Originally published online as doi:10.1189/jlb.0306130 on August 14, 2006
Published online before print August 14, 2006
(Journal of Leukocyte Biology. 2006;80:973-983.)
© 2006
by Society for Leukocyte Biology
HIV accomplices and adversaries in macrophage infection
Sharon M. Wahl1,
Teresa Greenwell-Wild and
Nancy Vázquez
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
1 Correspondence: Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30, Rm. 320, 30 Convent Dr., MSC 4352, Bethesda, MD 20892-4352. E-mail: smwahl{at}dir.nidcr.nih.gov
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ABSTRACT
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Cell surface and intracellular proteins in macrophages influence various steps in the life cycle of lentiviruses. Characterization of these restriction and/or cofactors is essential to understanding how macrophages become unwitting HIV hosts and in fact, can coexist with a heavy viral burden. Although many of the cellular pathways co-opted by HIV in macrophages mimic those seen in CD4+ T cells, emerging evidence reveals cellular constituents of the macrophage, which may be uniquely usurped by HIV. For example, in addition to CD4 and CCR5, membrane annexin II facilitates early steps in infection of macrophages, but not in T cells. Blockade of this pathway effectively diminishes macrophage infection. Viral binding engages a macrophage-centric signaling pathway and a transcriptional profile, including genes such as p21, which benefit the virus. Once inside the cell, multiple host cell molecules are engaged to facilitate virus replication and assembly. Although the macrophage is an enabler, it also possesses innate antiviral mechanisms, including apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3) family DNA-editing enzymes to inhibit replication of HIV. Differential expression of these enzymes, which are largely neutralized by HIV to protect its rebirth, is associated with resistance or susceptibility to the virus. Higher levels of the cytidine deaminases endow potential HIV targets with a viral shield, and IFN-
, a natural inducer of macrophage APOBEC expression, renders macrophages tougher combatants to HIV infection. These and other manipulatable pathways may give the macrophage a fighting chance in its battle against the virus.
Key Words: APOBEC • monocyte • SLPI • annexin II • IFN • retrovirus • p21 • Vpr • Vif
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INTRODUCTION
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In its bid for supremacy over its cellular targets, HIV takes host cell molecules as accomplices in enabling binding, entry, and completion of its life cycle. Although macrophages possess defensive countermeasures, HIV, more often than not, has devised the means to neutralize these innate defense pathways. Initial interactions of macrophages with HIV, whether in vitro or in situ, involve the binding of HIV envelope (Env) gp120 to target cell membrane CD4, unmasking sites recognized by seven transmembrane-spanning chemokine coreceptors (CCR5 and/or CXCR4) to engage the entry and infection process [1
]. CCR5 (R5 strains, M tropic) is preferred by most HIV-1 primary isolates, and CXCR4 selects for T cell tropic X4 strains, although macrophages are permissive for X4, R5, or R5X4 virus [2
3
4
5
]. Whereas direct and indirect T cell depletion and immunopathogenesis may result from T cell tropic virus [6
, 7
], interactions of macrophages with R5 HIV may result in long-term coexistence of host cell and pathogen [8
9
10
]. Although many of the mechanisms underlying successful infection of T cells and macrophages are shared, additional, distinct pathways in macrophages may enable their longevity, despite an enormous viral burden.
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HIV BINDING AND ENTRY IN MACROPHAGES
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Although indisputable that CD4 and CCR5 orchestrate macrophage viral binding and entry, evidence continues to accumulate that the host-pathogen encounter may be more complex and that additional cofactors may support and/or enhance the early steps in HIV infection of macrophages [11
12
13
]. Binding of HIV to its target cell is essential to the infectious process, and it appears that the initial HIV attachment may take advantage of multiple cell-surface molecules (Fig. 1
), including, but not limited to, those identified in Table 1
. Potential use of adjunctive or alternative pathways likely ensures that HIV has a backup plan for cell attachment, retention, and internalization, even in a host cell without abundant CD4, such as macrophages, to perpetuate its vicious life cycle.
