Use of dendritic cell vaccine in association with strategies for elimination of viral reservoirs aiming at the sterilizing cure of HIV-1 infection in chronically infected persons using antiretroviral treatment

• Grant number: 19/17461-7
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Start date: November 02, 2020
• End date: November 01, 2021
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Ricardo Sobhie Diaz
• Grantee: Ricardo Sobhie Diaz
• Visiting researcher: Iart Luca Shytaj
• Visiting researcher institution: Heidelberg University, Germany
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

AIDS, caused by human immunodeficiency virus (HIV), is a pandemic disease, affecting approximately 37 million people worldwide. Antiretroviral therapy (ART), typically comprising a combination of three drugs, cannot completely eradicate the virus from HIV positive individuals. The elimination of HIV from the body is hampered by the existence of long-lived viral reservoirs, mainly memory T-cells [Chomont et al. 2009; Hiener et al. 2017]. These viral reservoirs cannot be targeted by antiretroviral drugs or the immune system.The aim of the project is to test, in a phase II clinical trial, a drug combination intended to reduce HIV reservoirs that are not targeted by standard ART, as well as the safety of analytic treatment interruptions (ATI) thereafter. The efficacy of the experimental drug combination will be assessed during the whole trial period and compared to that of a control group receiving ART only. The two investigational compounds [i.e. auranofin and buthionine sulfoximine (BSO)] employed in this trial target the reservoirs in memory T-cells and macrophages (Shytaj et al. 2013 and 2015). Auranofin is a gold-based drug that has long been used for the treatment of rheumatoid arthritis. Auranofin can decrease immune activation and exert a pro-apoptotic and pro-differentiating effect on central memory T-cells. BSO is known to inhibit the synthesis of glutathione and has been used in several phase I and II clinical trials against advanced cancers (reviewed in Benhar et al. 2016). Moreover, it was also shown to induce partially selective killing of HIV-infected cells in vitro (Shytaj et al. 2015). The combination of a highly intensified antiretroviral regimen (H-iART) with auranofin and BSO following therapy suspension was shown to result in a functional cure-like condition in macaques chronically infected with the HIV homolog simian immunodeficiency virus (SIV)mac251 (Shytaj et al. 2013). This cure-like status has been shown to persist for a period of over two years Shytaj et al. 2015). The safety of the combined administration of auranofin and ART was demonstrated in a recent clinical trial conducted in São Paulo. Of note, in this clinical trial auranofin was able to decrease total viral DNA in PBMCs as compared to ART-only regimens and induced a decrease in the integrated proviral DNA (Diaz et al. under revision). In addition to this, the safety of combined auranofin and BSO has been shown in both macaques and mice (Shytaj et al. 2013, Fath et al. 2011). The above described pre-clinical and clinical data pave thus the way for the proposed clinical trial aimed at assessing the curative potential of the addition of auranofin and BSO to ART. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SHYTAJ, IART LUCA; PROCOPIO, FRANCESCO ANDREA; TAREK, MOHAMMAD; CARLON-ANDRES, IRENE; TANG, HSIN-YAO; GOLDMAN, AARON R.; MUNSHI, MOHAMEDHUSEN; PAL, VIRENDER KUMAR; FORCATO, MATTIA; SREERAM, SHEETAL; et al. Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress. EMBO MOLECULAR MEDICINE, v. 13, n. 8, JUL 2021. (13/11323-5, 19/17461-7)

SHYTAJ, IART LUCA; FARES, MOHAMED; GALLUCCI, LARA; LUCIC, BOJANA; TOLBA, MAHMOUD M.; ZIMMERMANN, LIV; ADLER, JULIA M.; XING, NA; BUSHE, JUDITH; GRUBER, ACHIM D.; et al. The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters. MBIO, v. 13, n. 2, p. 23-pg., 2022-04-26. (19/17461-7)

DE ALMEIDA BAPTISTA, MARCELLA VASSAO; DA SILVA, LAIS TEODORO; SAMER, SADIA; OSHIRO, TELMA MIYUKI; SHYTAJ, IART LUCA; GIRON, LEILA B.; PENA, NATHALIA MANTOVANI; CRUZ, NICOLLY; GOSUEN, GISELE CRISTINA; ABRAO FERREIRA, PAULO ROBERTO; et al. mmunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical tria. AIDS RESEARCH AND THERAPY, v. 19, n. 1, JAN 12 2022. (19/17461-7, 13/11323-5)