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An overview of intracellular interactions between immunodeficiency viruses and their hosts

Bieniasz, Paul D.

doi: 10.1097/QAD.0b013e328353bd04
Special Reviews
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Many studies have documented how extensively HIV-1 and related viruses interact with host cells. Virus–host interactions are of two conceptual types. First, viruses have evolved to make use of numerous host-cell functions to facilitate their own replication. Second, hosts have evolved a number of activities to inhibit virus replication. Understanding the scope and details of HIVhost interactions has been an extraordinary rich scientific endeavor, and in addition to their biomedical importance, studies in this area have established HIV as a model system in virology. Here, I present an overview of how HIV-1 interacts with some key host cell factors during its replication cycle.

Laboratory of Retrovirology, Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.

Correspondence to Paul D. Bieniasz, Laboratory of Retrovirology, Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA. Tel: +1 212 448 5070; fax: +1 212 725 1126; e-mail: pbienias@adarc.org

Abbreviations: ABCE1, ATP binding cassette protein E1; AP1, AP2, adapter protein -1, -2 complexes; APOBEC3G, apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like-3; ALIX, Apoptosis-linked gene-2- interacting protein-X; β-COP, Coatamer subunit β; β-TrCP, beta-transducin repeat containing protein; CBF-β, core binding factor β; CDK9, Cyclin-dependent kinase 9; CPSF6, Cleavage and polyadenylation specificity factor subunit 6; Crm1/Xpo1, Chromosomal region maintenance-1/exportin-1; CUL4, Cullin 4; CUL5, Cullin5; CycT1, Cyclin T1; CypA, Cyclophilin A; DCAF/VprBP, DDB-1/CUL4 associated factor/Vpr Binding protein; DDB1, UV damaged DNA binding protein-1; [ESCRT-I], endosomal sorting complex requited for transport-I; hnRNP, heterogeneous ribonuclear protein family; LEDGF, Lens epithelium derived growth factor; MHC-I, major histocompatibility complex-I; NFAT, Nuclear factor of activated T-cells; NF-kappaB, nuclear factor kappa-light-chain-enhancer of activated B cells; NUP153, Nucleoporin 153; NUP155, Nucleoporin 155; NUP358/RanBP2, Nucleoporin 358/Ran Binding Protein 2; PACS-1, 2, phosphofurin acidic cluster sorting protein-1,-2; PAK-1, p21-activated kinase-1; PI[4,5]P2, Phosphatidylinositol 4,5-bisphosphate; P-TEFb, Positive transcription elongation factor-b; Rbx1, ring box-1; SamHD1, sterile alpha motif domain and hydrolase domain-1; SP1, specificity protein 1; Src, Sarcoma kinases; Skp1, suppressor of kinetochore protein; SR, serine-arginine-rich protein family; TAK1, Transforming growth factor β–activated kinase 1; TNPO3, Transportin 3; TRIM5α, Tripartite motif-5α; TRIMCyp, TRIM5-CypA fusion protein; Tsg101, tumor suppressor gene 101

Received 29 February, 2012

Accepted 15 March, 2012

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Introduction

The 25 years since the first publication of AIDS, coincide with a period of intense discovery of the molecular and cellular biology of HIV-1, HIV-2 and SIVs. Studies of this group of viruses have progressed from basic characterization to an intricate and deep understanding of how they interact with their hosts. Interactions between viral and host components within the cell have become a major theme in the study of HIV/SIV biology, and accumulated studies have demonstrated how extensively HIV/SIVs interact with, exploit and manipulate the cellular environment.

The interactions between HIV/SIVs and host cells are of two conceptual types. First, viruses have evolved to make use of numerous host-cell functions to enable or facilitate their own replication. Second, as virus replication is rarely beneficial and sometimes deleterious to host survival, hosts have evolved a number of activities to inhibit virus replication. In an elaboration of these two basic tenets, viruses have also evolved to evade inhibitory host activities, and acquired new activities to turn host functions against factors that would otherwise inhibit virus replication. What follows is a ‘tour’ of the HIV-1 replication cycle, and an overview of how HIV-1 interacts with some key host cell factors (see Table 1 for a list of viral components and their host binding partners). By necessity, this review is selective, in that only interactions of likely importance in viral replication are discussed.

