Factors associated with resistance of HIV-1 reservoir viruses to neutralization by autologous IgG antibodies
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
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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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 3

Inhibitory effect of aNAbs at physiologic IgG concentrations.

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Inhibitory effect of aNAbs at physiologic IgG concentrations. (A) Hypoth...
(A) Hypothetical dose-response curves for inhibition of infection by autologous IgG antibodies. The fraction of infection events not inhibited (fraction unaffected or fu) declines with increasing antibody concentrations. Curves show inhibition by 3 different antibody preparations that have the same IC50 (1 μg/mL, dotted line) but different slopes (m), a measure of cooperativity. In vitro neutralization assays are conducted at IgG concentrations well below physiologic IgG concentrations (shaded area). (B) Curves from A plotted with a logarithmic y-axis, illustrating the dramatic effect of m on inhibition. (C) Instantaneous inhibitory potential (IIP), the logs of inhibition of a single round of infection, for the same antibody preparations. (D) Effect of m on IIP for distinct isolates from the aNAb-resistant (orange, n = 31) and aNAb-sensitive (blue, n = 48) groups. IC50 value trend lines are shown at 3 indicated concentrations. For many resistant isolates, m, IC50, and IIP, could not be determined because infection did not consistently decrease with increasing IgG concentrations. (E) Distribution of slope values for the isolates from D. Circles represent distinct isolates, and colors represent participants. Bar represents median. Significance was calculated using the Mann Whitney test. **P < 0.01. (F) Distribution of IIP values for the isolates from D. Dotted line indicates the IIP value above which effective suppression of viral replication by combination ART regimens is observed (85). IIP values for single antiretroviral drugs at average plasma concentrations are shown (80, 85). Significance was calculated using the Mann Whitney test. ****P < 0.0001.