Secondary Logo

Journal Logo

Special Reviews

An overview of intracellular interactions between immunodeficiency viruses and their hosts

Bieniasz, Paul D.

Author Information
doi: 10.1097/QAD.0b013e328353bd04
  • Free



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:
Some key interactions between HIV/SIV and host factors.
Table 1-b:
Some key interactions between HIV/SIV and host factors.

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:
Role of host cell factors in the postentry, preintegration phases of the HIV/SIV replication cycle.Antiviral host factors are colored red, host factors that facilitate replication are colored magenta. See text for details.

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].

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.

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.

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:
Role of some host cell factors in nuclear events of the HIV/SIV replication cycle (viral DNA integration, transcription, RNA splicing and export).See text for details.

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.

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:
Role of host cell factors in the virion production phase of the HIV/SIV replication cycle.Host factors that inhibit virion production are colored red, host factors that facilitate replication are colored magenta. See text for details.

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].

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].

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.

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].


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.


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).

Conflicts of interest

There are no conflicts of interest.


1. 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.
2. 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.
3. Sayah DM, Sokolskaja E, Berthoux L, Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 2004; 430:569–573.
4. Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia 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.
5. Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 2011; 474:658–661.
6. Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, et al. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor. Proc Natl Acad Sci U S A 2006; 103:5514–5519.
7. Ganser-Pornillos BK, Chandrasekaran V, Pornillos O, Sodroski JG, Sundquist WI, Yeager M. Hexagonal assembly of a restricting TRIM5alpha protein. Proc Natl Acad Sci U S A 2011; 108:534–539.
8. Perez-Caballero D, Hatziioannou T, Zhang F, Cowan S, Bieniasz PD. Restriction of human immunodeficiency virus type 1 by TRIM-CypA occurs with rapid kinetics and independently of cytoplasmic bodies, ubiquitin, and proteasome activity. J Virol 2005; 79:15567–15572.
9. Anderson JL, Campbell EM, Wu X, Vandegraaff N, Engelman A, Hope TJ. Proteasome inhibition reveals that a functional preintegration complex intermediate can be generated during restriction by diverse TRIM5 proteins. J Virol 2006; 80:9754–9760.
10. Pertel T, Hausmann S, Morger D, Zuger S, Guerra J, Lascano J, et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 2011; 472:361–365.
11. Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, Bieniasz PD. Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5alpha. Proc Natl Acad Sci U S A 2004; 101:10774–10779.
12. Kirmaier A, Wu F, Newman RM, Hall LR, Morgan JS, O’Connor S, et al.TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species. PLoS Biol 2010; 8:e1000462.
13. Lim SY, Rogers T, Chan T, Whitney JB, Kim J, Sodroski J, Letvin NL. TRIM5alpha modulates immunodeficiency virus control in rhesus monkeys. PLoS Pathog 2010; 6:e1000738.
14. Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P, Yu XF. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science 2003; 302:1056–1060.
15. Holmes RK, Koning FA, Bishop KN, Malim MH. APOBEC3F can inhibit the accumulation of HIV-1 reverse transcription products in the absence of hypermutation. Comparisons with APOBEC3G. J Biol Chem 2007; 282:2587–2595.
16. Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, et al. DNA deamination mediates innate immunity to retroviral infection. Cell 2003; 113:803–809.
17. Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 2003; 424:99–103.
18. Lecossier D, Bouchonnet F, Clavel F, Hance AJ. Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 2003; 300:1112.
19. Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 2003; 424:94–98.
20. Powell RD, Holland PJ, Hollis T, Perrino FW. Aicardi-goutieres syndrome gene and HIV-1 restriction factor SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase. J Biol Chem 2011; 286:43596–43600.
21. Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI, Christodoulou E, et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 2011; 480:379–382.
22. Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol 2012; 13:223–228.
23. Laguette N, Rahm N, Sobhian B, Chable-Bessia C, Munch J, Snoeck J, et al. Evolutionary and functional analyses of the interaction between the myeloid restriction factor SAMHD1 and the lentiviral Vpx protein. Cell Host Microbe 2012; 11:205–217.
24. Lim ES, Fregoso OI, McCoy CO, Matsen FA, Malik HS, Emerman M. The ability of primate lentiviruses to degrade the monocyte restriction factor SAMHD1 preceded the birth of the viral accessory protein Vpx. Cell Host Microbe 2012; 11:194–204.
25. Wen X, Duus KM, Friedrich TD, de Noronha CM. The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor. J Biol Chem 2007; 282:27046–27057.
26. Schrofelbauer B, Hakata Y, Landau NR. HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1. Proc Natl Acad Sci U S A 2007; 104:4130–4135.
27. Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, et al. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc Natl Acad Sci U S A 2007; 104:11778–11783.
28. Le Rouzic E, Belaidouni N, Estrabaud E, Morel M, Rain JC, Transy C, Margottin-Goguet F. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase. Cell Cycle 2007; 6:182–188.
29. Weinberg JB, Matthews TJ, Cullen BR, Malim MH. Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J Exp Med 1991; 174:1477–1482.
30. Lewis P, Hensel M, Emerman M. Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J 1992; 11:3053–3058.
31. Yamashita M, Emerman M. Capsid is a dominant determinant of retrovirus infectivity in nondividing cells. J Virol 2004; 78:5670–5678.
32. Yamashita M, Perez O, Hope TJ, Emerman M. Evidence for direct involvement of the capsid protein in HIV infection of nondividing cells. PLoS Pathog 2007; 3:1502–1510.
33. Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 2008; 319:921–926.
34. Lee K, Ambrose Z, Martin TD, Oztop I, Mulky A, Julias JG, et al. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 2010; 7:221–233.
35. Krishnan L, Matreyek KA, Oztop I, Lee K, Tipper CH, Li X, et al. The requirement for cellular transportin 3 (TNPO3 or TRN-SR2) during infection maps to human immunodeficiency virus type 1 capsid and not integrase. J Virol 2010; 84:397–406.
36. Lee K, Mulky A, Yuen W, Martin TD, Meyerson NR, Choi L, et al.HIV-1 capsid targeting domain of cleavage and polyadenylation specificity factor 6. J Virol 2012; 86:3851–3860.
37. Schaller T, Ocwieja KE, Rasaiyaah J, Price AJ, Brady TL, Roth SL, et al. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog 2011; 7:e1002439.
38. Luban J, Bossolt KL, Franke EK, Kalpana GV, Goff SP. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 1993; 73:1067–1078.
39. Franke EK, Yuan HE, Luban J. Specific incorporation of cyclophilin A into HIV-1 virions. Nature 1994; 372:359–362.
40. Thali M, Bukovsky A, Kondo E, Rosenwirth B, Walsh CT, Sodroski J, Gottlinger HG. Functional association of cyclophilin A with HIV-1 virions. Nature 1994; 372:363–365.
41. Hatziioannou T, Perez-Caballero D, Cowan S, Bieniasz PD. Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells. J Virol 2005; 79:176–183.
42. Keckesova Z, Ylinen LM, Towers GJ. Cyclophilin A renders human immunodeficiency virus type 1 sensitive to Old World monkey but not human TRIM5 alpha antiviral activity. J Virol 2006; 80:4683–4690.
43. Berthoux L, Sebastian S, Sokolskaja E, Luban J. Cyclophilin A is required for TRIM5{alpha}-mediated resistance to HIV-1 in Old World monkey cells. Proc Natl Acad Sci U S A 2005; 102:14849–14853.
44. Zhang F, Hatziioannou T, Perez-Caballero D, Derse D, Bieniasz PD. Antiretroviral potential of human tripartite motif-5 and related proteins. Virology 2006; 353:396–409.
45. Qi M, Yang R, Aiken C. Cyclophilin A-dependent restriction of human immunodeficiency virus type 1 capsid mutants for infection of nondividing cells. J Virol 2008; 82:12001–12008.
46. Yamashita M, Emerman M. Cellular restriction targeting viral capsids perturbs human immunodeficiency virus type 1 infection of nondividing cells. J Virol 2009; 83:9835–9843.
