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

• Published in: Journal of virology Vol. 91; no. 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: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.08.2017
• 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; SMART trial; HIV-1 cure; analytical treatment interruption; latency; latency-reversing agent; ADCC; panobinostat
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/JVI.00603-17

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 in vitro . 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. IMPORTANCE 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 in vivo , 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.