ABX464 Decreases the Total Human Immunodeficiency Virus (HIV) Reservoir and HIV Transcription Initiation in CD4+ T Cells From Antiretroviral Therapy-Suppressed Individuals Living With HIV

Abstract

Background: Antiretroviral therapy (ART) intensification and disruption of latency have been suggested as strategies to eradicate HIV. ABX464 is a novel antiviral that inhibits HIV RNA biogenesis. We investigated its effect on HIV transcription and total and intact HIV DNA in CD4+ T cells from ART-suppressed participants enrolled in the ABIVAX-005 clinical trial (NCT02990325).

Methods: Peripheral CD4+ T cells were available for analysis from 9 ART-suppressed participants who were treated daily with 150 mg of ABX464 for 4 weeks. Total and intact HIV DNA and initiated, 5'elongated, unspliced, polyadenylated, and multiply-spliced HIV transcripts were quantified at weeks 0, 4, and 8 using ddPCR.

Results: We observed a significant decrease in total HIV DNA (P = .008, median fold change (mfc) = 0.8) and a lower median level of intact HIV DNA (P = not significant [n.s.], mfc = 0.8) after ABX464 treatment. Moreover, we observed a decrease in initiated HIV RNA per million CD4+ T cells and per provirus (P = .05, mfc = 0.7; P = .004, mfc = 0.5, respectively), a trend toward a decrease in the 5'elongated HIV RNA per provirus (P = .07, mfc = 0.5), and a lower median level of unspliced HIV RNA (P = n.s., mfc = 0.6), but no decrease in polyadenylated or multiply-spliced HIV RNA.

Conclusions: In this substudy, ABX464 had a dual effect of decreasing total HIV DNA (and possibly intact proviruses) and HIV transcription per provirus. To further characterize its specific mechanism of action, long-term administration of ABX464 should be studied in a larger cohort.

Clinical trials registration: NCT02990325.

Keywords: ABX464; HIV-1 DNA; HIV-1 RNA; HIV-1 transcription; antiviral drugs.

Published by Oxford University Press for the Infectious Diseases Society of America 2021.

Figures

Figure 1.

Effect of ABX464 on the HIV reservoir. A, Diagram of the assays used to quantify total, intact, 3’defective, and 5’defective HIV DNA. B, Dynamics of total, intact, 3’defective, and 5’defective HIV DNA. C, Spearman correlations between total (long terminal repeat [LTR] or Gag) and intact proviral DNA assay (IPDA) HIV DNA. D, Relative frequency of IPDA over total (LTR or Gag) HIV DNA and of IPDA over the sum of hypermutated/3’defective, 5’defective, and intact HIV DNA (values ≤1 were censored to 1). Each color represents a different assay; each symbol/shape represents a different individual from the ABX464-005 study; bars represent medians. Determinations below the limit of detection are represented as open dots. Abbreviation: HIV, human immunodeficiency virus.

Figure 2.

Effect of ABX464 on HIV transcription. A, Diagram of the assays used to characterize the HIV transcription profile. B, Dynamics of each HIV transcript per million CD4+ T cells. C, Dynamics of each HIV transcript per provirus (HIV RNA-to-HIV DNA). Each color represents a different assay; each symbol/shape represents a different individual; bars represent medians. Determinations below the limit of detection are represented as open dots. Abbreviation: HIV, human immunodeficiency virus.