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Figure 1. Membrane constituents associated with HIV-macrophage interactions and signal transduction. In addition to the canonical HIV binding and entry receptors, CD4 and CCR5/CXCR4, additional macrophage membrane constituents may facilitate attachment, binding, entry, and fusion of the virus. These membrane-embedded molecules may also have potential roles in signaling cellular events underlying completion of the virus life cycle. Glycoprotein (Gp)120 engagement of CCR5 results in signal transduction, and PI-3K activation leads to serine/threonine protein kinase (AKT), proline-rich tyrosine kinase-2 (Pyk2) and MAPK [p38, JNK/stress-activated protein kinase (SAPK), Erk1/2] phosphorylation, forming the link to transcriptional events. NF- B is instrumental in HIV replication. Annexin II (Ann II), a calcium (Ca++)-binding protein, which interacts with HIV Env phosphatidylserine, may be linked to actin cytoskeletal rearrangement and viral trafficking. Actin and annexin II have also been implicated in endosomal compartments, where HIV budding is remarkable. Macrophage mannose receptors (MMR), gp340, CD63, galactosylcerebroside (GalCer), and syndecan (Syn) have been implicated in HIV gp120-macrophage interactions. Dotted-line arrows refer to pathways identified by purified gp120 stimulation and/or inferred from T cells.
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Among the macrophage membrane components implicated as candidates for cofactor status (Table 1)
are those that interact primarily with HIV gp120 or gp41: heparan sulfate proteoglycans, such as syndecan [14
, 15
], the cysteine-rich scavenger receptor, gp340 [20
], MMR [17
18
19
], and elastase [28
]. Human leukocyte elastase, localized to the cell surface, interacts directly with HIV gp41, and copatching of elastase with the canonical HIV receptors, promoted by its natural ligand 1 proteinase inhibitor, enhances infection. HIV attachment to macrophage membranes may also be facilitated by mechanisms in which gp120 associates with the glycolipid GalCer [16
], the sulfated polysaccharide, heparan sulfate [21
, 22
], or possibly, DC-SIGN [19
, 24
, 25
]. Evidence also supports a gp120-induced assembly of a tetramolecular protein complex involving CD4, CXCR4, and PDI as a portal of HIV entry [25
26
27
]. Depending on circumstances, each of these molecules may participate independently or in tandem to entice attachment, concentrate virus at the cell surface, promote fusion, and/or influence signal transduction (Fig. 1)
.
In addition to gp120, the dominant viral ligand engaging CD4 and chemokine coreceptors, the architecture of the HIV Env includes constituents of the host cell membrane hijacked during viral budding. In macrophages, it has long been appreciated that viruses bud from cytoplasmic vacuolar membranes (Fig. 2A
), in preference to the surface [47
]. How or why the virus exploits this replicative stance in macrophages is ill-defined, but this intracellular budding sequence, with accumulation of large numbers of virions in vacuoles, may provide a protective compartment from which the virions escape immune surveillance. Whether from the plasma membrane or endosomal membranes, as it buds, the virus grafts host cell membrane components onto its own coat. This construction of the hybrid viral coat includes not only viral glycoproteins but also macrophage adhesion molecules (ICAM-1), MHC Classes I and II, and phospholipids [49
] but not CD14 or CD45 [36
]. These newly acquired viral surface constituents may, in turn, represent additional recognizable ligands, which interact with molecules on the target cell to favor virus binding, entry, and/or fusion (Table 1)
. In this regard, CD63, a tetraspan transmembrane glycoprotein, found at the cell surface and in endosomal compartments, participates in the events associated with infection, in that antibodies to CD63 selectively blocked R5 HIV infection of primary macrophages without altering CD4, CCR5, or ß chemokines [50
, 51
]. The significance and precise roles played by the interaction of many of these virus-anchored molecules with various cell surface receptors on macrophages in the uptake and transfer of competent virus remain murky but are clearly context-dependent and cannot necessarily be extrapolated from cell lines to primary target cells as a result of differences in their surface constituents. In this regard, the importance of the association between virus ICAM-1, originating from one host cell, and its subsequent interaction with a new host membrane integrin, LFA-1, in HIV uptake and transfer in cell lines could not be demonstrated in primary macrophages and DC [39
].
