Nicotinamide activates latent HIV-1 ex vivo in ART suppressed individuals, revealing higher potency than the association of two methyltransferase inhibitors, chaetocin and BIX01294

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Sadia Samer ^[1] ; Muhammad Shoaib Arif ^[2] ; Leila Bertoni Giron ^[3] ; Jean Paulo Lopes Zukurov ^[4] ; James Hunter ^[5] ; Bruna Teresa Santillo ^[6] ; Gislene Namiyama ^[7] ; Juliana Galinskas ^[8] ; Shirley Vasconcelos Komninakis ^[9] ; Telma Miyuki Oshiro ^[10] ; Maria Cecilia Sucupira ^[11] ; Luiz Mario Janini ^[12] ; Ricardo Sobhie Diaz ^[13]

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^[1] Emory University. Yerkes National Primate Research Center - Geórgia

^[2] Northwestern University. Feinberg School of Medicine. Department of Cell and Developmental Biology - Estados Unidos

^[3] Wistar Institute - Estados Unidos

^[4] Federal University of São Paulo. Department of Microbiology, Immunology and Parasitology - Brasil

^[5] Federal University of Sao Paulo. Department of Medicine - Brasil

^[6] University of Sao Paulo. Department of Dermatology - Brasil

^[7] Institute of Adolfo Lutz. Department of Electron Microscopy - Brasil

^[8] Federal University of Sao Paulo. Department of Medicine - Brasil

^[9] Federal University of Sao Paulo. Department of Medicine - Brasil

^[10] University of Sao Paulo. Department of Dermatology - Brasil

^[11] Federal University of Sao Paulo. Department of Medicine - Brasil

^[12] Federal University of São Paulo. Department of Microbiology, Immunology and Parasitology - Brasil

^[13] Federal University of Sao Paulo. Department of Medicine - Brasil

• Tipo de documento: Artigo Científico
• Fonte: Brazilian Journal of Infectious Diseases; v. 24, n. 2, p. 150-159, 2020-06-26.

Resumo

ABSTRACT Background: Latent HIV-1 is a major hurdle in obtaining HIV-1 sustained virological remission (SVR). Here we explored histone deacetylation inhibition property of nicotinamide (NAM; n = 17) for the first time in comparison to a combination of methyltransferase inhibitors (MTIs; Chaetocin and BIX01294; n = 25) to reactivate latent HIV ex vivo in CD8-depleted PBMCs from antiretroviral treated aviremic individuals. Results: NAM reactivated HIV-1 from 13/17 (76.4%) samples compared to 20/25 (80.0%) using MTIs with mean viral load (VLs) of 4.32 and 3.22 log10 RNA copies/mL, respectively (p = 0.004). Mean purging time after NAM and MTIs stimulation was 5.1 and 6.75 days, respectively (p = 0.73). Viral purging in autologous cultures exhibited blunted HIV recovery with fluctuating VLs followed by a complete viral extinction when expanded in allogenic system. Electron microscopy from five supernatants revealed anomalous viral particles, with lack of complete viral genomes when characterized by ultradeep sequencing through metagenomics approach (n = 4). Conclusion: NAM alone was more potent HIV-1 activator than combination of MTIs, with potential of clinical use. (AU)

• Processo FAPESP: 13/11323-5 - Uso de vacina de células dendríticas em associação com estratégias para eliminação de reservatórios virais almejando a cura esterilizante da infecção pelo HIV-1 em pessoas cronicamente infectadas em uso de tratamento antirretroviral
• Beneficiário: Ricardo Sobhie Diaz
• Modalidade de apoio: Auxílio à Pesquisa - Regular