47. Manel N, Hogstad B, Wang Y, Levy DE, Unutmaz D, Littman DR. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 2010; 467:214–217.
48. Ambrose Z, Lee K, Ndjomou J, Xu H, Oztop I, Matous J, et al.Human immunodeficiency virus type 1 (HIV-1) capsid mutation N74D alters cyclophilin a dependence and impairs macrophage infection. J Virol 2012; 86:4708–4714.
49. Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, et al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J Biol Chem 2003; 278:372–381.
50. Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J Biol Chem 2003; 278:33528–33539.
51. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, et al. An essential role for LEDGF/p75 in HIV integration. Science 2006; 314:461–464.
52. Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev 2007; 21:1767–1778.
53. Marshall HM, Ronen K, Berry C, Llano M, Sutherland H, Saenz D, et al. Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting. PLoS One 2007; 2:e1340.
54. Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR. Identification of a putative regulator of early T cell activation genes. Science 1988; 241:202–205.
55. Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A 1989; 86:5974–5978.
56. Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A 1989; 86:2336–2340.
57. Heisig V, Benter T, Josephs SF, Sadaie MR, Okamoto T, Gallo RC, Wong-Staal F. Interaction of viral and cellular factors with the HTLV-III LTR target sequences in vitro. Haematol Blood Transfus 1987; 31:423–429.
58. 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.
59. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 1997; 94:13193–13197.
60. Chun T-W, Fauci AS. HIV reservoirs: pathogenesis and obstacles to viral eradication and cure.AIDS 2012; 26:1261–1268.
61. Wei P, Garber ME, Fang SM, Fischer WH, Jones KA. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 1998; 92:451–462.
62. Marshall NF, Peng J, Xie Z, Price DH. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J Biol Chem 1996; 271:27176–27183.
63. O’Reilly MM, McNally MT, Beemon KL. Two strong 5’ splice sites and competing, suboptimal 3’ splice sites involved in alternative splicing of human immunodeficiency virus type 1 RNA. Virology 1995; 213:373–385.
64. Stoltzfus CM. Chapter 1. Regulation of HIV-1 alternative RNA splicing and its role in virus replication. Adv Virus Res 2009; 74:1–40.
65. Purcell DF, Martin MA. Alternative splicing of human immunodeficiency virus type 1 mRNA modulates viral protein expression, replication, and infectivity. J Virol 1993; 67:6365–6378.
66. Malim MH, Hauber J, Le SY, Maizel JV, Cullen BR. The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature 1989; 338:254–257.
67. Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 1997; 90:1051–1060.
68. Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M, Nishida E. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 1997; 390:308–311.
69. Bishop KN, Holmes RK, Sheehy AM, Davidson NO, Cho SJ, Malim MH. Cytidine deamination of retroviral DNA by diverse APOBEC proteins. Curr Biol 2004; 14:1392–1396.
70. Virgen CA, Hatziioannou T. Antiretroviral activity and Vif sensitivity of rhesus macaque APOBEC3 proteins. J Virol 2007; 81:13932–13937.
71. Zennou V, Perez-Caballero D, Gottlinger H, Bieniasz PD. APOBEC3G incorporation into human immunodeficiency virus type 1 particles. J Virol 2004; 78:12058–12061.
72. Zhang W, Du J, Evans SL, Yu Y, Yu XF. T-cell differentiation factor CBF-beta regulates HIV-1 Vif-mediated evasion of host restriction. Nature 2011; 481:376–379.
73. Jager S, Kim DY, Hultquist JF, Shindo K, LaRue RS, Kwon E, et al.Vif hijacks CBF-beta to degrade APOBEC3G and promote HIV-1 infection. Nature 2011; 481:371–375.
74. Willey RL, Maldarelli F, Martin MA, Strebel K. Human immunodeficiency virus type 1 Vpu protein regulates the formation of intracellular gp160-CD4 complexes. J Virol 1992; 66:226–234.
75. Garcia JV, Miller AD. Serine phosphorylation-independent downregulation of cell-surface CD4 by nef. Nature 1991; 350:508–511.
76. Ross TM, Oran AE, Cullen BR. Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein. Curr Biol 1999; 9:613–621.
77. Lama J, Mangasarian A, Trono D. Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner. Curr Biol 1999; 9:622–631.
78. Benson RE, Sanfridson A, Ottinger JS, Doyle C, Cullen BR. Downregulation of cell-surface CD4 expression by simian immunodeficiency virus Nef prevents viral super infection. J Exp Med 1993; 177:1561–1566.
79. Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, et al. A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol Cell 1998; 1:565–574.
80. Greenberg ME, Bronson S, Lock M, Neumann M, Pavlakis GN, Skowronski J. Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation. EMBO J 1997; 16:6964–6976.
81. Jin YJ, Cai CY, Zhang X, Zhang HT, Hirst JA, Burakoff SJ. HIV Nef-mediated CD4 down-regulation is adaptor protein complex 2 dependent. J Immunol 2005; 175:3157–3164.
82. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 2008; 451:425–430.
83. Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC, et al. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 2008; 3:245–252.
84. Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, Bieniasz PD. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell 2009; 139:499–511.
85. Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, Johnson MC, et al. Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host Microbe 2009; 6:54–67.
86. Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, et al. Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. PLoS Pathog 2009; 5:e1000429.
87. Sauter D, Schindler M, Specht A, Landford WN, Munch J, Kim KA, et al. Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host Microbe 2009; 6:409–421.
88. Douglas JL, Viswanathan K, McCarroll MN, Gustin JK, Fruh K, Moses AV. Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism. J Virol 2009; 83:7931–7947.
89. Tokarev AA, Munguia J, Guatelli JC. Serine-threonine ubiquitination mediates downregulation of BST-2/tetherin and relief of restricted virion release by HIV-1 Vpu. J Virol 2010; 85:51–63.
90. Dube M, Roy BB, Guiot-Guillain P, Binette J, Mercier J, Chiasson A, Cohen EA. Antagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartment. PLoS Pathog 2010; 6:e1000856.
91. Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, Ruiz A, et al. Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. PLoS Pathog 2009; 5:e1000450.
92. Collins KL, Chen BK, Kalams SA, Walker BD, Baltimore D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 1998; 391:397–401.
93. Roeth JF, Williams M, Kasper MR, Filzen TM, Collins KL. HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail. J Cell Biol 2004; 167:903–913.
94. Schaefer MR, Wonderlich ER, Roeth JF, Leonard JA, Collins KL. HIV-1 Nef targets MHC-I and CD4 for degradation via a final common beta-COP-dependent pathway in T cells. PLoS Pathog 2008; 4:e1000131.
95. Piguet V, Wan L, Borel C, Mangasarian A, Demaurex N, Thomas G, Trono D. HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes. Nat Cell Biol 2000; 2:163–167.
96. Blagoveshchenskaya AD, Thomas L, Feliciangeli SF, Hung CH, Thomas G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell 2002; 111:853–866.
97. Atkins KM, Thomas L, Youker RT, Harriff MJ, Pissani F, You H, Thomas G. HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) down-regulation: analysis using short interfering RNA and knock-out mice. J Biol Chem 2008; 283:11772–11784.
98. Ohno H, Stewart J, Fournier MC, Bosshart H, Rhee I, Miyatake S, et al. Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science 1995; 269:1872–1875.
99. Byland R, Vance PJ, Hoxie JA, Marsh M. A conserved dileucine motif mediates clathrin and AP-2-dependent endocytosis of the HIV-1 envelope protein. Mol Biol Cell 2007; 18:414–425.
100. Landi A, Iannucci V, Nuffel AV, Meuwissen P, Verhasselt B. One protein to rule them all: modulation of cell surface receptors and molecules by HIV Nef. Curr HIV Res 2011; 9:496–504.
101. Arhel NJ, Kirchhoff F. Implications of Nef: host cell interactions in viral persistence and progression to AIDS. Curr Top Microbiol Immunol 2009; 339:147–175.
102. Postler TS, Desrosiers RC. The cytoplasmic domain of the HIV-1 glycoprotein gp41 induces NF-kappaB activation through TGF-beta-activated kinase 1. Cell Host Microbe 2012; 11:181–193.
103. Jowett JB, Planelles V, Poon B, Shah NP, Chen ML, Chen IS. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J Virol 1995; 69:6304–6313.
104. Pizzato M, Helander A, Popova E, Calistri A, Zamborlini A, Palu G, Gottlinger HG. Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef. Proc Natl Acad Sci U S A 2007; 104:6812–6817.
105. Chowers MY, Spina CA, Kwoh TJ, Fitch NJ, Richman DD, Guatelli JC. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. J Virol 1994; 68:2906–2914.
