ARTICLE: Factors associated with resistance of HIV-1 reservoir viruses to neutralization by autologous IgG antibodies
AUTHORS: Natalie F McMyn, Joseph Varriale, Hanna W S Wu, Vivek Hariharan, Milica Moskovljevic, Toong Seng Tan, Jun Lai, Anushka Singhal, Kenneth Lynn, Karam Mounzer, Pablo Tebas, Luis J Montaner, Rebecca Hoh, Xu G Yu, Mathias Lichterfeld, Francesco R Simonetti, Colin Kovacs, Steven G Deeks, Janet M Siliciano, Robert F Siliciano
JOURNAL: J Clin Invest. 2025 Jul 29;135(19):e194081. doi: 10.1172/JCI194081. eCollection 2025 Oct 1.
Abstract
BACKGROUND: Antiretroviral therapy (ART) prevents HIV-1 replication but does not eliminate the latent reservoir, the source of viral rebound if treatment is stopped. Autologous neutralizing antibodies (aNAbs) can block in vitro outgrowth of a subset of reservoir viruses and therefore potentially affect viral rebound upon ART interruption.
METHODS: We investigated aNAbs in 31 people with HIV-1 (PWH) on ART.
RESULTS: Participants fell into 2 groups based on a high or low fraction of aNAb-resistant reservoir isolates, with most isolates being aNAb-resistant (IC50 > 100 μg/mL). Time on uninterrupted ART was associated with higher aNAb resistance. However, pharmacodynamic analysis predicted that many isolates would be partially inhibited at physiologic IgG concentrations, to the same degree as by single antiretroviral drugs. Steep dose-response curve slopes, an indication of cooperativity, were observed for the rare isolates that were very strongly inhibited (> 5 logs) by aNAbs. Resistance to aNAbs was not fully explained by declining in aNAb titers and may be driven partially by ADCC-mediated elimination of infected cells carrying aNAb-sensitive viruses over long time intervals, leaving only aNAb-resistant viruses, which can contribute to viral rebound.
CONCLUSION: Inhibition of reservoir viruses by aNAbs may be affected by dose-response curve slope, time on uninterrupted ART, waning of antibody responses, and selection against cells with aNAb-sensitive viruses.
FUNDING: This work was supported by NIH Martin Delaney Collaboratories for HIV Cure Research grant awards UM1AI164556, UM1AI164570, and UM1AI164560, and the Howard Hughes Medical Institute.
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