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Figure 2. Gene expression in macrophages during active viral replication. (A) Peripheral blood monocytes, differentiated to macrophages during 6 days adherence in culture, were infected with HIVBaL, and after 14 days, the cultures were processed for microarray analysis and transmission electron microscopy. At this interval, virions are present and actively budding from intracellular macrophage vacuole membranes. N denotes nucleus, and V is vacuole-containing virions. (B) Summary table of data representing macrophage genes expressed greater than twofold above donor-matched, uninfected cells, as determined in replicate donors by microarray analysis 14 days after infection with HIV, when massive replication is occurring in intracellular vacuoles [49
]. MAPKAP, MAPK-activated protein kinase; GTP, guanosinetriphosphatase; PKC, protein kinase C; CDKN1A, cyclin-dependent kinase inhibitor 1A.
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Another host cell membrane constituent incorporated into the viral envelope is phosphatidyl serine (PS), an anionic phospholipid captured during budding [41
]. As PS is expressed on macrophage membranes but not on viable T cells, fabrication of the patchwork viral cloak will only include PS if the virus has transited through macrophages and possibly apoptotic T cells, which externalize PS. A binding partner for acidic phospholipids expressed on macrophage but not T cell membranes is the protein annexin II, which serves as a recognition molecule for virions expressing PS to favor macrophage-macrophage transmission [29
]. Annexin II, a member of the larger annexin gene family, recognized for its involvement in exocytosis, endocytosis, and ion channel activity, is expressed on the cell surface and endosomal membranes [52
53
54
] as a monomer or a heterotetrameric complex with S100A10 (p11). First recognized as a receptor for CMV and then Rous sarcoma virus [55
, 56
], annexin II has more recently been shown to contribute to the early events of macrophage HIV infection [29
]. In these studies, an interaction between macrophage annexin II and viral PS was documented when blocking annexin II on macrophages with a specific antibody prior to or coincident with exposure to HIV resulted in a significant suppression of R5 HIV infection, as did silencing the expression of annexin II with small interfering RNA (siRNA) [29
]. Blocking annexin II with the mucosal epithelial innate defense molecule, secretory leukocyte protease inhibitor (SLPI), an annexin II ligand, also compromised the infection process [30
, 31
].
Although dramatically inhibiting nascent viral DNA synthesis, the presence of multiple annexin II inhibitors, including SLPI, annexin II-specific siRNA, antiannexin II antibody, or excess soluble annexin II tetramer, during the initial virus inoculation period did not appear to interfere directly with virus binding to the macrophages [29
]. From these data, it was determined that interference with membrane annexin II inhibits infectivity postbinding but prereverse transcription, likely during viral entry/fusion and/or uncoating. It is conceivable that virion binding triggers an association of annexin II with actin, which participates in cytoskeletal reorganization involved in uptake and translocation of the virus from its point of entry at the cell membrane to the innards of the cell. Annexin II, in its monomeric or complexed form with p11, is concentrated at sites where F-actin is coordinated with the plasma membrane and can bind and bundle actin filaments in a Ca++-dependent manner [52
]. Receptor clustering via actin microfilament redistribution has been shown to facilitate virion fusion to the targeted host cell [42
, 57
, 58
]. One might speculate that the lack of PS on certain non-M-tropic viral strains, which were replication-competent in primary CD4+ T cells and used CCR5 for entry in transfected cells, might contribute to the bottleneck in virus entry and/or an early postentry step in macrophages [43
] as a result of an inability to engage annexin II-actin interactions. Those viruses emanating from macrophages and expressing PS would presumably be preferentially transmitted as a result of their added benefit of an annexin II-mediated boost in internalization. Collectively, the data emphasize that the determinants underlying macrophage tropism and cell-to-cell transmission are much more complex than CD4 binding and coreceptor specificity of the virus.
