Anti-HIV-1 ADCC antibodies following latency reversal and treatment interruption

WS Lee, AB Kristensen, TA Rasmussen… - Journal of …, 2017 - Am Soc Microbiol
WS Lee, AB Kristensen, TA Rasmussen, M Tolstrup, L Østergaard, OS Søgaard, BD Wines…
Journal of Virology, 2017Am Soc Microbiol
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 …
Abstract
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.
American Society for Microbiology