The acute phase of HIV-1 infection is the most critical stage of this infection. Virus interactions with the immune system during acute HIV-1 infection (AHI) determine whether the transmitted virus is eliminated at mucosal sites or establishes expanding foci of infection and disseminates; the magnitude of the ensuing acute burst of viral replication and extent of associated damage to the immune system; and the efficiency of control of virus replication and establishment of set-point levels of viremia and immune activation, independent predictors of subsequent disease progression. Adaptive responses start to be induced during the acute viremic burst [1,2] and contribute to containment of HIV-1 replication and establishment of the persisting virus load , but there is no evidence that they constrain HIV-1 replication during the initial stages of infection . By contrast, innate responses are activated very rapidly after virus exposure, and increasing evidence indicates that interactions between HIV-1 and the innate immune system are key determinants of events from the earliest stages of AHI onwards (Fig. 1). This review covers recent advances in understanding of the activation of innate responses during AHI, roles played by innate responses in control of HIV-1 replication and viral strategies for subverting and exploiting innate defences.
HIV-1: innate interactions at mucosal infection sites during the initial stages of acute HIV-1 infection
HIV-1 infection is generally acquired by sexual mucosal transmission. Studies in macaques infected intravaginally with simian immunodeficiency virus (SIV) show that virus replication is initially confined to the mucosal infection site. Small foci of infection are established locally, some of which expand and disseminate virus to the draining lymph node (DLN) and blood [5•]. The length of the eclipse period before widespread virus dissemination occurs ranges from 5–6 days to several weeks, with exposure to lower virus doses being associated with longer eclipse periods [6•,7•]. Mucosal HIV-1 transmission is inefficient: more than 100 exposures may be required before disseminated infection occurs, and infection is commonly initiated by a single founder virus . This finding suggests that HIV-1 struggles to establish infection at mucosal sites and may frequently be eliminated during the eclipse period. Two factors hamper HIV-1 replication at the mucosa: relatively few CD4+ target cells are present, and local host defences need to be evaded. HIV-1's ability to overcome these hurdles is critically dependent on interactions with the innate immune system.
HIV-1 exploits dendritic cells to overcome the problem of limited target availability at mucosal infection sites
HIV-1 replication at mucosal transmission sites predominantly occurs in CD4+ T cells [5•]. CD4+ T cells are sparsely distributed at noninflamed genital mucosae, so induction of an influx of additional target cells is crucial for virus propagation. In macaques infected intravaginally with SIV, epithelial cells are rapidly stimulated to produce macrophage inflammatory protein (MIP)3α (CCL20) which recruits plasmacytoid dendritic cells (pDCs) to the endocervix. The virus then triggers pDCs to produce factors including type 1 interferons (IFN-1) (discussed below) and the chemokines MIP1α and β (CCL3 and CCL4) which recruit CD4+ T cells, amplifying the pool of locally available target cells  (although they may also contribute to control of the replication of CCR5-utilizing viruses).
HIV-1 also exploits conventional dendritic cells (cDCs) in the subepithelium to help it cope with the low density of CD4+ T-cell targets. HIV-1 does not infect these dendritic cell-specific, intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)+ cDCs efficiently, but by binding to DC-SIGN achieves multiple goals: DC-SIGN-bound virions are sequestered and efficiently transferred to CD4+ T cells with which the dendritic cell interacts , a process facilitated by signalling via DC-SIGN ; signalling via DC-SIGN also promotes production of pro-inflammatory cytokines that stimulate virus replication ; and signalling via both DC-SIGN and Toll-like receptor (TLR)8 can enable HIV-1 to replicate productively within the dendritic cell itself [13•]. cDCs also express other HIV-1 capture/transfer receptors . The importance of dendritic cell-mediated HIV-1 transfer in virus spread during early AHI is suggested by the fact that stromal cell-derived factor-1 (SDF-1) (CXCL12) production by dendritic cells impairs transfer of CXCR4-utilizing viruses across the dendritic T-cell synapse, and CXCR4-utilizing viruses are rarely transmitted [15,16].
HIV-1 employs multiple strategies to evade control by type 1 interferons early after transmission
Although local immune activation and cellular infiltration facilitate virus replication, HIV-1 must simultaneously avoid being controlled by innate antiviral defences activated at the mucosa, particularly IFN-1.