Other candidate host cell surface proteins anchored in HIV membranes include CD28, CD44, and CD62L [39
] (Table 1)
, although their roles and/or cellular partners are less well-delineated. Whereas some of these surface components of cellular origin may become embedded in the budding viral membrane merely as a result of their location in lipid membrane rafts, endosomal membranes, and/or association with HIV Gag proteins and have no evident function in targeting the next host, others are biologically active and contribute to HIV pathogenesis. A systematic analysis between virions sprouting from T cells compared with macrophage-derived virions with regard to host-encoded molecules embedded in the viral membrane has not been performed nor has a comparison of in vivo with in vitro viral progeny. Nonetheless, a constellation of host membrane proteins appears to be incorporated into HIV, irrespective of tropism [45
, 59
], and may foster attachment or binding, stabilize complex formation between the canonical HIV receptors or other conformational membrane protein associations, or promote fusion. In many cases, these membrane molecules serve as modulators of virus entry, intracellular trafficking, signaling, or other cellular functions rather than as essential effectors (Fig. 1
, Table 1
) and depending on their relative contributions, may be considered as therapeutic targets.
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CYTOSKELETAL ASSISTANCE IN HIV LIFE CYCLE
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After engaging one or more of these potential supportive pathways on its new host, HIV fuses with the macrophage membrane, enters the cell, and decloaks to release its capsid into the cell cytoplasm. Disassembly of the capsid frees genomic viral RNA for reverse-transcription into linear, double-stranded cDNA and transport to the nucleus, where it integrates into genomic cellular DNA, and transcripts generated from this provirus provide for synthesis of new, regulatory and structural viral proteins assembled into new progeny [60
]. One of the HIV accessory proteins, Nef, a small, myristoylated protein, interacts with the actin cytoskeleton to facilitate early phases of infection [61
62
63
] associated with penetration of the cortical actin network barrier [62
]. Obstruction of actin polymerization blocks multiple steps in the viral life cycle, including envelope formation with disorganized capsid proteins evident in the host cell cytoplasm [64
]. HIV association with actin during intracellular maturation and assembly provides the virus with the correct conditions for transport, assembly, and viral budding and ultimately, in directing these progeny to sites of cell-cell contact. Interaction of the Gag precursor molecule with actin has been spotted in HIV-infected T cells and macrophages [65
] in structures where virions are budding [66
]. In macrophages, where much of the budding occurs in intracellular vacuoles [47
], characterized as endosomes [51
], molecules such as annexin II and actin further support and regulate these events. Within this specialized platform for viral assembly and production of progeny, macrophages as viral incubators can control the pace of viral release and transmission to new cellular targets, as well as orchestrate pathogenic manifestations with myriad gene products released as a consequence of their initial membrane encounter with HIV, as well as their eventual heavy viral burden.
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HIV SIGNALING PATHWAYS
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Subsequent to soluble gp120 interactions with CD4 and the seven transmembrane G protein-coupled receptor, CCR5, a signaling pathway(s), is engaged, involving intracellular calcium mobilization and PI-3K activation with downstream phosphorylation of MAPKs, ERK1/2, JNK/SAPK, and p38 (Fig. 1)
[67
68
69
]. An intermediate signaling event likely involves Pyk2, a cytoskeletal-associated calcium-regulated protein tyrosine kinase, which is chemokine receptor-activated and an upstream regulator of MAPK [68
]. By implication, intact virions trigger an analogous, intracellular signaling pathway, albeit less evidence has accumulated to clearly define these virion-dependent signaling pathways, in part as a result of subthreshold signal transduction, which may occur in response to limited numbers (physiological) of intact virus [48
]. PI-3K activation triggered by intact virions [11
, 48
, 70
71
72
73
74
], gp120, Nef, and/or Tat is reportedly necessary for viral replication [75
], as it triggers the host cell transcriptional response, fundamental to support of the HIV life cycle (Figs. 1
and 2)
.
