Vedolizumab and ART in recent HIV-1 infection unveil the role of α4β7 in reservoir size

• Published in: JCI insight Vol. 9; no. 16
• Main Authors: Jimenez-Leon, Maria Reyes, Gasca-Capote, Carmen, Roca-Oporto, Cristina, Espinosa, Nuria, Sobrino, Salvador, Fontillon-Alberdi, Maria, Gao, Ce, Roseto, Isabelle, Gladkov, Gregory, Rivas-Jeremias, Inmaculada, Neukam, Karin, Sanchez-Hernandez, Jose German, Rigo-Bonnin, Raul, Cervera-Barajas, Antonio J, Mesones, Rosario, García, Federico, Alvarez-Rios, Ana Isabel, Bachiller, Sara, Vitalle, Joana, Perez-Gomez, Alberto, Camacho-Sojo, María Inés, Gallego, Isabel, Brander, Christian, McGowan, Ian, Mothe, Beatriz, Viciana, Pompeyo, Yu, Xu, Lichterfeld, Mathias, Lopez-Cortes, Luis F, Ruiz-Mateos, Ezequiel
• Format: Journal Article
• Language: English
• Published: United States 09.07.2024
• Subjects: Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - therapeutic use; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - therapeutic use; CD4-Positive T-Lymphocytes; Female; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; Humans; Ileum - metabolism; Ileum - virology; Integrins - metabolism; Male; Middle Aged; RNA, Viral - blood; Viral Load - drug effects; AIDS/HIV; Immunotherapy; Immunology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.182312

BACKGROUNDWe evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the effect of α4β7 on the HIV-1 reservoir size.METHODSParticipants started ART with monthly vedolizumab infusions, and ATI was performed at week 24. Biopsies were obtained from ileum and cecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry, and cell-sorting and antibody competition experiments were assayed.RESULTSVedolizumab was safe and well tolerated. No participant achieved undetectable viremia off ART 24 weeks after ATI. Only a modest effect on the time to achieve more than 1,000 HIV-1 RNA copies/mL and the proportion of participants off ART was observed, being higher in the vedolizumab group compared with historical controls. Just before ATI, α4β7 expression was associated with HIV-1 DNA and RNA in peripheral blood and with PD1 and TIGIT levels. Importantly, a complete blocking of α4β7 was observed on peripheral CD4+ T cells but not in gut (ileum and cecum), where α4β7 blockade and vedolizumab levels were inversely associated with HIV-1 DNA.CONCLUSIONOur findings support α4β7 as an important determinant in HIV-1 reservoir size, suggesting the complete α4β7 blockade in tissue as a promising tool for HIV-cure combination strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT03577782.FUNDINGThis work was supported by the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, "a way to make Europe," research contracts FI17/00186 and FI19/00083 and research projects PI18/01532, PI19/01127, PI22/01796), Conserjería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (research projects P20/00906), the Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020), and the Spanish National Research Council.