Table 1-a

Table 1-a

Table 1-b

Table 1-b

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Running the gauntlet from the plasma membrane to the nuclear envelope

Fusion of the virion envelope with the target cell plasma or endosomal membrane delivers the viral capsid and its contents to the target cell cytoplasm (Fig. 1). At this point, the viral RNA genome is reverse transcribed, and must also traverse the cytoplasm to gain access to the nucleus. Host cells appear to have selected these processes as points of vulnerability in the retroviral lifecycle. Indeed, at least three host cell factors have arisen or adapted to inhibit virus replication by launching attacks on incoming viral components, or reducing the permissivity of cells at this stage of HIV/SIV replication [1–5] (Fig. 1). For example, the TRIM5α/TRIMcyp family of antiviral proteins can greet incoming HIV/SIV capsids by directly binding to them within a few minutes of viral entry, and assembling into a lattice on the capsid surface [6–8]. This action can induce premature uncoating of the viral capsid and block both reverse transcription and nuclear import of viral DNA [6,9]. It may also trigger innate immune signaling [10]. Although TRIM5α is a potent antiviral protein, HIV/SIVs generally avoid the bulk of its effects by encoding capsids that are not efficiently recognized [11]. Consequently, the true potency of TRIM5α is only appreciated when cells from an incompatible species are challenged by HIV/SIVs. Nevertheless, sequence variation in TRIM5α can also be an important determinant of intraspecies variation in SIV pathogenicity [12,13].

Fig. 1

Fig. 1

Another set of antiviral proteins, the APOBEC3 cytidine deaminases, can inhibit infection at this phase of the viral replication cycle [1]. Although APOBEC proteins are normally removed from infected cells by the action of the accessory protein Vif [14], they can be incorporated into assembling virions if Vif function is inhibited (see below). APOBEC3 proteins that are carried along with the viral genome into new target cells can inhibit reverse transcription [15]. However, their major mechanism of action involves deamination of numerous cytidines in nascent negative strand viral DNA during reverse transcription [16–19]. This deamination is manifested as G-to-A hypermutation of the coding strand, which fundamentally changes the coding capacity of the DNA provirus rendering it incapable of further propagation (Fig. 1).

Very recently, SamHD1 has been identified as a third host protein that inhibits HIV/SIV DNA synthesis in myeloid cells [4,5]. SamHD1 is a deoxynucleotide triphosphohydrolase [20,21], and appears to inhibit HIV/SIV infection by reducing the levels of the cellular deoxynucleotides that are required for reverse transcription [22]. In some cases, the effect of SamHD1 is ameliorated by HIV/SIV accessory proteins of the Vpx/Vpr family [23,24]. These viral proteins are carried by virions, and upon delivery to the target cell cytoplasm, remove SamHD1 by recruiting it to a ubiquitin ligase complex containing the host proteins, DDB1; DCAF1 and CUL4 [25–28].

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Gaining access to the nucleus

A striking feature of lentiviruses such as the HIV/SIVs is that they are able to infect nondividing cells with much greater efficiency than are retroviruses of other genera [29,30]. The mechanisms by which infection of cells with intact nuclear envelopes is achieved remain somewhat mysterious, but the viral capsid appears to be a key determinant of this property [31,32] (Fig. 1). Whether the HIV/SIV capsid contains specific signals that direct the incoming subvirion complex through nuclear pores, or have some propensity to uncoat at a particular time or in a particular manner to enable other viral signals to direct nuclear import remains to be determined. However, moderate infectivity defects on HIV-1 can be imposed if a specific nuclear transport protein (TNPO3), or a subset of nucleoporins (NUP358/RANBP2 or NUP153) are depleted from target cells [33,34]. Moreover, there are genetic interactions between the HIV-1 capsid and this nuclear transport machinery [35]. For example, capsid mutations selected to confer resistance to a truncated cytoplasmic form of the HIV-1 capsid-binding protein CPSF-6 [36] (ordinarily CPSF-6 is a nuclear protein) can confer resistance to the effects of TNPO3, NUP358/RANBP2 or NUP153 depletion. At the same time, these mutations can confer sensitivity to depletion of a different nucleoporin (NUP155) [34,35,37]. Thus, there is apparent flexibility in the manner with which HIV/SIVs interact with nuclear transport machinery. Surprisingly, these effects are often evident in dividing as well as nondividing cells. Clearly there is much to be learned about how HIV/SIVs exploit host cell factors to access host cell DNA in both dividing and nondividing cells.

