Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption

There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be suffic...

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Bibliographic Details
Published in:Journal of virology 2017-08, Vol.91 (15)
Main Authors: Lee, Wen Shi, Kristensen, Anne B, Rasmussen, Thomas A, Tolstrup, Martin, Østergaard, Lars, Søgaard, Ole S, Wines, Bruce D, Hogarth, P Mark, Reynaldi, Arnold, Davenport, Miles P, Emery, Sean, Amin, Janaki, Cooper, David A, Kan, Virginia L, Fox, Julie, Gruell, Henning, Parsons, Matthew S, Kent, Stephen J
Format: Article
Language:English
Subjects:
Adaptive Immunity
Adult
Anti-Retroviral Agents - administration & dosage
Antibody-Dependent Cell Cytotoxicity
Female
HIV Antibodies - immunology
HIV Infections - drug therapy
HIV Infections - immunology
HIV-1 - immunology
Humans
Hydroxamic Acids - administration & dosage
Indoles - administration & dosage
Male
Middle Aged
Panobinostat
Pathogenesis and Immunity
Time Factors
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Summary:There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells. The "shock and kill" HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined , but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.00603-17