IFN-1 is a pleiotropic cytokine that acts by upregulating transcription of hundreds of IFN-stimulated genes (ISGs), many of which have antiviral activity [17••]. The most intensively studied of the ISGs that restrict the replication of HIV-1 and related viruses are tripartite motif (TRIM)5α, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)3G and tetherin, the antiretroviral effects of which are emphasized by the fact that HIV-1 and related viruses have evolved strategies for counteracting them [18•]. The most recently discovered of these restriction factors was tetherin, a cell-surface protein that ‘tethers’ virions to virus-producing cells, preventing their release [19,20•,21•], and is also incorporated into virions, reducing their infectivity [22•]. Tetherin is antagonized by HIV-1 Vpu, which reduces tetherin levels on infected cells by targeting it for degradation and sequestering it in a perinuclear compartment [23•–25•]. Although tetherin restricts transfer of virions from an infected cell to neighbouring cells by cell-to-cell spread [26•,27•], increased tetherin expression on uninfected cells enhances their infection [27•,28•]. The IFN-induced increase in tetherin expression may, thus, benefit HIV-1 by enhancing cell-to-cell transmission.
Many other ISGs also inhibit HIV-1 replication, including protein kinase R, Mx, ISG15, TRIM22 and interferon-induced transmembrane proteins 1–3 [17••,29•–31•]. There are also additional as-yet-unidentified factors that restrict HIV-1 replication, for example IFNα induces a postentry block to HIV-1 replication in macrophages [32,33] and HIV-1 replication in monocyte-derived dendritic cells (MDDCs) is blocked by a restriction factor antagonized by SIV Vpx [34••]. The relative importance of these different antiviral pathways in constraining HIV-1 replication in vivo remains to be determined. Correlations have been reported between adjuvant/vaccine-induced APOBEC3G expression and virus replication following mucosal SIV challenge in macaques [35,36]; however although this situation suggests a role for ISGs in virus control, it is unclear whether the effects observed were mediated by APOBEC3G or other ISGs upregulated in parallel.
The importance of IFN-1 in HIV-1 control is underlined by the fact that HIV-1 employs multiple strategies to block IFN-1 production in infected cells. HIV-1 genomic RNA is recognized by the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I), but in HIV-1-infected cells the viral protease sequesters RIG-I and targets it to lysosomes to block IFN-I induction [37••]. Likewise, HIV-1 DNA would be recognized by an as-yet-unidentified nucleic acid sensor in infected cells, but this is prevented by the cytosolic nuclease 3′ repair exonuclease 1 (TREX1) which binds to and digests excess cytoplasmic HIV-1 DNA [38••]. In MDDCs, HIV-1 infection can also be sensed by a pathway involving interaction of newly synthesized capsids with cyclophilin A and subsequent IFN regulatory factor (IRF)3 activation [34••] that HIV-1 does not appear to evade, perhaps because it does not normally replicate efficiently in cDCs. HIV-1 also prevents IRF3-mediated triggering of IFN-1 production: in T cells and macrophages Vpr and Vif target IRF3 for degradation , although in MDDCs Vpr blocks IRF3 activation without inducing its degradation [40•].
Although HIV-1 avoids triggering IFN-1 production in infected cells, IFN-1 are nonetheless produced by pDCs at the mucosal transmission site and subsequently in lymph nodes [9,41–43]. HIV-1 is endocytosed by pDCs following binding to CD4 and chemokine coreceptors, and interaction of viral RNA with TLR7 in endosomes triggers IRF7 activation and IFN-1 induction . pDCs can also recognize HIV-1-infected cells by both endosomal (IRF7-dependent) and cytoplasmic (IRF3-dependent) pathways [45•]. Notably, HIV-1-stimulated pDCs can be repeatedly triggered to produce IFN-1, which is associated with virion trafficking to early endosomes and induction of a partially matured, persistently IFN-1-secreting phenotype [46••]. That HIV-1 activates potent secretion of IFN-1 and other cytokines/chemokines by pDCs but suppresses IFN-1 production by infected cells likely reflects a balance between its need to drive inflammation and attract CD4+ cells to enhance replication, while simultaneously minimizing local upregulation of antiviral ISGs. Table 1 summarizes HIV-1: host pattern recognition receptor interactions that are subverted/exploited during AHI.
Activation and subversion of systemic innate responses during the viral expansion phase of acute HIV-1 infection
After amplification at the transmission site, HIV-1 spreads to the DLN and rapidly undergoes systemic dissemination [5•]. An exponential increase in viral replication ensues, associated with extensive depletion of CD4+ T cells, particularly from the gut-associated lymphoid tissues (GALT). During this phase of AHI there is widespread activation of innate responses.
