Factors associated with resistance of HIV-1 reservoir viruses to neutralization by autologous IgG antibodies
Natalie F. McMyn, … , Janet M. Siliciano, Robert F. Siliciano
Natalie F. McMyn, … , Janet M. Siliciano, Robert F. Siliciano
Published July 29, 2025
Citation Information: J Clin Invest. 2025;135(19):e194081. https://doi.org/10.1172/JCI194081.
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Clinical Research and Public Health AIDS/HIV Infectious disease Virology

Factors associated with resistance of HIV-1 reservoir viruses to neutralization by autologous IgG antibodies

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

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

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Figure 1

Variation in sensitivity of reservoir isolates to aNAbs.

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Variation in sensitivity of reservoir isolates to aNAbs. (A) aNAb IC50 v...
(A) aNAb IC50 values were determined in TZM.bl-based neutralization assays for distinct pseudoviruses generated from outgrowth viruses from PWH on ART (n = 138 isolates). Autologous IgG concentrations up to 100 μg/mL were used. Circles represent distinct isolates, and colors represent participants. (B) Percentage of distinct outgrowth viruses resistant (IC50 > 100 μg/mL) to neutralization by contemporaneous aNAbs per PWH. Each data point (n = 28) represents the % of resistant viruses among the total number of viruses tested in each PWH. Bar represents median. (C) aNAb neutralization of distinct isolates shown in A with additional data points representing independent isolates from the same PWH with env sequences identical to those shown in A, n = 591. IC50 values determined for one member of a set of isolates with identical env sequence were used for all members of the set. (D) Percentage of outgrowth viruses resistant to neutralization (IC50 > 100 μg/mL) by aNAbs per PWH, n = 28, using values from (C). All isolates from each participant, including sequence-identical isolates, are considered in the percentage calculation. Bar represents median.