CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

323 PRESENCE MACROPHAGE-TROPIC HIV-1 VARIANTS FOLLOWING ANALYTIC TREATMENT INTERRUPTION

322 NONSTRUCTURED TREATMENT INTERRUPTIONS CONTRIBUTE TO LATENT HIV-1 RESERVOIR IN PWID Gregory D. Kirk 1 , Shruti H. Mehta 1 , Jacquie Astemborski 1 , Kristen D. Ritter 2 , Gregory Laird 2 , Robert Siliciano 3 1 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 2 Accelevir Diagnostics, Baltimore, MD, USA, 3 Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: Persons with a history of injecting drugs (PWID) often struggle to maintain stable viral suppression and experience ART non-structured treatment interruptions (NTIs). Injecting drugs has been associated with increased inflammation and alterations in T cell homeostasis. However, the long-term effects of NTIs or of injection drug use on the HIV-1 latent reservoir have not been defined. Methods: We performed the intact proviral DNA assay (IPDA) on 108 HIV-1+ adult participants of the ALIVE cohort who at a minimumwere on suppressive ART with plasma HIV-1 RNA <50 copies/mL at the time of sampling and at the study visit 6 months prior; a minimum of 5 HIV RNA measurements (2.5 years of observation) was required. Participants were selected based on self-report of current drug use: active heroin use (n=28), active cocaine use (n=23), combined cocaine and heroin use (n=29), and no reported drug use (n=28). Participants were further selected to include those with a history of stable viral suppression (n=36) and those with past periods of viremia due to NTIs (n=72). Results: Participants were 71%male, 96% black, and median age was 53 years. No significant differences were observed by current patterns of drug use, with median frequencies of intact proviruses ranging from 1.95 to 2.44 log 10 per 10 6 CD4+ T cells across groups, values comparable to those seen in other cohorts not selected based on illicit drug use (Figure, Panel A). However, we did observe notably higher intact provirus frequency among persons who had experienced NTIs (Figure, Panel B) compared to those with stable suppression (mean 2.15 vs. 1.50 log 10 per 10 6 CD4+ T cells, respectively; P=0.0011). In multi-variable linear regression adjusting for demographics and drug use, NTIs were strongly associated with higher intact provirus (coef= 0.576; P=0.026). Conclusion: We found no apparent long-term effect of injecting drugs on latent reservoir size as measured by IPDA. However, we found a notable increase in reservoir size for those with past periods of viremia due to NTIs compared to those with a history of more stable viral suppression. Our data have important implications for the field. First, they support the inclusion of PWID with stable suppression in cure studies. Second, they demonstrate that a history of viremia due to NTIs may have lasting effects on the size of the reservoir, and as such, virologic history should be considered when designing or analyzing HIV-1 cure studies.

Viviane M. Andrade 1 , Carla Mavian 2 , Dunja Babic 1 , Thaissa Cordeiro Alvarado 1 , Mark Sharkey 1 , Labelle Barrios 1 , Christian Brander 3 , Judith Dalmau 3 , Michael S. Seaman 4 , Marco Salemi 2 , Javier Martinez-Picado 3 , Mario Stevenson 1 1 University of Miami, Miami, FL, USA, 2 University of Florida, Gainesville, FL, USA, 3 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 4 Beth Israel Deaconess Medical Center, Boston, MA, USA Background: HIV-1 persists in cellular reservoirs that can replenish viremia if antiretroviral therapy (ART) is interrupted. Therefore, insight into the nature of those reservoirs may be revealed from the composition of recrudescing viremia following treatment cessation. Most attention has focused on the CD4+ T cell reservoir in patients on ART. We hypothesize that macrophages also serve as a viral reservoir under ART. To assess this, we examined the composition of rebound viremia in individuals undergoing an analytic treatment interruption (ATI). Specifically we examined whether post-ATI viremia harbored viral variants that exhibited a highly macrophage-adapted phenotype. Methods: A total of 551HIV-1 full-length envelopes were isolated by single genome amplification from plasma of six individuals who underwent ATI. Isolated envsequences were used to construct recombinant, infectious HIV-1 molecular clones. The recombinant viruses were assessed for the ability to fuse and replicate within primary macrophages.To determine whether macrophages were a source for macrophage-adapted HIV-1 variants, immunoprecipitation of plasma-containing virions was performed using a macrophage-specific marker (CD14). To assess whether macrophage-tropic viruses identified in post-ATI viremia originated frommacrophages prior to treatment interruption, we inferred time-scaled phylogenies, through Bayesian phyloanatomy framework using a robust estimate of intra-host evolutionary rate in the envgene (7.53 10-3 nt substitutions/site/year). Results: Macrophage-tropic viruses were identified at low frequency in a library of recombinant viruses constructed with individual envelope genes that were obtained from plasma of six individuals undergoing analytic treatment interruption (ATI). Macrophage-tropic viruses could also be enriched from post-ATI plasma using macrophage-specific (CD14) but not CD4+ T cell-specific (CD3) antibodies, suggesting that macrophage-tropic viruses had a macrophage origin. Phylogenetic relationships indicatethat the establishment of macrophage-tropic HIV-1 variants predated ATI in 4 out of 6 study participants. Conclusion: Collectively, these data suggest that macrophages are a viral reservoir in HIV-1-infected individuals on effective ART and contribute to viral recrudescence when treatment is interrupted. These findings have implications for the design of curative strategies for HIV-1. Laurens Lambrechts 1 , Basiel Cole 1 , Marie-Angélique D. De Scheerder 1 , Zoe Boyer 2 , Ytse Noppe 1 , Katie Fisher 2 , John-Sebastian Eden 2 , Wim Van Criekinge 3 , Lisa Frenkel 4 , Sarah Palmer 2 , Linos Vandekerckhove 1 1 HIV Cure Research Center, Ghent University, Ghent, Belgium, 2 The Westmead Institute for Medical Research, Westmead, NSW, Australia, 3 Ghent University, Ghent, Belgium, 4 Seattle Children's Research Institute, Seattle, WA, USA

Poster Abstracts

324 THE ELUSIVE SOURCE OF HIV-1 REBOUND AFTER TREATMENT INTERRUPTION

CROI 2020 111