CD36-specific antibodies block release of HIV-1 from infected primary macrophages and its transmission to T cells

Berrè, Stefano; Gaudin, Raphaël; Alencar, Bruna Cunha de; Desdouits, Marion; Chabaud, Mélanie; Naffakh, Nadia; Rabaza-Gairi, Marc; Gobert, François-Xavier; Jouve, Mabel; Benaroch, Philippe

doi:10.1084/jem.20130566

Cited by 43 publications

(50 citation statements)

References 67 publications

(121 reference statements)

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“…HIV-1 Gag colocalized substantially with CD81 but was significantly reduced in regions labeled with lysosomal marker Lamp-1, consistent with the reported VCC-like location of virus ( Fig. 2A and B) (3,39,40).…”

Section: Efficient Contact-mediated Hiv-1 Infection From Mdm To T Cellssupporting

confidence: 89%

“…MAb access to the VCC is likely to be limited by very low rates of diffusion through the narrow surface-connecting conduits (38). However, MAbs specific for cellular molecules may be actively trafficked to the VCC, as demonstrated by CD36-specific MAb binding to its cognate antigen on macrophages leading to internalization into the VCC and inhibition of virus release (39).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

High-Multiplicity HIV-1 Infection and Neutralizing Antibody Evasion Mediated by the Macrophage-T Cell Virological Synapse

Duncan

Williams

Schiffner

et al. 2014

J Virol

100

113

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Section: Efficient Contact-mediated Hiv-1 Infection From Mdm To T Cellssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

High-Multiplicity HIV-1 Infection and Neutralizing Antibody Evasion Mediated by the Macrophage-T Cell Virological Synapse

Duncan

Williams

Schiffner

et al. 2014

J Virol

100

113

View full text Add to dashboard Cite

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“…Taken together, these studies suggest that by using clodronate or its analogs, the gut macrophage reservoir could potentially be reduced to decrease the viral burden in patients undergoing therapy. Berre et al (63) examined the inhibitory effect of an antibody against the scavenger receptor CD36 that is used by newly formed virions in virus-containing compartments in macrophages. Their results showed that silencing of CD36 in HIV-infected macrophages inhibited both the release of virions and the transmission of virus to CD4 T cells, suggesting that therapeutic blocking of CD36 could potentially prevent viral dissemination from infected macrophages.…”

Section: Gut Macrophage Hiv Reservoir and Functional Curementioning

confidence: 99%

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Brown¹,

Mattapallil²

2014

Clin. Vaccine Immunol.

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The gastrointestinal tract (GIT) is a primary site for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection, replication, and dissemination. After an initial explosive phase of infection, HIV establishes latency. In addition to CD4 T cells, macrophages are readily infected, which can persist for long periods of time. Though macrophages at various systemic sites are infected, those present in the GIT constitute a major cellular reservoir due to the abundance of these cells at mucosal sites. Here, we review some of the important findings regarding what is known about the macrophage reservoir in the gut and explore potential approaches being pursued in the field to reduce this reservoir. The development of strategies that can lead to a functional cure will need to incorporate approaches that can eradicate the macrophage reservoir in the GIT. Macrophages are one of the most abundant immune cells in the gut (1, 2). Morphologically, gut macrophages are similar to most resident tissue macrophages, with a mononuclear shape and a granular cytoplasm, and they are highly phagocytic and microbicidal (3-5). They express major histocompatibility complex (MHC) class II, CD36, CD68, CD163 (6, 7), and CD209 (7) but have low levels of CD80, CD86, and CD40 (8-11). Unlike monocytes in peripheral blood that are largely CD14 ϩ , human mucosal macrophages in the gut have been shown to express aϪ phenotype (12, 13). The expression of CD4 and CCR5/CXCR4 key receptors for human immunodeficiency virus (HIV) infection, on macrophage populations has been shown to differ based on the sites the cells reside in. Shen et al. (14) showed that vaginal macrophages expressed CD4 and CCR5/CXCR4 similarly to blood monocytes, whereas intestinal macrophages expressed little or no detectable CD4 and CCR5/CXCR4 (15-17).Interestingly, under normal conditions or in response to Tolllike receptor (TLR) ligands, gut macrophages constitutively secrete anti-inflammatory cytokines, such as interleukin-10 (IL-10), rather than proinflammatory mediators, such as IL-12, IL-23, tumor necrosis factor alpha (TNF-␣), IL-1, IL-6, and interferoninducible protein 10 (IP-10) (18)(19)(20)(21)(22), suggesting that intestinal macrophages may be critical for maintaining immune homeostasis in the gastrointestinal tract (6). Smythies et al. (23) reported that intestinal macrophages displayed significant inflammation anergy even though they had avid phagocytic and bactericidal activity. Depletion of mucosal macrophages was shown to be associated with increased susceptibility to colitis and graft-versus-host disease in mice (24-26). Likewise, altering the phenotype of macrophages to that of a proinflammatory phenotype as seen during HIV replication was associated with increased inflammation and tissue damage (27).In addition to their role in maintaining mucosal immune homeostasis, gut macrophages, like dendritic cells (DC), have been shown to sample microbes directly from the intestinal lumen and transfer these antigens to DC for processing or tran...