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Capsid–cyclophilin binding: multiple but enigmatic roles en route to the nucleus

The capsids of some HIV/SIV strains bind to CypA, a highly abundant cytoplasmic peptidyl prolyl isomerase [38]. Although the capsid–CypA binding can occur in virus-producing cells and drive CypA incorporation into virions [39,40], it is the target cell CypA that mediate most of the effects of this protein on HIV-1 replication [41]. How capsid-CypA binding benefits HIV/SIV replication is not clear, as it is absent in some SIVs (particularly SIVmac). However, perturbing this interaction via mutation of the CypA-binding sites on the capsid can have a range of effects on HIV-1 replication (Fig. 1). These effects include changes in sensitivity to TRIM5 [42–44], infection of nondividing cells [45,46], utilization of nuclear transport machinery [37], and induction of innate immune signaling [47]. Analyses of the effect of CypA on HIV-1 infection are complicated by the fact that one of the NUPs implicated in HIV-1 nuclear import (NUP358/RANBP2) contains a CypA-like domain that can also bind the HIV-1 capsid [37]. Moreover, the effects of the CypA–capsid interaction are strongly dependent on the particular cell type that is infected [41,48]. These findings suggest the involvement of other cellular factors in determining the fate of the viral capsid and the role of CypA in viral infection. Overall, the precise role of the expanding range of host proteins that genetically and physically interact with the incoming HIV/SIV capsid, and how these interactions facilitate or inhibit infection is one of the most challenging and interesting aspects of HIV/SIV research.

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Using host cell factors to enable proviral integration and expression

Although the integrase enzyme is primarily responsible for catalyzing the insertion of a double-stranded DNA copy of the viral genome into host cell DNA, it does not act alone. Specifically, a host protein, termed LEDGF, binds directly to lentiviral integrases [49] and simultaneously to host DNA [50] (Fig. 2). These binding events not only dramatically increase the efficiency of viral DNA integration [51,52], but also influence the distribution of sites in the target cell genome into which viral DNA is inserted. Specifically, HIV-1 has a propensity to integrate into active transcription units, a characteristic that is largely abolished in cells from which LEDGF has been depleted [52,53]. Plausibly, the selectivity of integration might lead to more efficient transcription of integrated proviruses, although this possibility is yet to be demonstrated.

Fig. 2

Fig. 2

Once integrated into host cell DNA, transcription from the integrated provirus is regulated by several host transcription factors, the most critical of which are NF-kB, NFAT and Sp1 [54–57] (Fig. 2). The constellation of factors that bind directly to the HIV/SIV enhancer/promoter conspire to make the level of transcription quite sensitive to the activation state of the T-cell in which a provirus would normally reside. The corollary of this scenario is that a small fraction of integrated proviruses become transcriptionally silent if they become integrated into the genome of T-cells that are, or become, resting [58,59]. These so-called latent proviruses constitute a profound obstacle to eradication using conventional antiretroviral therapy (see [60], this issue). HIV/SIVs also use a somewhat unique positive feedback mechanism to drive transcription (Fig. 2). The viral Tat protein binds to a complex termed positive transcription elongation factor-b (P-TEFb), minimally comprising a cyclin–CDK pair (Cyclin T1 and CDK9) [61]. This kinase complex can efficiently hyperphosphorylate the C-terminal domain of RNA polymerase II, rendering it much more processive [62]. The Tat:P-TEFb complex has high affinity for Tat response element (TAR), (an RNA stem loop element situated at the extreme 5′ end of HIV-1 mRNAs) [61] Thus, the major role of Tat is to recruit P-TEFb complex to paused polymerases, and it is required for the generation of high levels of full length primary viral RNA transcripts.

