Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells

Lee, Wen Shi; Richard, Jonathan; Lichtfuss, Marit; Smith, Amos B.; Park, Jongwoo; Courter, Joel R.; Melillo, Bruno; Sodroski, Joseph; Kaufmann, Daniel E.; Finzi, Andrés; Parsons, Matthew S.; Kent, Stephen J.

doi:10.1128/jvi.02717-15

Cited by 54 publications

(58 citation statements)

References 56 publications

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“…In addition, decreased amounts of Env at the cell surface due to efficient internalization also help the virus to avoid ADCC responses (17). In agreement with the need for HIV-1 to avoid exposing Env in the CD4-bound conformation, it was recently shown that forcing Env to adopt this conformation with small CD4-mimetic compounds (CD4mcs) sensitizes HIV-1-infected cells to ADCC responses (18)(19)(20). Accordingly, we recently reported that the transition of Env to the CD4-bound conformation is required for efficient interactions with ADCC-mediating antibodies (14).…”

mentioning

confidence: 90%

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Prévost

Zoubchenok

Richard

et al. 2017

J Virol

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibodydependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_ AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.

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confidence: 90%

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Prévost

Zoubchenok

Richard

et al. 2017

J Virol

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“…The kick-and-kill paradigm gained traction when it was demonstrated that latency reversal (kick) alone, with the LRA vorinostat, was insufficient to cause the death of infected cells in a postactivation in vitro latency model, whereas the addition of expanded HIV-specific CD8 + T cells resulted in infected cell elimination (5). Others have since reported similar results using additional in vitro latency models, combined with natural or engineered CD8 + T cells, or NK cells as effectors (9)(10)(11)(12)(13)(14). These results have motivated the translation of the kick-and-kill approach into clinical trials that, thus far, have failed to achieve reductions in infectious viral reservoirs (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells

Huang

Ren

Thomas

et al. 2018

Journal of Clinical Investigation

165

151

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“…Recently a small compound has been reported that inhibits Vpu mediated degradation of tetherin, providing a novel approach to sensitising infected cells for ADCC [140]. Together such approaches may play a role in cure strategies involving reactivation of latently infected cells by enhancing Env surface expression and revealing CD4i epitopes in Env, thereby sensitising them to elimination by ADCC [21].…”

Section: Hiv Evasion and Subversion Of Fcγr-mediated Ab Functionsmentioning

confidence: 99%

“…The assay measures LDH released upon cell lysis and has been used, for example, in recent studies examining the potential of HIV-1 specific ADCC in killing latently infected cells upon viral reactivation [21] [157].…”

Section: Cell Based Functional Assays For Fcr Activating Antibodiesmentioning

confidence: 99%

“…Importantly, there is evidence that each activating FcγR can contribute to some protective effects of anti-HIV antibodies (e.g. [18][19][20][21][22][23]). Aggregation of cellular Fc receptors [24], or possibly their reorganisation in the membrane [25] leads to the activation of src family and syk kinases which initiate a cell activation cascade and, depending on the innate cell type, stimulate effector functions such as ADCC and ADCP [1][2][3]26].…”

Section: Introductionmentioning

confidence: 99%

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Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

Wines¹,

Billings²,

Mcleand³

et al. 2017

CHR

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Background:There is now intense interest in the role of HIV-specific antibodies and the engagement of FcγR functions in the control and prevention of HIV infection. The analyses of the RV144 vaccine trial, natural progression cohorts, and macaque models all point to a role for Fc-dependent effector functions, such as cytotoxicity (ADCC) or phagocytosis (ADCP), in the control of HIV. However, reliable assays that can be reproducibly used across different laboratories to measure Fcdependent functions, such as antibody dependent cellular cytotoxicity (ADCC) are limited. Method: This brief review highlights the importance of Fc properties for immunity to HIV, particularly via FcγR diversity and function. We discuss assays used to study FcR mediated functions of HIV-specific Ab, including our recently developed novel cell-free ELISA using homo-dimeric FcγR ectodomains to detect functionally relevant viral antigen-specific antibodies. Results: The binding of these dimeric FcγR ectodomains, to closely spaced pairs of IgG Fc, mimics the engagement and cross-linking of Fc receptors by IgG opsonized virions or infected cells as the essential prerequisite to the induction of Ab-dependent effector functions. The dimeric FcγR ELISA reliably correlates with ADCC in patient responses to influenza. The assay is amenable to high throughput and could be standardized across laboratories. Conclusion: We propose the assay has broader implications for the evaluation of the quality of antibody responses in viral infections and for the rapid evaluation of responses in vaccine development campaigns for HIV and other viral infections.

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Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells

Abstract: Lifelong antiretroviral therapy (ART

Cited by 54 publications

References 56 publications

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

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