Nanoparticle delivery of Tat synergizes with classical latency reversal agents to express HIV antigen targets.

Autor:	Raines SLM; Department of Medicine and UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Falcinelli SD; Department of Medicine and UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Peterson JJ; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Van Gulck E; Janssen Infectious Diseases, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium., Allard B; Department of Medicine and UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Kirchherr J; Department of Medicine and UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Vega J; Arcturus Therapeutics, Science Center Drive, San Diego, California, USA., Najera I; Janssen Infectious Diseases, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium., Boden D; Janssen Infectious Diseases, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium., Archin NM; Department of Medicine and UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Margolis DM; Department of Medicine and UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Jul 09; Vol. 68 (7), pp. e0020124. Date of Electronic Publication: 2024 Jun 03.
DOI:	10.1128/aac.00201-24
Abstrakt:	Limited cellular levels of the HIV transcriptional activator Tat are one contributor to proviral latency that might be targeted in HIV cure strategies. We recently demonstrated that lipid nanoparticles containing HIV tat mRNA induce HIV expression in primary CD4 T cells. Here, we sought to further characterize tat mRNA in the context of several benchmark latency reversal agents (LRAs), including inhibitor of apoptosis protein antagonists (IAPi), bromodomain and extra-Terminal motif inhibitors (BETi), and histone deacetylase inhibitors (HDACi). tat mRNA reversed latency across several different cell line models of HIV latency, an effect dependent on the TAR hairpin loop. Synergistic enhancement of tat mRNA activity was observed with IAPi, HDACi, and BETi, albeit to variable degrees. In primary CD4 T cells from durably suppressed people with HIV, tat mRNA profoundly increased the frequencies of elongated, multiply-spliced, and polyadenylated HIV transcripts, while having a lesser impact on TAR transcript frequencies. tat mRNAs alone resulted in variable HIV p24 protein induction across donors. However, tat mRNA in combination with IAPi, BETi, or HDACi markedly enhanced HIV RNA and protein expression without overt cytotoxicity or cellular activation. Notably, combination regimens approached or in some cases exceeded the latency reversal activity of maximal mitogenic T cell stimulation. Higher levels of tat mRNA-driven HIV p24 induction were observed in donors with larger mitogen-inducible HIV reservoirs, and expression increased with prolonged exposure time. Combination LRA strategies employing both small molecule inhibitors and Tat delivered to CD4 T cells are a promising approach to effectively target the HIV reservoir. Competing Interests: J.V. was an employee of Arcturus and may be a stockholder. E.V.G. and D.B. were employees of Johnson & Johnson and may be stockholders. D.M.M. has consulted for Merck and ViiV, outside the area of this work, and holds common stock in Gilead. No other conflicts are declared.
Databáze:	MEDLINE
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