Skip Navigation LinksHome > September 2011 - Volume 6 - Issue 5 > Macrophages and HIV-1
Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e3283497203
Innate immunity: Edited by William A. Paxton and Teunis B.H. Geijtenbeek

Macrophages and HIV-1

Cobos-Jiménez, Viviana; Booiman, Thijs; Hamann, Jörg; Kootstra, Neeltje A.

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Author Information

Department of Experimental Immunology, Sanquin Research, Landsteiner Laboratory, and Center for Infectious Diseases and Immunity Amsterdam (CINIMA) at the Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands

Correspondence to Dr Neeltje A. Kootstra, Department of Experimental Immunology (M01-107), Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The NetherlandsTel: +31 20 5668291; fax: +31 20 5669756; e-mail: n.a.kootstra@amc.uva.nl

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Abstract

Purpose of review: Macrophages play an important role in HIV-1 pathogenesis and contribute to the establishment of the viral reservoir responsible for continuous virus production. This review will discuss new insights into HIV-1 infection in macrophages and the effect of infection on immune function and pathology.

Recent findings: New cellular factors interacting with various steps of the HIV-1 replication cycle, such as entry, integration, transcription, and assembly of new viral progeny, have been identified. Cellular and viral microRNAs have been shown to regulate virus replication, promote viral latency, and prolong cell survival. Interference with innate immune functions, like phagocytosis, autophagy, cytokine production, and T-cell activation by HIV-1 has been found to contribute to virus replication and latency. Growing evidence indicates an important role of infected macrophages in a variety of HIV-1-associated diseases, including neurocognitive disorders.

Summary: Under combined antiretroviral therapy (cART), HIV-1 continues to persist in macrophages. Better understanding of HIV-1 infection in macrophages may lead to new adjunctive therapies to improve cART, specifically targeting the viral reservoir and ameliorating tissue-specific diseases.

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Introduction

Cells of the monocyte/macrophage lineage are key players in the innate immune system. Monocytes circulating in the blood stream continuously repopulate the macrophage population that resides in the tissues and provide a first line of defense against invading pathogens. Macrophages are important target cells for HIV-1 infection and are amongst the first cells that get infected. Furthermore, macrophages are more resistant to the cytopathic effects of viral infection, and therefore, they continue to produce virus and serve as a viral reservoir for extended periods of time.

In this review, recently identified cellular factors involved in HIV-1 infection in macrophages and the effect on innate functions of macrophages will be discussed. Additionally, an update on the role of HIV-1-infected macrophages in HIV-1-associated neurocognitive disorders (HANDs) will be given.

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Cellular factors involved in HIV-1 replication in macrophages

Monocytes are refractory to HIV-1 infection in vitro, yet become susceptible to infection during differentiation into macrophages [1,2]. However, cytokine-induced polarization towards a classically activated M1 or alternatively activated M2 phenotype by IFN-γ/TNF-α or IL-4, respectively, results in resistance to HIV-1 infection [3]. During the replication cycle, HIV-1 utilizes the cellular machinery of macrophages in order to produce new viral progeny. Differential expression of HIV-1 dependency or inhibitory factors during macrophage differentiation, activation, and polarization might explain changes in susceptibility of these cells to HIV-1 infection. Recently, a large number of cellular factors involved in HIV-1 replication have been identified in genome-wide siRNA screens using cell lines [4–7]. The overlap in identified genes in these studies was limited, indicating that dependency of HIV-1 on certain cellular factors might for instance be dependent on the cell types used in the screen. The ability of primary macrophages to support HIV-1 replication in vitro was found to be highly variable and dependent on the donor, suggesting that genetic variations may contribute to susceptibility to HIV-1 infection [8]. A genome-wide association study identifying genetic polymorphisms allowed identification of factors like DYRK1A (Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) that plays a role in HIV-1 susceptibility of primary macrophages; still, the function of the kinase DYRK1A in the HIV-1 replication cycle has to be established [9•].