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HIV-INDUCED TRANSCRIPTOME CHANGES
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HIV activation of MAPKs influences transcriptional and post-transcriptional events underlying viral permissiveness, cellular defense, and the host response. As the virus has a limited repertoire of genes and gene products, it must efficiently appropriate host cell molecules to support its nasty habits. To determine which virally induced host cell genes are actually instrumental in perpetuating the viral life cycle, recent studies focused on kinetics of transcription in macrophage populations exposed to R5 HIV [48
, 69
, 76
]. As an obligate parasite, HIV is totally dependent on its ability to enjoin host cell machinery required for it to enter into its target cell, replicate, exit, and spread to new hosts to control its destiny and continue its propagation.
Although expression of multiple genes is modified in macrophages in response to their early encounter with HIV [48
, 76
], this repertoire of inducible genes has not yet been systematically analyzed as to whether they are primary or secondary events and whether they are coincident or indispensable for the viral life cycle. Kinetic analyses revealed a contingent of HIV-induced, immediate early genes, which was transient, followed by a more limited profile of changing genes expressed at increasing intervals out to 1–2 weeks after infection [49
]. Considerably more emphasis has been placed on the early signaling events pursuant to HIV-macrophage encounters, and a paucity of data explored transcriptional events during active intracellular viral replication, until recently (Fig. 2
, Day 14 shown). As summarized in Figure 2
, at a time when HIV is predominantly replicating within macrophage vacuoles (Fig. 2A
, representative 10- to 14-day infected macrophage), a different transcriptional profile is seen (Fig. 2B
, summary data) than that observed following initial macrophage-HIV encounters [48
]. Among the genes recognized in a global gene analysis and then shown to be supportive of the HIV life cycle is p21, CDKN1A, uniquely up-regulated as an early response gene and in a biphasic manner, again, strikingly elevated during active viral replication (Fig. 2B)
. Furthermore, studies using a Vpr minus virus showed a decrease in p21 transcription with a corresponding reduction in viral replication, suggesting that Vpr represents at least one mechanism by which HIV drives p21 transcription [48
].
Following identification of p21 as a candidate molecule in facilitating viral replication, efforts to curtail its role were investigated as a mode of blunting infection in macrophages. RNA interference represents a tool to regulate gene expression, and when siRNA, specific for p21 or p21-specific oligonucleotides, was transfected into primary macrophages to silence the expression of p21, HIV infection was aborted, thereby validating p21 as a cellular factor essential to productive HIV infection in this population [48
] (Fig. 3
). Extending these observations, a pharmacologic agent, known to influence p21 expression, the synthetic triterpenoid and peroxisome proliferator-activated receptor 
ligand, CDDO, or its derivative di-CDDO, was shown to moderate virally induced p21 expression and concurrently dampen HIV infection [48
] (Fig. 3)
. CDDO is part of a class of synthetic triterpenoids based on natural products resembling steroids in their biogenesis (cyclization of squalene) and in their pleiotropic actions [77
]. A newly developed CDDO derivative, CDDO-methyl ester [78
], which is orally bioavailable, not only inhibits ERK1/2 activation, but also suppresses HIV (unpublished data). These results, coupled with the evidence that macrophage p21 is a requisite macrophage facilitator of viral replication, intensify the interest to further develop these compounds as antiretroviral agents. Current antiretroviral therapy, often characterized by high toxicity and the emergence of drug-resistant virus strains, may be augmented through the identification of these and other new, antiviral agents targeting host cellular molecules less prone to mutational events.