HIV-1 and SIV mRNAs encode up to nine different proteins, with most open reading frames accessed via alternative splicing of the primary viral transcript (Fig. 2). Splicing is regulated both by the use of suboptimal splice acceptors [63], and by interactions of the primary transcript with host proteins of the hnRNP and SR families (see [64] for review). These factors bind to so-called exonic splicing silencer and enhancer elements in the viral RNA and help to maintain balanced levels of more than 40 unspliced, partially spliced and completely spliced mRNAs in the nucleus of infected cells [65]. The completely spliced mRNA pool (which comprise mRNAs that encode early proteins: Tat, Rev and Nef) do not contain introns, and therefore can access the cytoplasm via conventional cellular mRNA export pathways. Conversely, the partly spliced mRNAs (encoding Vif, Vpr/Vpx, Vpu and Env) and the unspliced primary transcript (encoding Gag and GagPol) are retained in the nucleus of infected cells [66]. However, the viral Rev protein serves as an adapter to link incompletely spliced viral mRNAs to a host protein termed Crm1/Exportin1 [66–68] (Fig. 2). This nuclear transport factor ordinarily serves to mediate the export of proteins containing short leucine-rich signals from the nucleus. Rev simultaneously binds to Crm1/Exportin1 and a structured RNA element [the Rev response element (RRE)] that is present in incompletely spliced viral RNAs. In so doing, Rev enables incompletely spliced viral mRNAs to be exported and the full repertoire of viral proteins to be expressed.

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Preparing the host cell to generate viral progeny by removal of inhibitory host factors

Once viral mRNAs arrive in the cytoplasm and are translated into proteins, HIV/SIVs undertake a range of activities to make the host cell a better environment for the generation of infectious progeny (Fig. 3). These activities primarily involve the removal, or redistribution of host-cell molecules that would otherwise reduce the quantity or infectiousness of new virion particles. In this regard, three accessory proteins, Vif, Vpu and Nef, play key roles in preparing the cell to be an efficient producer of new infectious virions.

Fig. 3

Fig. 3

A striking example of this type of host-cell manipulation by HIV/SIVs is the effective removal of the APOBEC3 cytidine deaminases from the cell to enable the production of fully infectious virons [1,14]. In the absence of viral Vif proteins, several APOBEC3 proteins can be incorporated into virions, and subsequently inhibit infection of new cells [69,70] (see above). In the case of APOBEC3G, the prototype member of the APOBEC3 family, virion incorporation is driven by its binding to RNA and nucleocapsid, and appears not to require any specific sequence encoded by the virus [71]. The promiscuous incorporation of APOBEC3 proteins into particles presents a formidable obstacle to HIV/SIV; it should be difficult to evolve resistance by changes in viral sequences that result in a loss of binding of virion components to APOBEC3G. Thus, HIV/SIVs have been required to evolve a new biological function to antagonize APOBEC3 proteins. Specifically, Vif assembles a ubiqitin ligase complex comprising CUL5, Elongins B and C, Rbx1 and CBFβ and recruits APOBEC3 proteins to this complex [14,72,73]. In so doing, Vif induces APOBEC3 ubiquitination and proteasome-mediated degradation, effectively denuding the host of a potent antiretroviral defense (Fig. 3).

Two viral accessory proteins (Vpu and Nef) manipulate the levels of particular membrane proteins at the surface of infected cells. Both Vpu and Nef downregulate CD4+, the primary receptor for HIV/SIVs [74,75]. Although CD4+ is the primary receptor for HIV/SIVs and is generally required for infection, high-level CD4+ expression is deleterious to virus production by infected cells. This is because CD4+ can reduce the yield and infectiousness of HIV-1 particles, by binding to gp120 molecules that are incorporated into virions [76,77]. CD4+ downregulation may also provide a selective advantage by preventing superinfection [78], perhaps reducing competition from cocirculating viral variants. Vpu accomplishes CD4+ downregulation by recruiting it to a ubiquitin ligase, β-TRCP, which results in the intracellular degradation of CD4+ [79], whereas Nef recruits the AP2 clathrin adapter complex to CD4+ [80,81], accelerating its internalization from the cell surface (Fig. 3).