106. Carl S, Greenough TC, Krumbiegel M, Greenberg M, Skowronski J, Sullivan JL, Kirchhoff F. Modulation of different human immunodeficiency virus type 1 Nef functions during progression to AIDS. J Virol 2001; 75:3657–3665.
107. Serra-Moreno R, Jia B, Breed M, Alvarez X, Evans DT. Compensatory changes in the cytoplasmic tail of gp41 confer resistance to tetherin/BST-2 in a pathogenic nef-deleted SIV. Cell Host Microbe 2011; 9:46–57.
108. Jouvenet N, Neil SJ, Bess C, Johnson MC, Virgen CA, Simon SM, Bieniasz PD. Plasma membrane is the site of productive HIV-1 particle assembly. PLoS Biol 2006; 4:e435.
109. Ono A, Ablan SD, Lockett SJ, Nagashima K, Freed EO. Phosphatidylinositol (4,5) bisphosphate regulates HIV-1 Gag targeting to the plasma membrane. Proc Natl Acad Sci U S A 2004; 101:14889–14894.
110. Saad JS, Miller J, Tai J, Kim A, Ghanam RH, Summers MF. Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly. Proc Natl Acad Sci U S A 2006; 103:11364–11369.
111. VerPlank L, Bouamr F, LaGrassa TJ, Agresta B, Kikonyogo A, Leis J, Carter CA. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag). Proc Natl Acad Sci U S A 2001; 98:7724–7729.
112. Garrus JE, von Schwedler UK, Pornillos OW, Morham SG, Zavitz KH, Wang HE, et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 2001; 107:55–65.
113. Martin-Serrano J, Zang T, Bieniasz PD. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nat Med 2001; 7:1313–1319.
114. von Schwedler UK, Stuchell M, Muller B, Ward DM, Chung HY, Morita E, et al. The protein network of HIV budding. Cell 2003; 114:701–713.
115. Martin-Serrano J, Yarovoy A, Perez-Caballero D, Bieniasz PD. Divergent retroviral late-budding domains recruit vacuolar protein sorting factors by using alternative adaptor proteins. Proc Natl Acad Sci U S A 2003; 100:12414–12419.
116. Carlton JG, Martin-Serrano J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 2007; 316:1908–1912.
117. Babst M, Katzmann DJ, Snyder WB, Wendland B, Emr SD. Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev Cell 2002; 3:283–289.
118. Babst M, Katzmann DJ, Estepa-Sabal EJ, Meerloo T, Emr SD. Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev Cell 2002; 3:271–282.
119. Katzmann DJ, Babst M, Emr SD. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 2001; 106:145–155.
120. Strack B, Calistri A, Craig S, Popova E, Gottlinger HG. AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Cell 2003; 114:689–699.
121. Morita E, Sandrin V, McCullough J, Katsuyama A, Baci Hamilton I, Sundquist WI. ESCRT-III protein requirements for HIV-1 budding. Cell Host Microbe 2011; 9:235–242.
122. Martin-Serrano J, Neil SJ. Host factors involved in retroviral budding and release. Nat Rev Microbiol 2011; 9:519–531.
123. Zimmerman C, Klein KC, Kiser PK, Singh AR, Firestein BL, Riba SC, Lingappa JR. Identification of a host protein essential for assembly of immature HIV-1 capsids. Nature 2002; 415:88–92.
124. Zhang F, Zang T, Wilson SJ, Johnson MC, Bieniasz PD. Clathrin facilitates the morphogenesis of retrovirus particles. PLoS Pathog 2011; 7:e1002119.
125. Popov S, Strack B, Sanchez-Merino V, Popova E, Rosin H, Gottlinger HG. Human immunodeficiency virus type 1 and related primate lentiviruses engage clathrin through Gag-Pol or Gag. J Virol 2011; 85:3792–3801.
126. Bieniasz PD, Grdina TA, Bogerd HP, Cullen BR. Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat. EMBO J 1998; 17:7056–7065.
127. Garber ME, Wei P, KewalRamani VN, Mayall TP, Herrmann CH, Rice AP, et al. The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein. Genes Dev 1998; 12:3512–3527.
128. Sherer NM, Swanson CM, Hue S, Roberts RG, Bergeron JR, Malim MH. Evolution of a species-specific determinant within human CRM1 that regulates the posttranscriptional phases of HIV-1 replication. PLoS Pathog 2011; 7:e1002395.
129. Hatziioannou T, Bieniasz PD. Antiretroviral restriction factors. Curr Opin Virol 2012; 1:526–532.
130. Hatziioannou T, Princiotta M, Piatak M Jr, Yuan F, Zhang F, Lifson JD, Bieniasz PD. Generation of simian-tropic HIV-1 by restriction factor evasion. Science 2006; 314:95.
131. Ambrose Z, KewalRamani VN, Bieniasz PD, Hatziioannou T. HIV/AIDS: in search of an animal model. Trends Biotechnol 2007; 25:333–337.
132. Jager S, Cimermancic P, Gulbahce N, Johnson JR, McGovern KE, Clarke SC, et al. Global landscape of HIV-human protein complexes. Nature 2011; 481:365–370.

HIV; host; interactions; SIV

© 2012 Lippincott Williams & Wilkins, Inc.