Several studies identified cellular proteins that interact with HIV-1 at different steps in the replication cycle in primary macrophages. HIV-1 infects macrophages through binding of the HIV-1 envelope protein gp120 to CD4 and CCR5, followed by viral uptake and entry into the cell. The integrin αvβ5 has been described as novel contributor to HIV-1 entry and viral replication in macrophages [10]. Moreover, Carter et al.[11•] identified a novel endocytic entry pathway, similar to macropinocytosis. They showed that this pathway does not depend on caveolin but on actin rearrangements, Na+/H+ exchange, and cellular factors, like Rac GTPase, N-WASP, Pak1, and dynamin GTPase. Other components of the macropinocytosis pathway, such as PI-3 kinase, Rho kinase, myosin II, and clathrin, did not affect HIV-1 entry into macrophages.

In the cytoplasm, the viral RNA is reverse-transcribed into a double-stranded DNA genome. In macrophages, reverse transcription and subsequent integration were restricted by the cyclin-dependent kinase inhibitor p21Cip1/Waf1 upon activation by immune complexes that form through binding of antibodies to HIV-1 or other coinfecting microorganisms throughout the course of infection [12]. When the Fc portion of IgG, present in antibody-coated microorganisms, antigens, or cell debris, binds and cross-links FcγR, expressed on the cell surface of macrophages, several cellular functions are triggered, which affect the capacity of these cells to enable HIV-1 productive infection [12].

In contrast, CD63, a type II cellular membrane protein that is incorporated into viral particles, supported reverse transcription and subsequent steps of the viral replication cycle, possibly through intracellular signaling pathways essential for HIV-1 postentry replication steps. It was shown that silencing of CD63 by siRNA decreased formation of full-length HIV-1 cDNA and reduced the amount of integrated HIV-1 cDNA [13]. Furthermore, nuclear translocation and integration of the viral genome required phosphorylation of the inner nuclear envelope protein emerin by virion-associated Extracellular Signal-Regulated Kinase 2 (ERK2)/mitogen-activated protein kinase (MAPK) in nondividing cells [14].

After integration, the viral genome is transcribed by the cellular machinery, leading to protein production and assembly of new viral particles. Nerve growth factor (NGF), secreted by infected macrophages, enhanced HIV-1 transcription through Tropomyosin-related Kinase A (TrKA), Protein Kinase C (PKC) activation, and NF-κB, ERK, and p38 kinase signaling [15]. In microglia, the DNA repair protein Rad51 also enhanced NF-κB-induced transcription [16].

Late in the viral replication cycle, tail-interacting protein of 47 kDa (TIP47) was essential for the production of infectious new viral particles. Bauby et al.[17] demonstrated that TIP47 acts as a ‘bridge’ molecule between the matrix domain of Gag and the gp41 cytoplasmic domain of Env, allowing their incorporation into viral particles. Anexin 2, although not required for particle production, was also essential for maintaining infectivity of the viral progeny in infected primary macrophages [18].

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In summary, for efficient replication, HIV-1 continuously interacts with the cellular machinery of macrophages, and several studies have identified novel cell type-specific factors that are involved at different steps of the replication cycle of the virus. Moreover, environmental conditions, like cytokine production and immune responses, may induce cellular activation or differentiation that affects the macrophages and their ability to support HIV-1 replication.

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Role of microRNAs in HIV-1-infected macrophages

Cellular microRNA (miRNA) pathways have been described to interfere with HIV-1 replication and contribute to viral latency through direct targeting of HIV-1 transcripts or targeting of cellular RNAs encoding for proteins essential for replication. It was demonstrated that Tat-mediated HIV-1 gene expression is highly dependent on cyclin T1 [19], which can be regulated by miRNA-198, a miRNA abundantly present in monocytes [20]. A decrease in miRNA-198 during differentiation into macrophages resulted in enhanced levels of cyclin T1 [20], indicating that miRNA-198 regulates HIV-1 replication in monocytes/macrophages through regulation of cyclin T1 expression.