Systemic activation of innate responses during the viral expansion phase
The earliest systemic perturbations in innate factors detected in AHI are elevations in acute-phase proteins (APPs) including the acute form of serum amyloid A (A-SAA), plasma concentrations of which increase transiently during the eclipse phase and then increase again during the acute viremic phase [47••]. The second increase in APP levels is coincident with systemic elevations in pro-inflammatory cytokines including interleukin (IL)-1β and IL-6 , which are known to trigger APP production by the liver. No perturbations are detected in plasma cytokines during the eclipse phase, but the initial burst of APP production may reflect viral dissemination to the GALT and local production of pro-inflammatory cytokines that reach the liver via the portal venous system. APPs including A-SAA and α1-antitrypsin plus proteolytic fragments of the latter inhibit HIV-1 replication in vitro[47••] and, hence, may mediate direct antiviral activity during AHI; and A-SAA and other APPs have immunomodulatory effects [48,49], so they may also help to control HIV-1 replication indirectly.
The increase in viremia during AHI is associated with widespread activation of dendritic cells, coupled with elevations in circulating levels of innate cytokines/chemokines including IFN-1, IL-15, IL-18, tumour necrosis factor-α (TNFα) and IFNγ-induced protein 10 (CXCL10) . Circulating frequencies of pDCs and cDCs are dramatically reduced prior to the peak in viremia [50•]; and although they recover somewhat as viremia is contained, they remain reduced throughout infection. The decline in circulating dendritic cell frequencies during AHI likely reflects a combination of activation-associated recruitment into lymph nodes and apoptotic death. In SIV and HIV-1 infections pDCs accumulate in lymph nodes where they produce IFNα and undergo apoptosis [42,51–53] and high levels of cDC apoptosis are also observed [54,55•]. The dendritic cells that remain in the blood during AHI retain functional capacity and are in a heightened activation state wherein they exhibit hyper-responsiveness to stimulation with TLR7/8 ligands [50•].
Natural killer (NK) cells also become highly activated during the viral expansion phase and increase in frequency in the circulation . NK cell activation is stimulated by innate cytokines including IFN-1, IL-15 and IL-18 and is also regulated by receptor-ligand interactions. There is a specific increase in the frequency of NK cells expressing killer immunoglobulin receptor (KIR)3DS1 and 3DL1 in individuals expressing human leukocyte antigen (HLA)-Bw4 alleles with an isoleucine residue at position 80 (HLA-Bw480I), the putative HLA class I ligand for KIR3DL1/3DS1  which suggests an important role for KIR-HLA interactions in regulating NK cell expansion and/or survival during AHI.
The dramatic systemic activation of innate responses in AHI (Fig. 2) contrasts with the much more muted immune activation during acute infection with hepatitis B and C viruses , which adopt a ‘stealth’ approach to minimize control by innate defences. Triggering of widespread immune activation favours HIV-1 replication and spread, but HIV-1 then has to avoid innate control and impede the induction of adaptive responses by innate responses.
Natural killer cell-mediated control of HIV-1 replication and viral strategies for its evasion
NK cells combat HIV-1 replication by killing infected cells and producing antiviral factors including IFNγ, TNFα and β-chemokines. Triggering of NK effector functions following contact with HIV-1-infected cells involves a reduction in signalling through inhibitory receptors including KIRs that interact with HLA-A/B molecules (surface expression of which is downmodulated to reduce CD8+ T-cell recognition ), together with enhanced stimulation through activating/costimulatory/adhesion receptors including activating KIRs , NKG2D, NTB-A (CD352) and 2B4 (CD244)  (Table 2). No specific ligands for activating KIRs on HIV-1-infected cells have been identified yet, but they are hypothesized to recognize HLA molecules presenting viral or host stress protein-derived peptides, with the interaction perhaps being dependent on a viral/host protein co-expressed on the cell surface (analogous to Ly49P-mediated recognition of murine cytomegalovirus-infected cells ). NKG2D interacts with unique-long 16 binding proteins (ULBPs)-1, ULBP-2 and ULBP-3, expression of which is upregulated on infected cells by HIV-1 Vpr via a mechanism dependent on activation of the DNA damage/stress-sensing ataxia telangiectasia and rad-3-related kinase [62•,63•]. Interaction of HIV-1 gp41 with a binding protein for the globular head domains of complement component C1q (gC1qR) on CD4+ T cells has also been shown to induce expression of a ligand for the activating NK receptor NKp44 , NK activation via which may contribute to immunopathogenic destruction of uninfected CD4+ T cells . NK cells can also be targeted to combat HIV-1-infected cells via antibody-dependent cell-mediated cytotoxicity (ADCC), but although some of the first antibodies produced in AHI are thought to stimulate ADCC  this mechanism cannot operate prior to seroconversion.
