BACKGROUND: One approach to eradicate HIV is to interfere with mechanisms that maintain latency, and simultaneously enhance the clearance of infected cells without interrupting antiretroviral therapy (ART). The histone deacetylase (HDAC) inhibitor, vorinostat (VOR), can repeatedly induce the expression of latent HIV-1 in vivo, and allow clearance of infected cells in vitro. However, when paired with HIV vaccines or antibodies, this approach has not yielded substantial depletion of the latent reservoir in vivo. Adoptive T cell therapy has had dramatic success in the treatment of virus-related malignancies and infections following hematopoietic stem cell transplantation and has been adapted to produce ex-vivo expanded HIV-specific T cells (HXTCs), and other cell therapy products.
METHODS: In this pilot study we administered VOR and HXTCs to antiretroviral (ART)-suppressed people with HIV (PWH). Six PWH received five infusions of 2 x107 HXTCs/m² with VOR 400 mg every three days. Three PWH received five infusions of 10 x107 HXTCs/m² with VOR. Leukapheresis was performed at baseline and after final HXTC infusion to measure the frequency of persistent HIV by Quantitative Viral Outgrowth Assay (QVOA) of resting CD4+ cells, cell-associated HIV RNA (rcaRNA), and intact HIV provirus assay (IPDA).
RESULTS: Overall, PWH tolerated VOR and HXTCs, with only transient Grade 1 AEs related to study products. Biomarkers of serial VOR effect were detected in PBMCs, but evidence of enhanced antiviral activity in the total pool of circulating cells was not detected. One of 6 PWH exhibited a decrease in measures of persistent HIV after 2x107 HXTCs/m² infusions with VOR, and all three PWH exhibited such declines when 10x107 HXTCs/m² were given with VOR. However, most QVOA declines did not exceed 6-fold, a threshold required to definitively (p > 0.05) attribute QVOA decline to the study intervention, rather than assay variation.
CONCLUSIONS: These findings provide some support for the therapeutic strategy of HIV latency reversal and enhanced reservoir clearance, but the modest effects seen highlight the need for more effective latency reversal agents and clearance approaches that can be repeatedly employed to achieve the profound depletion of persistent HIV needed for clinical benefit.

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