HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated cell lysis through down-modulation of CD4 and BST2

Pham, Tram N. Q.; Lukhele, Sabelo; Hajjar, Fadi; Routy, Jean‐Pierre; Cohen, Éric A.

doi:10.1186/1742-4690-11-15

Cited by 108 publications

(113 citation statements)

References 41 publications

(52 reference statements)

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“…Most notably, Vpu augments virion release by downregulating CD4 (12)(13)(14)(15), whose presence on the cell surface would otherwise promote elimination of infected cells through antibody-dependent cellular cytotoxicity (16)(17)(18), as well as the host restriction factor tetherin (also known as BST2 or CD317), whose presence would otherwise capture mature virions at the cell surface (19)(20)(21)(22). Vpu is also reported to form cationselective ion channels (11,(23)(24)(25)(26)(27)(28)(29)(30); however, this property is controversial (31,32), and its role in HIV-1 replication is unknown (11).…”

mentioning

confidence: 99%

Novel Acylguanidine-Based Inhibitor of HIV-1

Moons

Tietjen

Miller

et al. 2016

J Virol

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The emergence of transmissible HIV-1 strains with resistance to antiretroviral drugs highlights a continual need for new therapies. Here we describe a novel acylguanidine-containing compound, 1-(2-(azepan-1-yl)nicotinoyl)guanidine (or SM111), that inhibits in vitro replication of HIV-1, including strains resistant to licensed protease, reverse transcriptase, and integrase inhibitors, without major cellular toxicity. At inhibitory concentrations, intracellular p24Gag production was unaffected, but virion release (measured as extracellular p24Gag ) was reduced and virion infectivity was substantially impaired, suggesting that SM111 acts at a late stage of viral replication. SM111-mediated inhibition of HIV-1 was partially overcome by a Vpu I17R mutation alone or a Vpu W22* truncation in combination with Env N136Y. These mutations enhanced virion infectivity and Env expression on the surface of infected cells in the absence and presence of SM111 but also impaired Vpu's ability to downregulate CD4 and BST2/tetherin. Taken together, our results support acylguanidines as a class of HIV-1 inhibitors with a distinct mechanism of action compared to that of licensed antiretrovirals. Further research on SM111 and similar compounds may help to elucidate knowledge gaps related to Vpu's role in promoting viral egress and infectivity. T he development and scale-up of effective combination antiretroviral therapies have significantly reduced human immunodeficiency virus type 1 (HIV-1)-related morbidity and mortality globally (1); however, selection and transmission of drug-resistant HIV-1 strains remain a concern (2, 3). Thus, new antivirals that overcome drug resistance or act via novel mechanisms are needed. Acylguanidines are a broad class of antiviral compounds that target ion channels and other host and viral factors (4-8). Their anti-HIV-1 activity is exemplified by 5-(N,N-hexamethylene) amiloride (HMA; Fig. 1A) (5, 6), as well as N-(5-(1-methyl-1H-pyrazol-4-yl)naphthalene-2-carbonyl)guanidine (BIT-225; Fig. 1B) (7). HMA and BIT-225 inhibit HIV-1 replication in monocyte-derived macrophages at low micromolar concentrations (6, 7). Moreover, treatment of infected cells with these compounds results in reduced budding and release of viral particles without affecting intracellular viral protein production, suggesting that blockade occurs at a late stage of viral replication (5, 7). IMPORTANCE New inhibitors of HIV-1 replication may be useful as therapeutics to counteract drug resistance and as reagents to perform more detailed studies of viral pathogenesis. SM111 is a small molecule that blocks the replication of wild-type and drug-resistant HIV-1 strains by impairing viral release and substantially reducing virion infectivity, most likely through its ability to preventHMA and BIT-225 are both reported to target the HIV-1 accessory protein Vpu, an ϳ81-amino-acid transmembrane protein that is found in HIV-1 and some simian immunodeficiency virus (SIV) lineages and enhances viral replication through multiple mechanisms (...