The importance of NK cells in HIV-1 infection is suggested by genetic associations between co-expression of KIR3DS1 or KIR3DL1 alleles encoding highly expressed KIR3DL1 proteins and HLA-Bw480I, and slow HIV-1 disease progression [67,68] (although similar associations are not observed in HIV-2 infection) . KIR3DS1/HLA-Bw480I is associated with establishment of a low persisting viral load, indicating that it exerts protective effects during AHI . KIRs are expressed by both NK cells and some CD8+ T cells, but the beneficial effects of the KIR/HLA compound genotypes likely involve effects on NK responses, as KIR3DS1+ NK cells mediate highly potent control of HIV-1 replication in HLA-Bw480I+ target cells  and KIR3DL1+ NK cells from individuals with protective KIR/HLA compound genotypes exhibit enhanced functional potential in vitro[71•]. KIR3DS1 expression is also associated with enhanced NK cell functionality in AHI .
Further evidence that NK cells exert pressure on HIV-1 replication in vivo is that HIV-1 has evolved multiple strategies for evading NK control (Table 2). Although surface expression of HLA-A/B molecules is reduced on HIV-1-infected cells, expression of HLA-C and HLA-E, which have a greater relative role in inhibiting NK activation, is retained . Nef also downregulates expression of the gp41-induced NKp44 ligand on HIV-1-infected cells ; likewise, CD48 and NTB-A, ligands for 2B4 and NTB-A, are downmodulated , the latter by Vpu [73••]. Selection for mutations in HIV-1 that affect the interaction of peptide–HLA complexes with inhibitory KIRs has also been observed [74,75], although as these mutations also reduce CD8+ T-cell recognition, it is unclear whether their selection is driven solely by T cells or also confers evasion by modulating NK activity.
HIV-1 may also induce abnormalities in innate functions that influence interactions between innate subsets and the induction of adaptive responses
pDCs, NK cells and cDCs mutually enhance one-another's activation via cytokine production and cell contact-dependent interactions. This activation is impaired during chronic HIV-1 infection [76,77], but during AHI may conversely be enhanced [46••,50•], furthering immune activation and viral replication. NK cells also mediate dendritic cell editing, lysing immature cDCs in lymph nodes to ensure that T cells interact with mature dendritic cells capable of mediating effective priming. Again, this is disrupted during chronic HIV-1 infection, perhaps because NK functions are progressively impaired  and/or due to production of IL-10, which makes immature dendritic cells resistant to NK lysis while increasing the sensitivity of mature dendritic cells to NKG2D-dependent NK elimination [79•]. HIV-1-infected dendritic cells are, however, rendered resistant to NK cell-mediated editing by a process that involves high-mobility group box 1 (HMGB1)-induced upregulation of antiapoptotic molecules [80•]. This situation prolongs HIV-1 persistence within dendritic cells. cDCs with a partly matured phenotype accumulate in lymph nodes during AHI , although whether this is due to alterations in NK-mediated editing or effects of HIV-1 itself on dendritic cell maturation is unknown.
HIV-1 infection of cDCs does not induce their maturation and impairs their ability to prime CD4+ and CD8+ T-cell responses in vitro. Mechanisms involved may include interaction of virions with DC-SIGN, which triggers signalling that impairs subsequent dendritic cell maturation  and/or interaction of Env with other receptor(s) leading to activation of the mammalian target of rapamycin pathway and shutdown of autophagy, which downregulates TLR responsiveness and impairs antigen presentation [83••]. HIV-1-exposed dendritic cells also promote T-cell exhaustion and stimulate induction of regulatory T-cell (Treg) responses [84•,85•]. In addition, HIV-1 activates pDCs to induce Tregs via an indoleamine 2,3-dioxygenase (IDO)-dependent mechanism, and these Tregs can in turn inhibit the maturation of cDCs . The extent to which these mechanisms impact on dendritic T-cell interactions in vivo remains unclear. IDO is upregulated during acute SIV infection ; and IDO production is associated with a decline in T helper 17 cells and increase in Treg cell activity in chronic HIV-1 infection, supporting a role for this pathway in disease progression . However, HIV-1-specific CD8+ T-cell responses with potent antiviral activity are elicited during AHI  and CD4+ T-cell responses are transiently expanded , suggesting that at least a proportion of dendritic cells retain functionality in vivo and/or that dendritic cell functions are not compromised rapidly enough to impair T-cell priming. Vpu has also been shown to interfere with CD1d expression on HIV-1-infected dendritic cells, which renders them poor stimulators of NKT cell activation in vitro[89•], although the in-vivo importance of this is again unclear. Notably, cDCs express increased levels of B lymphocyte stimulator (BLyS) from AHI onwards which, coupled with high expression of a proliferation-inducing ligand (APRIL), IL-6 and IL-10, may promote generalized B-cell activation and dysfunction and contribute to the delay in neutralizing antibody production in AHI [90••].