Recently, a number of cellular miRNAs that directly target HIV transcripts were identified [21]. Monocytes expressed high levels of the anti-HIV miRNAs miRNA-28, miRNA-150, miRNA-223, and miRNA-382. Expression levels of these miRNAs decreased during differentiation of monocytes into macrophages and were inversely correlated with the susceptibility to HIV-1 infection [22].

HIV-1 also expresses miRNAs of its own that might be able to target expression of cellular genes regulating viral replication. At present, at least three miRNAs derived from different regions [Trans-Activation Response element (TAR), Negative regulatory Factor (Nef), and Long Terminal Repeat (LTR)] of the HIV genome have been identified [23–28]. It has been shown that the TAR miRNA protects the infected cell from apoptosis, and two possible cellular targets, ERCC1 and IER3, which are involved in apoptosis, have been identified [25].

HIV-1 can modulate the host RNA interference pathways to promote either viral latency or suppress the innate responses against viruses. The HIV-1-accessory proteins Vpr and, to a lesser extent, Nef down-regulated Dicer expression, thus suppressing the complete miRNA pathway in Phorbol 12-Myristate 13-Acetate (PMA) or Macrophage-Colony Stimulating Factor (M-CSF)-treated macrophages derived from U937 cells [29]. Additionally, HIV-1 Tat disturbed the cellular RNA interference pathway through inhibition of Dicer [23,30]; however, the latter was contradicted by a recent study demonstrating that Tat expression had no effect on RNA interference mediated by endogenous and exogenous miRNA [31]. In microglial cells, the resident macrophages in the central nervous system (CNS), HIV-1 induced expression of miRNA-146a, which targets MCP-2, a potent inhibitor of CD4/CCR5-mediated HIV-1 entry [16].

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Innate immunity to HIV-1 and evasion strategies of the virus

HIV-1 replication and microbial translocation from the gut to the blood lead to immune activation. Recent studies revealed contrasting roles for Toll-like receptor (TLR) ligands, derived from different microbial invaders, in either suppressing or enhancing HIV-1 replication in macrophages. TLR3 activation inhibited HIV-1 infection likely through the combined induction of type I interferons, restriction factors, CCR5 ligands, and microRNAs [32]. Moreover, TLR3 signaling reduced Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) expression in breast milk macrophages, indicating a lowered risk of mother-to-child transmission [33]. Prothymosin α, secreted by CD8+ T cells and interacting uniquely with TLR4 in primary macrophages, induced production of IFN-β and TNF-α, which inhibit HIV-1 replication [34]. Furthermore, ligands for both TLR3 and TLR4 potently inhibited HIV-1 replication in macrophage-like cells and microglia through interferon regulatory factor 3 (IRF3), inducing a proinflammatory response [35,36]. Inhibition of virus replication was also observed upon TLR9 activation, whereas TLR5 activation was associated with enhanced virus replication [37]. The differential effects of TLR5/9 signaling on HIV-1 replication correlated with changes in the production of CC and CXC chemokines [37]. Finally, TLR8 stimulation activated HIV from latently infected monocytic cell lines via the MAPK pathway [38].

Upon viral infection, receptors that recognize viral nucleic acids initiate a cellular innate immune response. Central to this response are type I interferons that potently inhibit the early stage of HIV-1 replication. Further characterization of the IFNα-induced postentry block to HIV-1 infection revealed involvement of the proteasome [39] and excluded a role for the restriction factors APOBEC3G or tetherin [40]. Notably, HIV-1 infection in macrophages neither triggered NF-κB nor IRF3 pathways nor did it induce type I interferon gene expression [41]. The molecular basis behind the lack of functional recognition of HIV-1 in macrophages is not understood yet. TREX1 might be one of the cellular factors responsible for impeding type I interferon responses. This DNase prevented production of IFN-β by binding to HIV-1 DNA copies in the cytoplasm, allowing successful integration, thus evading activation of innate immune responses in primary macrophages [42••]. Moreover, Solis et al.[43] found a mechanism of HIV-1 protease-mediated sequestering of the cytoplasmic dsRNA sensor RIG-I.