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confidence: 99%

Novel Acylguanidine-Based Inhibitor of HIV-1

Moons

Tietjen

Miller

et al. 2016

J Virol

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“…(i) HIV-1 Vpu hijacks trafficking pathways of the clathrin adaptor protein complex 1 (AP1) and adaptor protein complex 2 (AP2) to induce postendocytic membrane trafficking events that remove tetherin from the cell membrane (456,458). (ii) Despite the fact that tetherin enhances the susceptibility of HIV-infected cells to antibodies, HIV-1 Vpu and Nef antagonize tetherin to protect HIV-infected cells from antibody-dependent cell-mediated cytotoxicity, a type of human immune response where virus-specific antibodies activate the killing of HIV-infected cells (470)(471)(472). (iii) Among four HIV-1 groups (groups M, N, O, and P), only HIV-1 group M encodes Vpu that robustly counteracts human tetherin (473).…”

Section: Vpu-tetherin/cd4-nef Associationmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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“…The accessory proteins Nef and Vpu independently downregulate the host cofactor CD4 (1,2), whereas the Vpu protein of group M strains downregulates the host antiviral factor BST2 (CD317; tetherin) (3,4). Recent observations indicate that the absence of CD4 Ϫ and BST2 downregulation increases the exposure of HIV-1 envelope glycoprotein (Env) molecules on the surface of the infected cell (5)(6)(7)(8)(9). The increase in cell surface Env is presumably due to the retention of virions on the cell surface by BST2 (3,10), although CD4 can also contribute to virion retention (11).…”

Section: Importancementioning

confidence: 99%

“…In addition, when in complex with CD4, the conformation of Env is changed and CD4-induced (CD4i) epitopes are exposed (12). These effects yield an increase in the sensitivity of infected cells to antibody-dependent cellular cytotoxicity (ADCC) (5)(6)(7)(8)(9). Thus, inhibiting Vpu and/or Nef should increase the sensitivity of infected cells to ADCC and could facilitate immunologic clearance of the infection.…”

Section: Importancementioning

confidence: 99%

Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1

Tokarev

Stoneham

Lewinski

et al. 2016

J Virol

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HIV-1 Vpu decreases the exposure of epitopes within the viral envelope glycoprotein (Env) on the surface of infected cells by downregulating both BST2 and CD4. To test the hypothesis that inhibiting Vpu activity would increase the exposure of these epitopes and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC), we treated cells with the Nedd8 activation enzyme (NAE) inhibitor MLN4924, which inhibits the cullin1-based ubiquitin ligase complex coopted by Vpu to degrade cellular targets. Treatment of HeLa cells with MLN4924 or expression of a dominant negative mutant of cullin1 inhibited the Vpu-mediated downregulation of CD4 but not the downregulation of BST2. NAE inhibition also increased the surface exposure of CD4-induced epitopes within Env on HEK293 cells containing an inducible HIV genome, on infected CEM T cells, and on infected primary T cells. In contrast, the Vpu-mediated downregulation of BST2 was substantially inhibited by MLN4924 only when T cells were treated with alpha interferon (IFN-␣) to induce high levels of BST2 expression. As reported previously, the absence of vpu or nef and even more so the combined absence of these two genes sensitized infected cells to ADCC. However, NAE inhibition affected ADCC minimally. Paradoxically, even in infected, IFN-treated cells in which NAE inhibition substantially rescued the surface level of BST2, the surface level of Env detected with an antibody recognizing a CD4-independent epitope (2G12) was minimally increased. Mutation of the C-terminal Vpu residue W76, which supports the ability of Vpu to stimulate virion release by displacing BST2 from assembly sites on the plasma membrane by a cullin1-independent mechanism, increased the exposure of Env detected by 2G12 on infected T cells. Thus, inhibiting the displacement function of Vpu together with its ability to degrade CD4 and BST2 may be required to sensitize infected cells to ADCC. IMPORTANCEPathogenic viruses encode gene products that enable evasion of host immune surveillance mechanisms. One such mechanism is antibody-dependent cellular cytotoxicity (ADCC), whereby host antibodies bind envelope glycoproteins of the virus that are inserted into the cellular membrane and direct the destruction of infected cells. Targeting pharmacologically the activity of HIV-1 Vpu, which contributes to evasion of ADCC, could potentially sensitize infected cells to this immune surveillance mechanism, an outcome that would have therapeutic implications with respect to the goal of curing HIV-1 infection. The Nedd8 activation enzyme inhibitor MLN4924 blocks the activity of the host ubiquitin ligase that Vpu coopts to direct the degradation of CD4 and BST2. We observed that while MLN4924 partially reverses the activity of Vpu and could become part of a therapeutic approach by virtue of CD4-induced epitope exposure, sufficient Vpu activity as an antagonist of BST2 persists despite this drug to allow escape from ADCC.T he accessory proteins of HIV-1 remain undeveloped drug targets whose inhibition...

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HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated cell lysis through down-modulation of CD4 and BST2

Cited by 108 publications

References 41 publications

Novel Acylguanidine-Based Inhibitor of HIV-1

Novel Acylguanidine-Based Inhibitor of HIV-1

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1

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