Roles of innate responses during the later stages of acute HIV-1 infection as viremia is contained
Systemic innate responses are maximally activated during the viral expansion phase: as viremia decreases and stabilizes later in AHI plasma cytokine/chemokine levels decline , circulating dendritic cell numbers begin to increase [50•] and peripheral blood NK frequencies normalize  (Fig. 2). However, although not as highly stimulated as during the acute viral burst, innate responses remain in a heightened state of activation.
Adaptive responses play a dominant role in containment of viremia during the later stages of AHI, but innate responses likely also contribute to control of virus replication. The major common genetic determinants of the persisting viral load established in early HIV-1 infection map to the major histocompatibility complex , polymorphisms which can influence innate as well as adaptive responses. For example, the beneficial effects of the KIR3DS1/HLA-Bw480I compound genotype likely reflect an important effector role for KIR3DS1+ NK cells in control of HIV-1 replication [59,67,70]; and, the detrimental effects of HLA-B35-Px alleles may be due to their ability to bind with high affinity to immunoglobulin-like transcript 4, an inhibitory receptor on dendritic cells, and promote dendritic cell dysfunction .
Importantly, maintenance of innate activation after control of viremia in AHI also has detrimental consequences, promoting viral replication and enhancing CD4+ T-cell loss. Ongoing stimulation of pDC production of IFN-1 and other cytokines may be particularly harmful, as IFN-1 promote the activation of innate and adaptive cells, have direct pro-apoptotic effects and also upregulate TNF-related apoptosis-inducing ligand (TRAIL) on CD4+ T cells and pDCs, indirectly furthering CD4+ cell apoptosis [93,94]. pDCs from women produce more IFN-1 following TLR7 ligation than pDCs from men, and women undergo faster HIV-1 disease progression than men with similar viral loads, supporting a detrimental role for pDC activation and IFN-1 production in chronic infection . Furthermore, although a strong IFN-1 response is activated during the acute phase of both pathogenic (e.g. HIV-1 infection of humans and SIV infection of rhesus macaques) and nonpathogenic (e.g. SIVsmm infection of sooty mangabeys and SIVagm infection of African green monkeys) immunodeficiency virus infections, IFN-1 production is downregulated following acute infection in the nonpathogenic infections, whereas high levels of ISG expression are sustained into chronic infection in the pathogenic infections [51,96–99]. Likewise, in HIV-2 infection, which is typically associated with slower CD4 decline and disease progression than HIV-1 infection, ISG expression levels during chronic infection are lower than those in HIV-1 infection . The mechanisms responsible for the differential regulation of immune activation in pathogenic and nonpathogenic primate immunodeficiency virus infections are unclear, but are of priority to understand.
Interactions between HIV-1 and the innate immune system determine critical events at all stages of AHI. Modulation of innate responses thus represents a promising approach for combating HIV-1 infection, although the complex combination of protective/pathogenic effects mediated by innate responses during AHI suggests that intervention strategies will need to act selectively. Definition of the ISGs that mediate the in-vivo antiviral activity of IFN-1 could enable their activity to be invoked to enhance HIV-1 control. Likewise, identification of receptor–ligand interactions involved in NK recognition of HIV-1-infected cells could enable the development of strategies for enhancing NK-mediated containment of viral replication. Conversely, dissection of the pathways via which HIV-1 stimulates pDC-mediated production of high levels of inflammatory mediators and understanding of mechanisms by which innate responses are downregulated following virus containment in nonpathogenic primate immunodeficiency virus infections may enable development of prophylactic or therapeutic strategies to combat HIV-1 infection via downmodulation of immunopathogenic innate activation. Finally, the impact of HIV-1-induced abnormalities in innate functions on the induction/maintenance of adaptive responses in acute/early infection is poorly understood, but counteraction of early innate dysfunction could also provide a means of enhancing HIV-1 control by adaptive responses.
The author's work is supported by funding from the National Institutes of Health, National Institute of Allergy and Infectious Disease, Division of AIDS, Center for HIV/AIDS Vaccine Immunology (CHAVI) (# U01 AI067854-06) and by the Grand Challenges in Global Health Program of the Bill and Melinda Gates Foundation (# 37874). The author is a Jenner Institute Investigator.
Conflicts of interest
There are no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 444–445).
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This article and reference [38••] describe mechanisms that prevent recognition of HIV-1 RNA and DNA by cytoplasmic nucleic acid sensors which enable HIV-1 to avoid triggering IFN-1 production in the cells it infects.