Another host protein that can be targeted by Vpu or Nef is the antiviral protein, tetherin [82,83]. This protein assembles into a dimeric extracellular coiled-coil that is anchored in the plasma membrane by a transmembrane domain at its N-termini and by a glycophosphatidyl inositol at its C-termini. As virions bud through the plasma membrane of infected cells, either or both of the paired membrane anchors become incorporated into virion envelopes [84]. Thus, tetherin forms a protein tether that traps nascent virions on the surface of infected cells (Fig. 3). Both Vpu and Nef can act as antagonists of tetherin [82,83,85,86], although which of these two proteins is used varies according to which particular HIV/SIV is analyzed [85,87]. In general, most SIVs that encode a Vpu utilize it as a tetherin antagonist. A notable exception is SIVcpz, which like most SIVs (and unlike its close relative, HIV-1), employs Nef in this role [87]. The mechanisms by which Vpu and Nef antagonize tetherin are related to the mechanisms by which they downregulate CD4+, and employ the same host factors (Fig. 3). In the case of Vpu, β-TRCP recruitment and tetherin degradation contribute to its overall antagonist activity [88,89]. However, Vpu also employs other less well understood mechanisms to antagonize tetherin, including intracellular sequestration and accelerated endocytosis [90,91]. Nef recruits the AP-2 complex to induce tetherin internalization [85], in much the same way as it induces CD4+ internalization, although the Nef sequences required for tetherin recognition differ from those used to target CD4+ [85].

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Manipulating the infected host cell to evade adaptive immunity and enhance virion production

The aforementioned activities, as well as the subsequent assembly of virion particles, generally occur in an immunologically hostile extracellular environment, populated by antiviral CD8+ cells that are potentially capable of dealing a lethal blow to the infected cell before it has yet generated new infectious virions. Presumably to evade immunological surveillance, and prolong the lifetime of infected cell (which in most cases is expected to be only a few hours from the onset of viral gene expression), the viral Nef protein also induces the removal of MHC-I from the cell surface [92]. This process is thought to be accomplished through the recruitment of AP-1 and β-COP, and the rerouting of MHC-I via the Golgi to degrative compartments [93,94]. However, a competing model invokes recruitment of kinase cascade and PACS proteins that sequester MHC-I molecules in the Golgi [95–97]. Another way in which HIV/SIV may attempt to evade the adaptive immune system is by regulating the levels of the gp120/g41 envelope protein complex at the plasma membrane. To accomplish this, the gp41 cytoplasmic tail of HIV/SIVs encode YXXL and dileucine motifs to engage the AP-2 clathrin adapter complex and drive gp120/g41 endocytosis [98,99].

In addition to its effects on CD4+, tetherin and MHC-I, Nef modulates the expression of a several other host membrane proteins. Furthermore, it binds to a number of cellular kinases (reviewed in [100,101]). The precise role of these additional interactions is not clear, but they likely underlie Nef's apparent ability to modulate the activation state of the infected cell, potentially providing an environment that is more conducive for viral expression and production. Nef may be assisted in this function by HIV/SIV Env proteins, whose cytoplasmic tails can bind to TAK-1, and thereby activate NF-κB [102] and Vpr, which can induce cell cycle arrest [103]. Additionally, Nef binds specifically to dynamin-2 [104], and this interaction appears critical for the poorly understood ability of Nef to enhance HIV-1/SIV particle infectivity [105]. Overall, Nef appears to be particularly promiscuous in the manner with which it associates with host cell molecules, and flexible in its ability to acquire and discard functions according to which particular host environment it is found. Indeed, some evidence even suggests that Nef function can change during the course of infection [106,107].

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Using host cell factors to help build and release new HIV/SIV particles

Having expressed the requisite viral proteins, and prepared the cell to be an efficient producer of new virus particles, virion components coalesce at discrete locations on the plasma membrane to assemble into particles (Fig. 3). The major viral structural protein, Gag, directs particle assembly to the plasma membrane [108] using generic membrane binding (N-terminal myristate modification) and specific targeting sequences within the N-terminal matrix domain. The specific targeting information is in the form of a binding site for a host cell lipid, namely phosphatidylinositol-(4,5)-bisphosphate (PI[4,5]P2), that is specifically present in the plasma membrane [109,110].

