| Autor: |
Lilie TJ; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, United States of America., Bouzy J; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, United States of America., Asundi A; Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, United States of America., Taylor J; Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, United States of America., Roche S; Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, United States of America., Olson A; Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, United States of America., Coxen K; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, United States of America., Corry H; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, United States of America., Jordan H; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, United States of America., Clayton K; Department of Pathology, University of Massachusetts T.H. Chan School of Medicine, Worchster, United States of America., Lin N; Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, United States of America., Tsibris A; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America. |
| Abstrakt: |
Opioid use may impact the HIV-1 reservoir and its reversal from latency. We studied forty-seven virally suppressed people with HIV (PWH) and observed that lower concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that did not reverse latency, synergistically increased the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combined a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, generated significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation, modulated surface activation-induced markers, and altered T cell production of TNFα, IL-2, and IFNγ. HIV-1 reservoirs in PWH contained unspliced and polyadenylated (polyA) virus mRNA, the ratios of which were greater in resting than total CD4+ T cells and correct to 1:1 with PMAi exposure. We characterized treated suppressed HIV-1 infection as a period of inefficient, not absent, virus transcription. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe mechanisms of an effective cellular HIV-1 latency reversal program. |