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“…VCCs have been shown to contain tetraspanins, such as CD9, CD53, CD81, and CD82 (12,15,23,24). In addition, CD18 (a leukocyte-specific ␤2 integrin), CD44 (a cell adhesion protein/hyaluronic acid receptor), and CD36 (a lowdensity lipoprotein [LDL] receptor) are also present (24)(25)(26). Cellular compartments with identical markers also exist in the absence of HIV-1.…”

mentioning

confidence: 99%

Molecular Determinants Directing HIV-1 Gag Assembly to Virus-Containing Compartments in Primary Macrophages

Inlora

Chukkapalli

Bedi

et al. 2016

J Virol

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The subcellular sites of HIV-1 assembly, determined by the localization of the structural protein Gag, vary in a cell-type-dependent manner. In T cells and transformed cell lines used as model systems, HIV-1 assembles at the plasma membrane (PM). The binding and localization of HIV-1 Gag to the PM are mediated by the interaction between the matrix (MA) domain, specifically the highly basic region, and a PM-specific acidic phospholipid, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ]. In primary macrophages, prominent accumulation of assembling or assembled particles is found in the virus-containing compartments (VCCs), which largely consist of convoluted invaginations of the PM. To elucidate the molecular mechanism of HIV-1 Gag targeting to the VCCs, we examined the impact of overexpression of polyphosphoinositide 5-phosphatase IV (5ptaseIV), which depletes cellular PI(4,5)P 2 , in primary macrophages. We found that the VCC localization and virus release of HIV-1 are severely impaired upon 5ptaseIV overexpression, suggesting an important role for the MA-PI(4,5)P 2 interaction in HIV-1 assembly in primary macrophages. However, our analysis of HIV-1 Gag derivatives with MA changes showed that this interaction contributes to Gag membrane binding but is dispensable for specific targeting of Gag to the VCCs per se. We further determined that deletion of the NC domain abolishes VCC-specific localization of HIV-1 Gag. Notably, HIV-1 Gag localized efficiently to the VCCs when the NC domain was replaced with a leucine zipper dimerization motif that promotes Gag multimerization. Altogether, our data revealed that targeting of HIV-1 Gag to the VCCs requires NC-dependent multimerization. IMPORTANCEIn T cells and model cell lines, HIV-1 Gag localizes to the PM in a manner dependent on the MA-PI(4,5)P 2 interaction. On the other hand, in primary macrophages, HIV-1 Gag localizes to convoluted intracellular membrane structures termed virus-containing compartments (VCCs). Although these compartments have been known for decades, and despite the implication of viruses in VCCs being involved in virus reservoir maintenance and spread, the viral determinant(s) that promotes Gag targeting to VCCs is unknown. In this study, we found that the MA-PI(4,5)P 2 interaction facilitates efficient Gag membrane binding in macrophages but is not essential for Gag targeting to VCCs. Rather, our results revealed that NC-dependent multimerization promotes VCC targeting. Our findings highlight the differential roles played by MA and NC in HIV-1 Gag membrane binding and targeting and suggest a multimerization-dependent mechanism for Gag trafficking in primary macrophages similar to that for Gag localization to uropods in polarized T cells.

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CD36-specific antibodies block release of HIV-1 from infected primary macrophages and its transmission to T cells

Abstract: Antibody targeting CD36 on HIV-1–infected macrophages results in rapid retention of virions within virus-containing compartments to inhibit release and viral transmission to T cells.

Cited by 43 publications

References 67 publications

High-Multiplicity HIV-1 Infection and Neutralizing Antibody Evasion Mediated by the Macrophage-T Cell Virological Synapse

High-Multiplicity HIV-1 Infection and Neutralizing Antibody Evasion Mediated by the Macrophage-T Cell Virological Synapse

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Molecular Determinants Directing HIV-1 Gag Assembly to Virus-Containing Compartments in Primary Macrophages

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