38••. Yan N, Regalado-Magdos AD, Stiggelbout B, et al. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol 2010; 11:1005–1013.
This article and reference [37••] describe mechanisms that prevent recognition of HIV-1 RNA and DNA by cytoplasmic nucleic acid sensors which enable HIV-1 to avoid triggering IFN-1 production in the cells it infects.
39. Doehle BP, Hladik F, McNevin JP, et al. Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells. J Virol 2009; 83:10395–10405.
40•. Harman AN, Lai J, Turville S, et al.
HIV infection of dendritic cells subverts the interferon induction pathway via IRF1 and inhibits type 1 interferon production. Blood 2011 May; [Epub ahead of print].
HIV-1 does not stimulate IFN-1 production when it replicates in cDCs, but this manuscript reports that IRF1 expression is upregulated, which induces a subset of ISGs and simultaneously enhances HIV-1 replication. It is also shown that Vpr blocks IRF3 activation in HIV-1-infected dendritic cells without inducing its degradation.
41. Abel K, Rocke DM, Chohan B, et al. Temporal and anatomic relationship between virus replication and cytokine gene expression after vaginal simian immunodeficiency virus infection. J Virol 2005; 79:12164–12172.
42. Malleret B, Maneglier B, Karlsson I, et al. Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression. Blood 2008; 112:4598–4608.
43. Stacey AR, Norris PJ, Qin L, et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 2009; 83:3719–3733.
44. Beignon AS, McKenna K, Skoberne M, et al. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 2005; 115:3265–3275.
45•. Lepelley A, Louis S, Sourisseau M, et al. Innate sensing of HIV-infected cells. PLoS Pathog 2011; 7:e1001284.
This article describes two mechanisms by which pDCs can be triggered to produce IFN-1 following contact with HIV-1-infected cells.
46••. O’Brien M, Manches O, Sabado RL, et al. Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-alpha-producing and partially matured phenotype. J Clin Invest 2011; 121:1088–1101.
This study addresses how HIV-1 stimulation of pDCs is able to elicit persistent IFN-1 production, and shows that this is due to accumulation of virions in early endosomes, which drives a partly matured, persistently IFN-1-secreting phenotype.
47••. Kramer HB, Lavender KJ, Qin L, et al. Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection. PLoS Pathog 2010; 6:e1000893.
In this study a proteomics-based approach was used to analyse unique plasma sample timecourses spanning the eclipse and viral expansion phases of AHI, and the earliest systemic perturbation in analyte levels was shown to be an increase in plasma APPs with antiviral activity that occurs prior to detection of viremia.
48. De Santo C, Arscott R, Booth S, et al. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nat Immunol 2010; 11:1039–1046.
49. Sander LE, Sackett SD, Dierssen U, et al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med 2010; 207:1453–1464.
50•. Sabado RL, O’Brien M, Subedi A, et al. Evidence of dysregulation of dendritic cells in primary HIV infection. Blood 2010; 116:3839–3852.
This study describes the frequency, phenotype and functions of the pDCs and cDCs in the blood during acute and early HIV-1 infection and makes the important observation that dendritic cells from AHI individuals exhibit hyper-responsiveness to stimulation with TLR ligands, which may participate in driving immunopathological immune activation.
51. Harris LD, Tabb B, Sodora DL, et al. Downregulation of robust acute type I interferon responses distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts from pathogenic SIV infection of rhesus macaques. J Virol 2010; 84:7886–7891.
52. Barratt-Boyes SM, Wijewardana V, Brown KN. In acute pathogenic SIV infection plasmacytoid dendritic cells are depleted from blood and lymph nodes despite mobilization. J Med Primatol 2010; 39:235–242.
53. Lehmann C, Lafferty M, Garzino-Demo A, et al. Plasmacytoid dendritic cells accumulate and secrete interferon alpha in lymph nodes of HIV-1 patients. PLoS One 2010; 5:e11110.
54. Dillon SM, Friedlander LJ, Rogers LM, et al. Blood myeloid dendritic cells from HIV-1-infected individuals display a proapoptotic profile characterized by decreased Bcl-2 levels and by caspase-3+ frequencies that are associated with levels of plasma viremia and T cell activation in an exploratory study. J Virol 2011; 85:397–409.
55•. Wijewardana V, Soloff AC, Liu X, et al. Early myeloid dendritic cell dysregulation is predictive of disease progression in simian immunodeficiency virus infection. PLoS Pathog 2010; 6:e1001235.
