Stable Latent HIV Infection and Low-level Viremia Despite Treatment With the Broadly Neutralizing Antibody VRC07-523LS and the Latency Reversal Agent Vorinostat

Abstract

We tested the combination of a broadly neutralizing HIV antibody with the latency reversal agent vorinostat (VOR). Eight participants received 2 month-long cycles of VRC07-523LS with VOR. Low-level viremia, resting CD4+ T-cell-associated HIV RNA (rca-RNA) was measured, and intact proviral DNA assay (IPDA) and quantitative viral outgrowth assay (QVOA) were performed at baseline and posttreatment. In 3 participants, IPDA and QVOA declines were accompanied by significant declines of rca-RNA. However, no IPDA or QVOA declines clearly exceeded assay variance or natural decay. Increased resistance to VRC07-523LS was not observed. This combination therapy did not reduce viremia or the HIV reservoir. Clinical Trials Registration. NCT03803605.

Keywords: HIV latency; broadly neutralizing antibody; latency reversal.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Impact of VOR and VRC07-523LS on HIV reservoir measurements. A, Changes in resting CD4 cell-associated HIV-1 gag RNA from baseline to week 16 after 2 cycles of VOR/VRC07-523LS. Declines (red) and increases (blue) were significant P<.0001 by Wilcoxon 2-sample test. At each time point 24–36 replicates of 1 × 106 rCD4+ T cells were evaluated. Mean and SD are shown. B, Linear scale frequency of replication-competent HIV in rCD4 T cells measured by quantitative viral outgrowth assay (red) and intact HIV DNA by IPDA (orange) before and after the study intervention. Dotted lines highlight the study period. Errors bars for QVOA represent the 95% CIs from the maximum likelihood method. Errors bars for IPDA measurements represent 95% CIs for the proviral frequency estimates using the total error from the QuantaSoft analysis software. C and D, Log scale changes in frequency of (C) replication-competent HIV by QVOA and (D) intact HIV DNA by IPDA. Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; IPDA, intact proviral DNA assay; QVOA, quantitative viral outgrowth assay; rCD4 T cell, resting CD4 T cell; VOR, vorinostat.

Figure 2.

VRC07-523LS binding to and elimination of LRV-infected cells. A, The frequency of infected cells with antibody bound to their surface (% p24+Ab+) and (B) MFI. CH65 antibody (Supplementary Reference 1) was used as negative control. C and D, End point concentrations (μg/mL), the concentration at which at least 15% target cell killing occurs. The data represent a single experiment with mAb starting with 100 µg/mL and subsequent 1:5 dilutions tested in duplicate. Statistical significance was calculated using Wilcoxon signed rank test. Horizontal lines indicate mean. Abbreviations: EC, end point concentration; LRV, latent reservoir virus; mAb, monoclonal antibody; MFI, mean fluorescence intensity; NS, not significant.