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Figure 3. Inhibition of HIV infection of macrophages by inhibitors of p21. Macrophages were not pretreated (HIV) or pretreated with oligonucleotides specific for p21 or p21-specific siRNA or with 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a triterpenoid that modulates p21 prior to infection with HIV, as detailed in Vazquez et al. [49
]. Supernatants were collected at 3-day intervals and analyzed for HIV p24 levels by ELISA (Day 10 shown). The positive control (HIV) represents cultures of HIV-infected macrophages not treated with p21 inhibitors. No p24 was detected in parallel, uninfected macrophage cultures (negative control, not shown). The data represent mean ± SEM of replicate experiments. Each of these mechanisms to reduce HIV-induced up-regulation of p21 resulted in suppression of HIV infection compared with untreated, HIV-infected cells (HIV) [49
]. (Inset) Structure of CDDO.
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In addition to the coalition of HIV-induced host cell genes that promote various stages of the viral life cycle, which underscores the persuasive effect of host genetics on viral replication as well as how cellular factors impact on the viral genome, other gene products, including soluble factors, can influence susceptibility to infection of proximal targets, be they recruited macrophages, T cells, dendritic cells (DC), or other populations. Viral induction (gp120-CCR5 signal) of chemokines and cytokines, including MCP-1 [90
], IL-8, myeloid-related protein 14, IL-12, IFN-inducible protein 10, TNF- [48
], and TGF-ß [91
], regulates viral replication, recruitment of new hosts, and immune activation, which cultivates permissiveness to infection and immunopathogenesis [63
, 92
]. Inappropriate activation and cytokine secretion compound the immune dysregulation associated with CD4+ T cell depletion in HIV-infected individuals. In this regard, NF-B activation not only triggers immune activation but also underlies HIV replication [93
, 94
]. DC, whether harboring or infected by HIV or triggered as a bystander effect of the inflammatory cascade, contribute to immune activation [95
] but are also culprits in their transfer of virus to CD4+ T cells. As this generalized immune activation has been associated with cell damage and pathogenesis, intervention studies, which focus on the use of immune suppressants, including mycophenolate mofetil [96
, 97
], hydroxyurea [90
], leflunomide [98
], CDDO [48
], proteosome inhibitors [99
], and other inhibitors of NF-B, such as SLPI [31
, 100
, 101
], warrant further consideration, particularly in light of the additional antiviral activities of some of these molecules, which may prove to be complementary with current antiretroviral therapies.
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CELLULAR RESISTANCE PATHWAYS
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Although macrophages proffer multiple accomplices in support of HIV infection, this population also possesses innate cellular resistance factors. In fact, they, like T cells, express the intracellular defense protein, APOBEC3G [103
], a member of the cytidine deaminase superfamily. In that APOBEC3G is an innate protein with lethal activity against HIV, expression of APOBEC3G in macrophages can potentially abort retroviral infection. This innate defense strategy involves incorporation of cellular APOBEC3G into progeny virions as they assemble and bud from macrophage intracellular or surface membranes to influence the reverse transcription step in subsequent newly infected cells. After entry of the viral core into the target cell, the viral RNA genome is reverse-transcribed into minus-strand cDNA, and at this point, APOBEC3G triggers deamination of the minus-strand cDNA with conversion of cytosines to uracils. Excessive G-to-A hypermutation in the plus strand of the cDNA leads to its degradation or inaccuracies in RT [102
103
104
105
]. APOBEC3G may also have nonenzymatic functions in the disruption of the viral life cycle [106
107
108
109
]. In self-defense, HIV encodes viral infectivity factor (Vif), which hinders the antiviral mutating activity of APOBEC3G by binding to and targeting it for proteasome-mediated degradation. Mechanistically, the Vif protein appears to contain a suppressor of cytokine signaling (SOCS) box, which mediates protein interactions with the cullin E3 ubiquitin ligase complex [Cul5, Elongin B (EloB)+EloC], consistent with reduced infectivity with Vif mutations in this region, although Vif may have additional activities in that Vif phosphorylation blocks EloC interaction [110
, 111
]. Targeting the interaction between E3 ubiquitin ligase complex and Vif might represent an intersect point to prevent APOBEC degradation, thus sustaining its antiviral potential. Moreover, augmentation of low or inadequate levels of APOBEC3G may conceivably tilt the balance between APOBEC and Vif in favor of cellular resistance.