This article reports that during acute SIV infection activated cDCs are recruited from blood to lymph nodes, in which they undergo apoptosis; and shows that the reduction in blood cDC numbers during early infection is predictive of the subsequent rate of disease progression.
56. Alter G, Teigen N, Davis BT, et al. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood 2005; 106:3366–3369.
57. Alter G, Rihn S, Walter K, et al. HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection. J Virol 2009; 83:6798–6805.
58. Bonaparte MI, Barker E. Killing of human immunodeficiency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules. Blood 2004; 104:2087–2094.
59. Alter G, Martin MP, Teigen N, 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.
60. Ward J, Bonaparte M, Sacks J, et al. HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts. Blood 2007; 110:1207–1214.
61. Kielczewska A, Pyzik M, Sun T, et al. Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response. J Exp Med 2009; 206:515–523.
62•. Richard J, Sindhu S, Pham TN, et al. HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing. Blood 2010; 115:1354–1363.
This study and reference [63•] show that the HIV-1 Vpr protein activates a stress response in infected cells that leads to upregulation of expression of ligands for the activating NK cell receptor NKG2D and promotes NK lysis.
63•. Ward J, Davis Z, DeHart J, et al. HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. PLoS Pathog 2009; 5:e1000613.
This study and reference [62•] show that the HIV-1 Vpr protein activates a stress response in infected cells that leads to upregulation of expression of ligands for the activating NK cell receptor NKG2D and promotes NK lysis.
64. Fausther-Bovendo H, Vieillard V, Sagan S, et al. HIV gp41 engages gC1qR on CD4+ T cells to induce the expression of an NK ligand through the PIP3/H2O2 pathway. PLoS Pathog 2010; 6:e1000975.
65. Fausther-Bovendo H, Sol-Foulon N, Candotti D, et al. HIV escape from natural killer cytotoxicity: Nef inhibits NKp44L expression on CD4+ T cells. AIDS 2009; 23:1077–1087.
66. Forthal DN, Landucci G, Daar ES. Antibody from patients with acute human immunodeficiency virus (HIV) infection inhibits primary strains of HIV type 1 in the presence of natural-killer effector cells. J Virol 2001; 75:6953–6961.
67. Martin MP, Gao X, Lee JH, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002; 31:429–434.
68. Martin MP, Qi Y, Gao X, et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 2007; 39:733–740.
69. Yindom LM, Leligdowicz A, Martin MP, et al. Influence of HLA class I and HLA-KIR compound genotypes on HIV-2 infection and markers of disease progression in a Manjako community in West Africa. J Virol 2010; 84:8202–8208.
70. Qi Y, Martin MP, Gao X, et al. KIR/HLA pleiotropism: protection against both HIV and opportunistic infections. PLoS Pathog 2006; 2:e79.
71•. Boulet S, Song R, Kamya P, et al. HIV protective KIR3DL1 and HLA-B genotypes influence NK cell function following stimulation with HLA-devoid cells. J Immunol 2010; 184:2057–2064.
This manuscript reports that KIR3DL1+ NK cells from individuals with KIR3DL1/HLA compound genotypes associated with good prognosis in HIV-1 infection exhibit enhanced functional potential in vitro.
72. Long BR, Ndhlovu LC, Oksenberg JR, et al. Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infection. J Virol 2008; 82:4785–4792.
73••. Shah AH, Sowrirajan B, Davis ZB, et al. Degranulation of natural killer cells following interaction with HIV-1-infected cells is hindered by downmodulation of NTB-A by Vpu. Cell Host Microbe 2010; 8:397–409.
This study describes a novel mechanism by which Vpu increases the resistance of HIV-1-infected cells to NK lysis.
74. Brackenridge S, Evans EJ, Toebes M, et al.
An early HIV mutation within a HLA-B*57-restricted T cell epitope abrogates binding to the killer inhibitory receptor 3DL1 (KIR3DL1). J Virol 2011; 85:5415–5422.
75. Thananchai H, Makadzange T, Maenaka K, et al. Reciprocal recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope by CD8+ T cells and NK cells. AIDS 2009; 23:189–193.
76. Conry SJ, Milkovich KA, Yonkers NL, et al. Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function. J Virol 2009; 83:11175–11187.
77. Reitano KN, Kottilil S, Gille CM, et al. Defective plasmacytoid dendritic cell-NK cell cross-talk in HIV infection. AIDS Res Hum Retroviruses 2009; 25:1029–1037.
78. Mavilio D, Lombardo G, Kinter A, et al. Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection. J Exp Med 2006; 203:2339–2350.
79•. Alter G, Kavanagh D, Rihn S, et al. IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection. J Clin Invest 2010; 120:1905–1913.