As particle assembly proceeds and approaches completion, HIV/SIV Gag proteins recruit an array of host cell factors that comprise the ESCRT pathway [111–115]. These factors are required for the membrane scission event that separates the virion envelope from the host cell plasma membrane and enables the release of HIV/SIV virons from cells (Fig. 3). Normally, this pathway is used by cells in topologically equivalent membrane scission events that accompany cell division and the generation of cytoplasm-containing vesicles within the lumen of endosomes [116–119]. HIV/SIV Gag proteins redirect this machinery to assembling virions by encoding specific binding sites for ESCRT pathway components within the Gag protein. The p6 domain of HIV/SIV Gag usually contains one or two PT/SAP motifs that serve as binding sites for Tsg101, a core component of the ESCRT-I complex [111–113]. Additionally, p6 contains a binding site for ALIX [114,120], an ESCRT-pathway component that itself binds ESCRT-I and ESCRT-III. The occurrence and importance of these ESCRT protein-binding sites vary somewhat among HIV/SIVs. For example, the Tsg101-binding PTAP motif bears the dominant role in recruiting the ESCRT pathway and driving HIV-1 budding. In contrast, a few SIVs completely lack PT/SAP motifs and instead employ only a single ALIX-binding site. Although there is some flexibility in the way in which HIV/SIVs engage the ESCRT machinery, a few key components of ESCRT-III (CHMP2 and CHMP4 family members, with more minor contributions from CHMP1 and CHMP3) and an associated ATPase (VPS4) are ultimately required to mediate the membrane scission event [112,121]. The precise mechanisms by which these ESCRT-III proteins mediate membrane scission are a current active area of investigation, and several different plausible models have been proposed (reviewed in [122]).

Other proteins have also been identified that may assist HIV-1 assembly. ABCE1, a cellular ATPase associates with intermediate Gag complexes during particle assembly [123], but how this facilitates particle morphogenesis is not known. Recent work has demonstrated that HIV/SIVs recruit clathrin into virions during assembly [124,125]. In the case of HIV-1, Pol is absolutely required for clathrin recruitment. Conversely, SIVmac encodes motifs within its Gag protein that mimic those found in clathrin adapter proteins. Depletion of clathrin from HIV/SIV producing cells can cause destabilizition of viral proteins in cells and reduced virion infectiousness [124,125]. The precise mechanism by which clathrin facilitates accurate virion assembly in not completely defined, but clathrin does appear to regulate the activity of the viral protease [124], and may act to facilitate the spatial organization of viral proteins during virion morphogenesis.

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HIV/SIV-host cell interactions and viral tropism

Several of the aforementioned interactions between HIV/SIV and host cell factors are major determinants of host range, as they involve binding sites on host proteins that differ in sequence among species. For example, the failure of HIV/SIV Tat and Rev proteins to function efficiently in rodent cells is due to incompatibility with rodent CycT1 and Crm1/exportin1 proteins [126–128]. Similarly, each of the aforementioned interactions between HIV/SIVs and host antiviral proteins (TRIM5–capsid, APOBEC3–Vif, Tetherin–Vpu/Nef, and SamHD1–Vpx/Vpr) exhibit strong dependence on the particular virus strain and host species that are analyzed. Apparently, HIV/SIVs have adapted to particular variants of these antiviral proteins that are present in their respective host species (reviewed in [129]). These species-specific differences in the ability of HIV/SIV to associate with host factors have historically been extremely useful. In many cases, they have aided the identification, validation and characterization of host factors that are important in facilitating or inhibiting HIV/SIV replication. These differences are also biologically important, as they constitute barriers to cross-species transmission and have likely prevented the transmission of many SIVs to humans. Conversely, these species-specific adaptations make it challenging to establish animal models of AIDS that employ HIV-1 [130,131].

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Conclusion

The identification and characterization of host factors that play key roles in the replication cycle of HIV/SIV continue to be an exciting and dynamic area of virology. Technological developments have greatly increased our ability to identify biochemical or genetic interactions between virus and host [33,132]. However, it is striking that the accumulated number of molecular interactions between HIV-1 and host molecules that have been reported in the scientific literature (many hundreds) greatly exceeds the number that are broadly accepted as being correct and biologically relevant. Apparently, our capacity to identify interactions currently exceeds our capacity to rigorously demonstrate their importance. Nonetheless, the examples discussed in this overview almost certainly do not represent the entire scope of the biologically relevant associations of HIV/SIVs components with host factors. Further exploration of the host factors that interact with HIV/SIVs and their role in viral replication will surely be a crucial contribution to a complete understanding of HIV/SIV pathogenesis and biology.

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Acknowledgements

I thank Theodora Haziioannou for advice and discussions. Work in my laboratory is supported by the Howard Hughes Medical Institute and NIH grants (R37AI64003 and R01AI50111).

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

HIV; host; interactions; SIV

© 2012 Lippincott Williams & Wilkins, Inc.