Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal

“…HIV-infected subjects receiving stable, standard-of-care ART with plasma HIV-1 RNA fewer than 50 copies per ml and a CD4 count of more than 300 μl -1 for at least 6 months were enrolled in the VOR clinical studies following informed consent (7,9,34); HIV-infected adults receiving ART with virological suppression (<50 copies per ml, at least 2 measurements per year) for at least 2 years and CD4 counts above 500 cells per μl were enrolled in the panobinostat study following informed consent (10). VOR studies were approved by the UNC institutional biomedical review board and the FDA (7,9,34); panobinostat clinical study was conducted at Aarhus University Hospital, Denmark, and approved by the ethics committee in accordance with the principles of the Declaration of Helsinki (10). For ex vivo studies, additional samples were obtained from HIV + donors with suppressed viremia (<50 copies per ml) from Philadelphia Fight and Sanguine Biosciences under IRB approval and patient informed consent.…”

“…HDACis are the most studied latency-reversing agents and have shown induction of cell-associated HIV RNA in vivo using single or multiple dosing paradigms (7)(8)(9)(10)(11)34); however, no study to date, to our knowledge, has demonstrated the direct induction of viral protein after clinical administration of HDACis. To determine if in vivo dosing of HDACis can induce viral protein expression, we examined changes in cell-associated p24 from peripherally isolated CD4 + T cells following clinical administration of 2 HDACis, either VOR or panobinostat.…”

“…To determine if in vivo dosing of HDACis can induce viral protein expression, we examined changes in cell-associated p24 from peripherally isolated CD4 + T cells following clinical administration of 2 HDACis, either VOR or panobinostat. A limited number of available samples were obtained from previously published or recently completed clinical trials (9,10,34). Briefly, aviremic HIV + individuals received either VOR (400 mg) at 72-hour intervals or panobinostat (20 mg) 3 times per week every other week for 8 weeks while maintaining combination ART (9,10,34).…”

“…A limited number of available samples were obtained from previously published or recently completed clinical trials (9,10,34). Briefly, aviremic HIV + individuals received either VOR (400 mg) at 72-hour intervals or panobinostat (20 mg) 3 times per week every other week for 8 weeks while maintaining combination ART (9,10,34). We quantified changes in p24 from baseline following administration of 1, 2, or 10 doses of VOR (9,34), as well as multiple doses (6 -10) of panobinostat (Supplemental Table 1), for subjects in whom remaining samples were available for p24 assessment.…”

“…Briefly, aviremic HIV + individuals received either VOR (400 mg) at 72-hour intervals or panobinostat (20 mg) 3 times per week every other week for 8 weeks while maintaining combination ART (9,10,34). We quantified changes in p24 from baseline following administration of 1, 2, or 10 doses of VOR (9,34), as well as multiple doses (6 -10) of panobinostat (Supplemental Table 1), for subjects in whom remaining samples were available for p24 assessment. In the VOR study, PBMCs were collected from HIV + subjects by leukapheresis 3-6 hours after VOR, and total CD4 + T cells were subsequently isolated and cultured for 48 hours with 1 μM raltegravir to prevent further rounds of infection.…”