Improved killing of HIV-infected cells using three neutralizing and non-neutralizing antibodies

Tuyishime, Marina; Garrido, Carolina; Jha, Shalini; Moeser, Matt; Mielke, Dieter; LaBranche, Celia C.; Montefiori, David C.; Haynes, Barton F.; Joseph, Sarah; Margolis, David M.; Ferrari, Guido

doi:10.1172/jci135557

Cited by 25 publications

(22 citation statements)

References 85 publications

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“…It is known that the full HIV-1 replication in primary T cells takes at least 24 h (23); hence the reduction in the p24 expressing cells in a short stimulation cycle used in this study could be ADCC mediated rather than suppression of new infection by antibody neutralization. The broadly neutralizing antibodies could lyse reactivated latent cells through the FC mediated involvement of NK cells (24)(25)(26). We could not test the HIV neutralization ability of the ADCC antibodies used in this study which is one of the limitations.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 96%

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

et al. 2021

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“…In a recent report, both for in vitro and in ex vivo patient samples, a combination of activators of HIV-1 specific innate immune response and epigenetic modulators has been shown to be effective in latency reversal and targeted killing of HIV-infected T cells [43]. Furthermore, an ex vivo study demonstrated the elimination of recrudesced HIV-1 latently infected cells treated with a combination of nnAb along with nAbs of diverse epitope specificities, implicating that administration of a combination of mAbs with distinct epitope specificities should be considered in strategies to clear latent HIV-1 infection in vivo [44].…”

Section: Discussionmentioning

confidence: 99%

Effect of combination antiretroviral therapy on human immunodeficiency virus 1 specific antibody responses in subtype-C infected children

Kumar

Batra

Singh

et al. 2020

Journal of General Virology

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Protective antibody responses to human immunodeficiency virus (HIV)-1 infection evolve only in a fraction of infected individuals by developing broadly neutralizing antibodies (bnAbs) and/or effector functions such as antibody-dependent cellular cytotoxicity (ADCC). HIV-1 chronically infected adults and children on combination antiretroviral therapy (cART) showed a reduction in ADCC activity and improvement in HIV-1 specific neutralizing antibody (nAb) responses. Early initiation of cART in infected adults is found to be beneficial in reducing the viral load and delaying disease progression. Herein, we longitudinally evaluated the effect of cART on HIV-1 specific plasma ADCC and nAb responses in a cohort of 20 perinatally HIV-1 subtype-C infected infants and children ≤2 years of age, pre-cART and up to 1 year post-cART initiation. Significant reductions in HIV-1 specific plasma ADCC responses to subtype-C and subtype-B viruses and improvement in HIV-1 neutralization were observed in HIV-1 infected children 1 year post-cART initiation. A positive correlation between reduction in viral load and the loss of ADCC response was observed. This study provides information aiding the understanding of the effects of early initiation of cART on antibody effector functions and viral neutralization in HIV-1 infected children, which needs to be further evaluated in large cohorts of HIV-1 infected children on cART to plan future intervention strategies.

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“…The neutralization potency against free virus combined with bNAb Fc interacting with FcγRs would be a strong force to eliminate infected cells via innate effector cells, such as natural killer cells, monocytes, and neutrophils ( 142 ). Studying 10 individuals with extended periods of viral suppression, Tuyishime et al reported that combinations of neutralizing and non-neutralizing mAbs were able to mediate ADCC and eliminate cells infected with viruses that were resistant to neutralization by the tested mAbs ( 143 ). The group found that a combination of 3 mAbs worked best for NK-specific killing viruses that were resistant to individual or multiple bNAbs.…”

Section: Cultivating Bnab Development For Treatment and Preventionmentioning

confidence: 99%

Advancing HIV Broadly Neutralizing Antibodies: From Discovery to the Clinic

Spencer

Shapiro

Haigwood

et al. 2021

Front. Public Health

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Despite substantial progress in confronting the global HIV-1 epidemic since its inception in the 1980s, better approaches for both treatment and prevention will be necessary to end the epidemic and remain a top public health priority. Antiretroviral therapy (ART) has been effective in extending lives, but at a cost of lifelong adherence to treatment. Broadly neutralizing antibodies (bNAbs) are directed to conserved regions of the HIV-1 envelope glycoprotein trimer (Env) and can block infection if present at the time of viral exposure. The therapeutic application of bNAbs holds great promise, and progress is being made toward their development for widespread clinical use. Compared to the current standard of care of small molecule-based ART, bNAbs offer: (1) reduced toxicity; (2) the advantages of extended half-lives that would bypass daily dosing requirements; and (3) the potential to incorporate a wider immune response through Fc signaling. Recent advances in discovery technology can enable system-wide mining of the immunoglobulin repertoire and will continue to accelerate isolation of next generation potent bNAbs. Passive transfer studies in pre-clinical models and clinical trials have demonstrated the utility of bNAbs in blocking or limiting transmission and achieving viral suppression. These studies have helped to define the window of opportunity for optimal intervention to achieve viral clearance, either using bNAbs alone or in combination with ART. None of these advances with bNAbs would be possible without technological advancements and expanding the cohorts of donor participation. Together these elements fueled the remarkable growth in bNAb development. Here, we review the development of bNAbs as therapies for HIV-1, exploring advances in discovery, insights from animal models and early clinical trials, and innovations to optimize their clinical potential through efforts to extend half-life, maximize the contribution of Fc effector functions, preclude escape through multiepitope targeting, and the potential for sustained delivery.

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Improved killing of HIV-infected cells using three neutralizing and non-neutralizing antibodies

Cited by 25 publications

References 85 publications

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

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

Effect of combination antiretroviral therapy on human immunodeficiency virus 1 specific antibody responses in subtype-C infected children

Advancing HIV Broadly Neutralizing Antibodies: From Discovery to the Clinic

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