwitz MS, Peffer N, Meyers H,
Et Al. Antiviral pressure exerted by HIV-1-specific cytotoxic T
lymphocytes (Ctls) during primary infection demonstrated by
rapid selection of CTL escape virus. Nat Med 1997; 3: 205-211.
38. Piguet V, Trono D. Living in oblivion: HIV immune evasion.
Semin Immunol 2001; 13: 51-57.
39. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C,
Chaisson RE, et al. Identification of a reservoir for HIV-1 in
patients on highly active antiretroviral therapy. Science 1997;
278: 1295-1300.
40. Sharkey ME, Teo I, Greenough T, Sharova N, Luzuriaga K,
Sullivan JL, et al. Persistence of episomal HIV-1 infection
intermediates in patients on highly active anti-retroviral therapy.
Nat Med 2000; 6: 76-81.
41. Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F,
et al. The decay of the latent reservoir of replication-competent
HIV-1 is inversely correlated with the extent of residual viral
replication during prolonged anti-retroviral therapy. Nat Med
2000; 6: 82-85.
42. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier
P, Sodroski J. The cytoplasmic body component TRIM5alpha
restricts HIV-1 infection in old world monkeys. Nature 2004;
427: 848-853.
43. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release
and is antagonized by HIV-1 Vpu. Nature 2008; 451: 425-430.
44. Van DN, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson
MC, et al. The interferon-induced protein BST-2 restricts HIV1 release and is downregulated from the cell surface by the viral
Vpu protein. Cell Host Microbe 2008; 3: 245-252.
45. Sheehy AM, Gaddis NC, Malim MH. The antiretroviral enzyme
2379
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
APOBEC3G is degraded by the proteasome in response To HIV1 Vif. Nat Med 2003; 9: 1404-1407.
Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier
P, Sodroski J. The cytoplasmic body component TRIM5alpha
restricts HIV-1 infection in old world monkeys. Nature 2004;
427: 848-853.
Song B. TRIM5alpha. Curr Top Microbiol Immunol 2009; 339:
47-66.
Neil S, Bieniasz P. Human immunodeficiency virus, restriction
factors, and interferon. J Interferon Cytokine Res 2009; 29: 569580.
Van DN, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson
MC, et al. The interferon-induced protein BST-2 restricts HIV1 release and is downregulated from the cell surface by the viral
Vpu protein. Cell Host Microbe 2008; 3: 245-252.
Neil SJ, Sandrin V, Sundquist WI, Bieniasz PD. An interferonalpha-induced tethering mechanism inhibits HIV-1 and ebola
virus particle release but is counteracted by the HIV-1 Vpu
protein. Cell Host Microbe 2007; 2: 193-203.
Strebel K, Klimkait T, Martin MA. A novel gene of HIV-1, Vpu,
and its 16-Kilodalton product. Science 1988; 241: 1221-1223.
Schindler M, Rajan D, Banning C, Wimmer P, Koppensteiner
H, Iwanski A, et al. Vpu Serine 52 dependent counteraction of
tetherin is required for HIV-1 replication in macrophages, but
not in ex vivo human lymphoid tissue. Retrovirology 2010; 7: 1.
Manel N, Littman DR. Hiding in plain sight: how HIV evades
innate immune responses. Cell 2011; 147: 271-274.
Izquierdo-Useros N, Naranjo-Gomez M, Erkizia I, Puertas
MC, Borras FE, Blanco J, et al. HIV and mature dendritic cells:
trojan exosomes riding the trojan horse? Plos Pathog 2010; 6:
E1000740.
Hrecka K, Hao C, Gierszewska M, Swanson SK, KesikBrodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV1 infection of macrophages mediated by the SAMHD1 protein.
Nature 2011; 474: 658-661.
Laguette N, Sobhian B, Casartelli N, Ringeard M, ChableBessia C, Segeral E, et al. SAMHD1 is the dendritic- and
myeloid-cell-specific HIV-1 restriction factor counteracted by
Vpx. Nature 2011; 474: 654-657.
Goujon C, Riviere L, Jarrosson-Wuilleme L, Bernaud J, Rigal D,
Darlix JL, et al. SIVSM/HIV-2 Vpx proteins promote retroviral
escape from a proteasome-dependent restriction pathway present
in human dendritic cells. Retrovirology 2007; 4: 2.
Hrecka K, Hao C, Gierszewska M, Swanson SK, KesikBrodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV1 infection of macrophages mediated by the SAMHD1 protein.
Nature 2011; 474: 658-661.
Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia
C, Segeral E, et al. SAMHD1 is the dendritic- and myeloid-cellspecific HIV-1 restriction factor counteracted by Vpx. Nature
2011; 474: 654-657.
Descours B, Cribier A, Chable-Bessia C, Ayinde D, Rice G,
Crow Y, et al. SAMHD1 restricts HIV-1 reverse transcription in
quiescent CD4+ T-cells. Retrovirology 2012; 9: 87.
Wu L. SAMHD1: a new contributor to HIV-1 restriction in
resting CD4+ T-Cells. Retrovirology 2012; 9: 88.
(Received December 15, 2012)
Edited by SUN Jing