Immune restoration by TIGIT blockade is insufficient to control chronic SIV infection.

Autor:	Webb GM; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA., Pessoa CT; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA., McCullen AJ; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA., Hwang JM; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA., Humkey MC; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA., Thormin-Odum R; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA., Kukula KA; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA., Smedley J; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA., Fischer M; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA., Sciurba J; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA., Bochart RM; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA., Shriver-Munsch C; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA., Ndhlovu LC; Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, New York, USA., Sacha JB; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.; Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2024 Jun 13; Vol. 98 (6), pp. e0027324. Date of Electronic Publication: 2024 May 22.
DOI:	10.1128/jvi.00273-24
Abstrakt:	TIGIT is a negative immune checkpoint receptor associated with T cell exhaustion in cancer and HIV. TIGIT upregulation in virus-specific CD8 + T cells and NK cells during HIV/SIV infection results in dysfunctional effector capabilities. In vitro studies targeting TIGIT on CD8 + T cells suggest TIGIT blockade as a viable strategy to restore SIV-specific T cell responses. Here, we extend these studies in vivo using TIGIT blockage in nonhuman primates in an effort to reverse T cell and NK cell exhaustion in the setting of SIV infection. We demonstrate that in vivo administration of a humanized anti-TIGIT monoclonal antibody (mAb) is well tolerated in both cynomolgus macaques and rhesus macaques. Despite sustained plasma concentrations of anti-TIGIT mAb, we observed no consistent improvement in NK or T cell cytolytic capacity. TIGIT blockade minimally enhanced T cell proliferation and virus-specific T cell responses in both magnitude and breadth though plasma viral loads in treated animals remained stable indicating that anti-TIGIT mAb treatment alone was insufficient to increase anti-SIV CD8 + T cell function. The enhancement of virus-specific T cell proliferative responses observed in vitro with single or dual blockade of TIGIT and/or PD-1 highlights TIGIT as a potential target to reverse T cell dysfunction. Our studies, however, reveal that targeting the TIGIT pathway alone may be insufficient in the setting of viremia and that combining immune checkpoint blockade with other immunotherapeutics may be a future path forward for improved viral control or elimination of HIV.IMPORTANCEUpregulation of the immune checkpoint receptor TIGIT is associated with HIV-mediated T cell dysfunction and correlates with HIV disease progression. Compelling evidence exists for targeting immune checkpoint receptor pathways that would potentially enhance immunity and refocus effector cell efforts toward viral clearance. In this report, we investigate TIGIT blockade as an immunotherapeutic approach to reverse immune exhaustion during chronic SIV/SHIV infection in a nonhuman primate model of HIV infection. We show that interfering with the TIGIT signaling axis alone is insufficient to improve viral control despite modest improvement in T cell immunity. Our data substantiate the use of targeting multiple immune checkpoint receptors to promote synergy and ultimately eliminate HIV-infected cells. Competing Interests: L.C.N. serves as a scientific advisor to Abbvie and ViiV Healthcare, serves on the board of Cytodyn, and has financial interests in Ledidi AS, all for work unrelated to this study.
Databáze:	MEDLINE
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