Anti-HIV-1 ADCC and HIV-1 Env Can Be Partners in Reducing Latent HIV Reservoir.

Poonam Suryawanshi,Ashwini Shete,Madhuri Thakar,Rajani Bagul

doi:10.3389/fimmu.2021.663919

Poonam Suryawanshi, Ashwini Shete + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2021.663919

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Abstract

BackgroundPersistence of HIV reservoir even in suppressive ART is the key obstacle in HIV-1 cure. We evaluated the ability of HIV-1 C Env to reactivate the latently infected resting memory CD4 cells and the ability of polyclonal HIV antibodies mediating ADCC to lyse the reactivated targets.MethodologyHIV-1 antibodies from 25 HIV infected individuals (14 ADCC responders and 11 non-responders) were tested against the Env-C reactivated primary cells; CD4+ and CD4+CD45RO+ memory T cells in the presence of autologous or heterologous effector cells using multicolor flow cytometry. The frequencies of p24+ve target cells were measured to determine the reactivation and antibody mediated lysis.ResultsIncrease in the frequency of p24 expressing cells (P < 0.01 in all cases) after Env-C stimulation of target cells indicated reactivation. When these reactivated targets were mixed with effector cells and HIV-1 antibodies, the frequencies of p24 expressing targets were decreased significantly when the ADCC mediating antibodies (P < 0.01 in all cases) were added but not when the antibodies from ADCC non-responders or HIV negative individuals were added. In parallel, the NK cell activation was also increased only when ADCC mediating antibodies were added.ConclusionThe study showed that the HIV-1 Env could act as latency reversal agent (LRA), and only ADCC mediating antibodies could lyse the reactivated HIV reservoirs. The short stimulation cycle used in this study could be useful in testing LRAs as well as immune mediated lysis of reactivated reservoirs. The observations have further implication in designing antibody mediated immunotherapy for eradication of latent HIV reservoir.

Highlights

Despite viral suppression in HIV-1 infected individuals on antiretroviral treatment (ART), the virus persists in long-lived latent reservoirs [1], the elimination or reduction of which is a major hurdle in achieving HIV cure [2]
The presence of anti-HIV Antibody Dependent Cell Cytotoxicity (ADCC) mediating antibodies was shown to be associated with slow HIV disease progression [8] and has been implicated as an immune correlate in the moderately successful HIV-1 RV144 vaccine trial [9]
We showed that the Env antigen can reactivate the HIV infected memory CD4 cells which were efficiently lysed by the ADCC mediated lysis

Summary

Introduction

Despite viral suppression in HIV-1 infected individuals on antiretroviral treatment (ART), the virus persists in long-lived latent reservoirs [1], the elimination or reduction of which is a major hurdle in achieving HIV cure [2]. The shock is to reactivate the latently infected cells, and the kill involves killing of these reactivated cells expressing HIV antigens by immune-mediated mechanisms. The ability of ADCC mediating anti-HIV antibodies to lyze the Env reactivated reservoirs has not been studied. In the present study, we assessed the ability of anti-HIV ADCC antibodies to induce NK cell mediated lysis of Env stimulated HIV reservoirs. We showed that the Env antigen can reactivate the HIV infected memory CD4 cells which were efficiently lysed by the ADCC mediated lysis. The short stimulation cycle model used in this study will be useful in latency reversal assessment of various LRAs . We evaluated the ability of HIV-1 C Env to reactivate the latently infected resting memory CD4 cells and the ability of polyclonal HIV antibodies mediating ADCC to lyse the reactivated targets

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