Differential expression of APOBEC3G and additional members of the APOBEC3 cytidine deaminase family in immature monocytes and differentiated macrophages is consistent with the ability of immature peripheral blood monocytes to resist infection, whereas macrophages, whether in culture or in tissues, are particularly vulnerable to this retrovirus [107
, 112
]. Moreover, in recent studies, it has been shown that the APOBEC3G protein exists in an enzymatically active configuration in monocytes, which becomes an inactive high molecular weight ribonucleoprotein complex in mature macrophages [107
]. Of the seven APOBEC3 protein family cytosine deaminases, APOBEC3G and APOBEC3F have been shown to counteract HIV infection [113
, 114
] and are expressed in macrophages [112
]. Recent evidence also indicates that APOBEC3B has antiviral activity [115
, 116
], but the role of the other cytosine deaminases recently identified in macrophages, including APOBEC3A, -C, and -D [112
] in neutralizing HIV, remains to be elucidated. Although cytidine deamination is considered a host defense against viruses, this pathway may also have been taken over ingeniously by HIV to facilitate its escape from immunological and pharmacological abuse [117
], providing yet another source of viral diversification.
Within macrophages, as well as other host cells, additional, innate restriction factors oppose viral replication [63
, 118
] (Fig. 4)
. In this regard, HMGB1, an abundant nuclear protein, inhibits HIV transcription in monocytic cells [119
]. Dicer is an RNase III-like enzyme, which mediates the cell’s RNA-silencing, antiviral defense by processing precursor dsRNAs into siRNAs but may be functionally outwitted by HIV Tat [120
]. Nevertheless, anti-HIV siRNAs are capable of blocking HIV replication under some circumstances [121
, 122
]. TRIM5, a member of the tripartite motif protein family, represents another inherent, host-derived molecule involved in influencing macrophage inhospitality to HIV, but it only works in Old World monkeys, not in human infection [123
]. Mechanistically, TRIM5 blocks an early step in retroviral infection prior to RT, possibly by ubiquitinating the capsid protein [124
]. When targeted by monkey-derived TRIM5, HIV capsid protein uncoating and subsequent initiation of RT are incomplete, and/or new reverse transcripts are targeted for destruction. If the clever maneuver by which HIV dodges TRIM5 suppression in human cells can be deciphered, it may uncover a pathway by which to overcome the nonantagonistic interaction between virus and restriction factor.
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Figure 4. Host cell factors: accomplices or adversaries in HIV infection. HIV infection of macrophages involves partners in binding and entry including CD4, CCR5/CXCR4, and annexin II, as well as additional host-derived factors, which have been co-opted by the virus to promote its life cycle. In addition to the cellular accomplices to HIV, innate, antiviral defense mechanisms are adversarial to productive infection, including the cytidine deaminases, apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3F (APOBEC3F)/G and tripartite motif protein 5 (TRIM5). IFN- may be up-regulated following infection, which in turn, induces IFN-stimulated genes (ISG) with antiviral functions. The balance between accomplices and adversaries may contribute to macrophage resistance or susceptibility to HIV.
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MODULATION OF MACROPHAGE VIRAL SUSCEPTIBILITY
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The majority of HIV accomplices, as well as adversaries in macrophages are constitutively expressed, leading one to surmise that once these barriers are overwhelmed, the cells are indefensible viral targets. However, recent evidence indicates that the antiviral cytokines, IFN- and IFN-, induce APOBEC [112
], in addition to mediating multiple other pathways, which interfere with HIV’s attempt to take over its host cell [125
] (Table 2
). In these studies, potentially in vivo, achievable concentrations of type I IFN, particularly IFN-, were able to augment the levels of APOBEC3G in macrophages with the consequence of improved resistance to HIV [112
]. IFN- and IFN-, upon binding to their cognate receptors and activation of the Jak-Stat signaling cascade, stimulate transcription of hundreds of independent and shared ISG (T. Greenwell-Wild, Z. Rangel, P. Munson, S. M. Wahl, in preparation) [136
], many with antiviral activity (Table 2)
. Nonetheless, silencing of APOBEC3G with siRNA in IFN-stimulated macrophages resulted in significant blockade of IFN-induced anti-HIV activity [112
], emphasizing the importance of this molecule in IFN-mediated, antiretroviral activity.
