This is the new submission in response to an R21/R33 (TaPHIR) funding opportunity determining whether targeting a novel immune-inhibitory pathway can deplete latently HIV infected CD4 memory T cells in HIV virally suppressed patients. Although highly active antiretroviral therapy (HAART) can suppress HIV replication and significantly improve the long-term health of the patient, it is unable to permanently remove latent reservoirs of virus. Therefore, novel strategies are needed to specifically target and destroy latently infected cells. The T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a newly described immune checkpoint inhibitory receptor expressed on subsets of activated T cells, and natural killer (NK) cells and found highly expressed on tumor infiltrating lymph nodes. In our preliminary studies we find increased TIGIT and PD-1 expression on effector memory CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue indicating that the TIGIT pathway is active in the non-human primate model. Our ongoing studies, reveal strikingly, that dual blockade of TIGIT and PDL-1 restores HIV and SIV effector T cell function indicating that potent anti-viral responses following dual blockade may aid in the killing of HIV-infected latent cells following reactivation. With the development of (1) TIGIT and PDL-1 mAbs and an anti-retroviral therapy regimen that consistently and potently inhibits SIV replication, we propose to determine whether targeting the TIGIT and PDL-1 immune-inhibitory pathway can deplete latently HIV and SIV infected CD4 memory T cells and serve as a novel HIV eradication approach in shock and kill cure approach. In the R21 phase we propose to determine the ability of TIGIT and PDL-1 blockade to increase antiviral efficacy in vitro and deplete or inactivate HIV and SIV latently activated cells by enhancing anti-HIV and SIV CD8 T cell activity. In the R33 we will test the ability of TIGIT and PDL-1 mAbs to clear the latent reservoir during fully suppressive HAART in the SIV infected rhesus macaque model of HIV. These studies are the first steps towards a novel approach that will lead to a sustained cure or functional cure. Given our exciting preliminary data, research capabilities we expect to reach the milestones outlined in this project.
Strategies to eliminate the HIV viral reservoir to date have not succeeded. This study proposal seeks to facilitate the elimination of HIV infected cells through increased antiviral T cell function. We propose to achieve this through a concerted study of a novel immune regulatory pathway that when blocked restores T cell function capable of depleting latently HIV infected T cells. This study will be extended to the SIV infected non-human primate model of AIDS to confirm whether this novel strategy specifically targets and destroy latently infected cells.
| SahBandar, Ivo N; Samonte, Genesis; Telan, Elizabeth et al. (2017) Ultra-Deep Sequencing Analysis on HIV Drug-Resistance-Associated Mutations Among HIV-Infected Individuals: First Report from the Philippines. AIDS Res Hum Retroviruses 33:1099-1106 |
| Leal, Fabio E; Premeaux, Thomas A; Abdel-Mohsen, Mohamed et al. (2017) Role of Natural Killer Cells in HIV-Associated Malignancies. Front Immunol 8:315 |