In spite of the muted changes to the macrophage transcriptome upon HIV-1 infection [41], different effects of HIV-1 have been reported. The HIV-1 accessory protein Nef was shown to induce MIP-1α and MIP-1β production in macrophages, thereby enhancing viral replication and dissemination by recruitment of T cells [44]. The motif in Nef responsible for the induction of MIP-1α/β production was not involved in other functions, like Major Histocompatibility Complex (MHC) class I and CD4 downmodulation [45]. Of notice, two studies reported upregulation of programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2 in HIV-1-infected monocytes and macrophages [46,47•]. PD-1 and PD-L1/2 belong to the B7-CD28 family and regulate T-cell activation and tolerance. When engaged in combination with the T-cell receptor, PD-1/ligand signaling resulted in an inhibitory signal affecting proliferation and cytokine production. HIV-1 entry into macrophages induced PD-L1 and PD-L2 expression [46], thereby inhibiting T-cell activation and recognition of the infected macrophage. In viremic HIV-1-infected individuals, high expression of PD-1 and PD-L1 was observed on monocytes and CD4+ T cells, respectively. Monocytes that expressed high levels of PD-1 produced large amounts of IL-10 upon PD-1 triggering, which resulted in inhibition of specific T-cell responses [47•].

Mazzolini et al.[48•] demonstrated that HIV-1 infection of macrophages impairs their ability to phagocytose pathogens opsonized by antibodies or complement. Opsonized pathogens efficiently attach to the HIV-1-infected macrophage, but pathogen uptake was impaired due to a defect in membrane remodeling involving recycling of endosomes bearing adaptor protein 1 (AP1), Vesicle associated membrane protein (VAMP3), and TNF-α. Nef interacted with AP1 and prevented recruitment of AP1 to the phagocytic cup [48•].

Autophagy is a homeostatic process involving degradation of cellular components and can act as an innate mechanism against pathogens. Notably, autophagy can also be exploited by pathogens to increase their replication. Efficient HIV-1 replication in macrophages required autophagy, as shown by the association of Gag proteins with vesicles positive for the autophagosome marker LC3 in macrophages [49,50]. Nef had a dual role in HIV-induced autophagy in macrophages during infection as it enhances formation of autophagosomes, but also inhibited maturation of early autophagosomes in order to protect the virus from degradation and limit presentation of viral peptides by MHC [50]. HIV-1 also inhibited autophagy activity of uninfected bystander cells. Tat produced by the infected cells regulated autophagy in adjacent cells through Src-Akt and STAT3 activation [51] and inhibition of IFNγ-induced STAT1 phosphorylation [52]. Disruption of autophagy by HIV-1 interferes with the host defense mechanisms against invading pathogens, thereby creating a favorable environment for opportunistic infections.

In conclusion, HIV-1 does not evoke a strong innate immune response, involving for instance type I interferons and NF-κB, upon infection of primary macrophages. Although HIV-1-infected macrophages are dysfunctional, they are able to evade recognition by the immune system and serve as viral reservoir, disseminating the virus to various tissues. Understanding the mechanisms behind these events will give more insight into the development of diseases related to HIV-1 infection in macrophages.

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Diseases associated with HIV-1 infection in macrophages: neurocognitive disorders

HIV-1-infected macrophages contribute to a multitude of tissue-specific diseases, including AIDS-related lymphomas, cardiovascular diseases, and HIV-1-associated neurocognitive disorders (HAND), of which HIV-1-associated dementia (HAD) is the most severe complication [53]. Early in the course of infection, HIV-1 transits to the CNS via infected macrophages and lymphocytes when it settles in perivascular macrophages, microglia, and astrocytes [54–56]. Although astrocytes are not productively infected, they form the majority of cells in the brain and are critical for maintaining essential brain functions. Replication in macrophages and activated microglia leads to production of viral and proinflammatory proteins creating a neurotoxic environment. Recently, therapeutic compounds that reduce secretion of proinflammatory cytokines and chemokines by HIV-1-infected macrophages such as kinase inhibitor CEP-1347 [57•] and platelet-activating factor (PAF) antagonist PMS-601 [58] have been identified.