Similar to APOBEC3G, by which IFN bolsters innate defense against HIV [112
], it has been reported that IFN- also up-regulates TRIM5 [126
], a first step in manipulating this monkey-specific restriction factor (Table 2)
. There are multiple complementary, antiviral pathways mediated by IFN, and among them is ubiquitin-like protein ISG15 [127
], which targets the ubiquitination steps in the HIV replication cycle to minimize HIV assembly. To this end, ISG15 may disrupt the interaction between Gag and TSG101, inhibiting their ubiquitination. Other components of the IFN-mediated innate antiviral barrier include exonuclease ISG20, specific for ssRNA and independently up-regulated by HIV Tat [128
], as well as molecules with known or suspected anti-HIV activity [129
, 131
] (Table 2)
. Moreover, IFN- itself is up-regulated by HIV [137
]. In a continuing tug-of-war, HIV persistently evolves diverse strategies to counteract these innate and IFN-mediated, antiviral mechanisms (Fig. 4)
.
As IFN induces APOBEC3G and other ISG targeting HIV, the question remains unresolved as to why endogenous IFN does not protect against infection. Although the host’s natural immunity likely plays a pivotal role in limiting HIV infection, it is usually inadequate for the enormous challenge and further compromised by the virus itself. Type I IFN production is markedly impaired in primary HIV infection [138
], and in later stages of HIV/AIDS, the relentless decline in the number of CD4+ T cells further blunts the production and availability of IFN and other antiviral molecules. If mechanisms to reverse or overcome the decline of these endogenous innate defense mechanisms can be identified, such interventions may complement vaccine approaches, as well as highly active antiviral therapies.
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SUMMARY
|
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Although HIV can infect and replicate in many cell types and in different tissues throughout the host, the two major cellular reservoirs are nonetheless latently infected resting CD4+ T cells and macrophages. With their major contribution to viral transmission, persistence, and dissemination, macrophages are of particular importance to the pathogenesis of HIV and remain a major obstacle in eradicating the virus. Barring interference at the multiple requisite steps in viral entry, replication, assembly, and budding or at separating the virus from its next host cell incubator, the HIV life cycle and the natural progression of the disease continue. Targeting viral post-entry functions [139
], although effectively subduing viral replication and its pathogenic sequelae, does not eradicate the virus, propelling continued efforts to focus interventional strategies on entry events [140
] and on host cell molecules exploited by the virus and essential to its life cycle. Recent data and ongoing studies, uncovering novel host cell-based HIV cofactors/restriction factors, offer new possibilities for intervention. In this regard, annexin II inhibitors, p21 inhibitors, and enhancers of APOBEC3 cytidine deaminases, used independently or in conjunction with current antiretroviral therapies, may inhibit HIV infection and replication. Continued characterization of such molecular determinants of macrophage infection is paramount to the identification of additional, effective inhibitors, vaccine strategies, and other modulators of infection and pathogenesis perpetrated by HIV. Defining and ultimately manipulating such requisite molecular events may enable restriction of macrophage HIV infection, thereby eliminating recalcitrant tissue bastions of virus.
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ACKNOWLEDGEMENTS
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This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. The authors are grateful to Dr. J. M. Orenstein, George Washington University School of Medicine, for transmission electron microscopy.
Received March 1, 2006;
revised May 5, 2006;
accepted May 8, 2006.
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ABSTRACT
INTRODUCTION