This article describes a mechanism via which persistent upregulation of IL-10 production during HIV-1 infection may skew NK editing of dendritic cells and potentially impact on the induction/maintenance of HIV-1-specific T-cell responses.
80•. Melki MT, Saidi H, Dufour A, et al. Escape of HIV-1-infected dendritic cells from TRAIL-mediated NK cell cytotoxicity during NK-DC cross-talk--a pivotal role of HMGB1. PLoS Pathog 2010; 6:e1000862.
This study shows that antiapoptotic molecules are upregulated in HIV-1-infected dendritic cells via a HMGB1-dependent mechanism, rendering these cells resistant to TRAIL-mediated destruction by NK cells.
81. Lore K, Sonnerborg A, Brostrom C, et al. Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection. AIDS 2002; 16:683–692.
82. Granelli-Piperno A, Golebiowska A, Trumpfheller C, et al. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc Natl Acad Sci U S A 2004; 101:7669–7674.
83••. Blanchet FP, Moris A, Nikolic DS, et al. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity 2010; 32:654–669.
This study describes a novel mechanism by which HIV-1 may impair the functions of cDCs during infection: via downregulation of autophagy.
84•. Che KF, Sabado RL, Shankar EM, et al. HIV-1 impairs in vitro priming of naive T cells and gives rise to contact-dependent suppressor T cells. Eur J Immunol 2010; 40:2248–2258.
This article and reference [85•] show that exposure of cDCs to HIV-1 in vitro impairs T-cell priming and promotes Treg cell induction.
85•. Shankar EM, Che KF, Messmer D, et al. Expression of a broad array of negative costimulatory molecules and Blimp-1 in T cells following priming by HIV-1 pulsed dendritic cells. Mol Med 2011; 17:229–240.
This article and reference [84•] show that exposure of cDCs to HIV-1 in vitro impairs T-cell priming and promotes Treg cell induction.
86. Manches O, Munn D, Fallahi A, et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest 2008; 118:3431–3439.
87. Favre D, Mold J, Hunt PW, et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2010; 2:32ra36.
88. Oxenius A, Fidler S, Brady M, et al. Variable fate of virus-specific CD4(+) T cells during primary HIV-1 infection. Eur J Immunol 2001; 31:3782–3788.
89•. Moll M, Andersson SK, Smed-Sorensen A, Sandberg JK. Inhibition of lipid antigen presentation in dendritic cells by HIV-1 Vpu interference with CD1d recycling from endosomal compartments. Blood 2010; 116:1876–1884.
This paper describes a mechanism via which interaction between HIV-1-infected cDCs and CD1d-restricted NKT cells can be subverted by HIV-1.
90••. Fontaine J, Chagnon-Choquet J, Valcke HS, et al. High expression levels of B lymphocyte stimulator (BLyS) by dendritic cells correlate with HIV-related B-cell disease progression in humans. Blood 2011; 117:145–155.
This article reports that expression of BLyS is upregulated on cDCs during AHI and remains elevated throughout infection in viremic individuals that is associated with polyclonal B-cell activation and hyperglobulinemia.
91. Fellay J, Shianna KV, Ge D, et al. A whole-genome association study of major determinants for host control of HIV-1. Science 2007; 317:944–947.
92. Huang J, Goedert JJ, Sundberg EJ, et al. HLA-B*35-Px-mediated acceleration of HIV-1 infection by increased inhibitory immunoregulatory impulses. J Exp Med 2009; 206:2959–2966.
93. Herbeuval JP, Hardy AW, Boasso A, et al. Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 2005; 102:13974–13979.
94. Stary G, Klein I, Kohlhofer S, et al. Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients. Blood 2009; 114:3854–3863.
95. Meier A, Chang JJ, Chan ES, et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med 2009; 15:955–959.
96. Bosinger SE, Li Q, Gordon SN, et al. Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J Clin Invest 2009; 119:3556–3572.
97. Jacquelin B, Mayau V, Targat B, et al. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest 2009; 119:3544–3555.
98. Lederer S, Favre D, Walters KA, et al. Transcriptional profiling in pathogenic and nonpathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog 2009; 5:e1000296.
99. Li Q, Smith AJ, Schacker TW, et al. Microarray analysis of lymphatic tissue reveals stage-specific, gene expression signatures in HIV-1 infection. J Immunol 2009; 183:1975–1982.
100. Cavaleiro R, Baptista AP, Soares RS, et al. Major depletion of plasmacytoid dendritic cells in HIV-2 infection, an attenuated form of HIV disease. PLoS Pathog 2009; 5:e1000667.
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