Production of proinflammatory chemokines, like CCL2, by infected macrophages, microglia, and astrocytes increased transmigration of circulating infected monocytes and macrophages over the blood–brain barrier (BBB) [59–62]. In-vitro experiments showed that a HIV-1-susceptible CD14+CD16+CD11b+Mac387+ monocyte/macrophage subpopulation preferentially migrated across the BBB in response to CCL2. Within this subpopulation, an upregulation of genes involved in chemotaxis and metastasis was observed [63]. The increase in CCL2 expression in astrocytes was induced through contact with membrane-associated TNF-α on HIV-1-infected macrophages [64].

Once infected, the CNS acts as a viral reservoir and is capable of re-seeding the periphery with HIV-1, most likely via the meninges as primary transport tissue [65]. Within the CNS, viral proteins, such as gp120, gp41, and Tat, have strong neurotoxic effects and have been implicated in the development of HAD [66]. In macrophages, microglia, and neuronal cells, HIV-1 gp120 elicits p38 MAPK activation, which is required for neurotoxicity [67]. HIV-1 Tat has a direct toxic effect on neurons and can induce expression of adhesion molecules and chemokines in astrocytes and microglia attracting monocytes/macrophages to the brain [68]. Tat also induced suppressor of cytokine signaling 3 (SOCS3), thereby inhibiting IFN-β signaling, thus enhancing viral replication in macrophages and promoting HAD development [69]. Recent studies indicated clade-specific differences in the induction of neuropathogenesis. Clade B viruses had higher replication kinetics in macrophages and their Tat protein was more neurotoxic as compared to clade C viruses [70,71].

Treatment of HIV-1-infected individuals with combined antiretroviral therapy (cART) has diminished the prevalence of severe AIDS-related complication, like HAD. However, milder forms of HAND are increasingly recognized in a substantial number of aging HIV-1-infected individuals on cART and are now one of the most feared complications of the infection [53,72•]. Future research will have to elucidate the role of HIV-1-infected macrophages in HAND development in the cART era.

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Conclusion

The introduction of cART has reversed the fatal course of HIV-1 infection; however, serious complications, like HAND are still frequently observed and have been associated with the persistent presence of HIV-1 in macrophages. cART controls virus replication and, at least partially, reverses the functional immune defects caused by HIV-1. Yet, due to resistance to HIV-1-induced apoptosis, efficient evasion from immunity, and wide tissue dissemination, virus-infected macrophages function as cellular reservoir for the virus, which is a main hurdle for the eradication of HIV-1. Identification of cellular factors involved in HIV-1 replication in macrophages will increase the understanding of both virus- and cell-type-specific aspects of viral replication and may identify new therapeutic targets specifically targeting HIV-1 reservoirs. Even though these therapies may not be able to completely eradicate HIV-1, a reduction of the viral load in macrophages will further improve life with HIV-1.

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Acknowledgements

The work was supported by the Landsteiner Foundation for Blood Transfusion Research (Grant 0526) and the Academic Medical Center of the University of Amsterdam.

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Conflicts of interest

There are no conflicts of interest.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

* • of special interest

* •• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 446).

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72•. Schouten J, Cinque P, Gisslen M, et al. HIV-1 infection and cognitive impairment in the cART-era: a review. AIDS 2010; 25:561–575.

This review gives an overview on HIV-1-associated neurocognitive disorders in the cART era, including clinical, neurological, and neuropsychological findings.

Keywords:

HIV; HIV-1-associated neurocognitive disorder; immune evasion; innate immunity; macrophage; microRNA

© 2011 Lippincott Williams & Wilkins, Inc.

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