J.V. Garcia1, H. Yang2, A. McMichael2, G. Doyon3 1University of Alabama at Birmingham, Microbiology, Birmingham, United States, 2University of Oxford, Dept. of Clinical Medicine, Oxford, United Kingdom, 3University of North Carolina, Infection Diseases, Chapel Hill, United States
BACKGROUND: To effectively cure HIV-1, it's essential to maintain ongoing antiviral T cell responses to achieve long-term suppression or clearance of the virus. This study examines the ability of nonpolymorphic Human Leukocyte Antigen-E (HLA-E) restricted T cells to suppress HIV-1 replication in humanized mice, utilizing a T cell receptor (TCR)-based immunotherapy approach.
METHODS: Bulk CD8+ T cells derived from humanized mouse tissues were transduced with HLA-E restricted TCRs specific for GAG epitope RMYSPTSIL (RL9) and REV epitope ILVESPAVL (IL9). TCR transductants were enriched and expanded in vitro prior to infusion into autologous humanized mice. To determine if the presence of the HIV-1-specific TCRs has an effect on suppressing HIV-1 virus replication, we infected humanized mice with HIV-1JRCSF , separately humanized mice receiving non-HIV-1 TCR transductants were used as controls.
RESULTS: Significant higher frequencies of TCR transductants were detected in PB and tissues in mice receiving HIV-1 TCRs compared to control mice, suggesting HIV-1 antigen specific expansion and long-term survival of HIV-1 TCR+ cells in vivo. HIV-1 TCR+ transduced cells were detected in all tissues analyzed. Importantly, during acute HIV-1 infection in the absence of antiretroviral therapy (ART), we observed significant reductions in plasma viral load (~90%, p=<0.04) and in cell associated viral RNA from tissues (>80%, p=0.0016). We then evaluated the efficacy of HLA-E restricted HIV-1 TCR transductants to reduce the size of the HIV reservoir in animal where HIV replication had been suppressed by ART. Using intact proviral DNA analysis we were able to demonstrate a 50% reduction in the levels of intact provirus in tissues (p=0.04).
CONCLUSIONS: Our findings demonstrate that HLA-E restricted HIV-1 TCR transductants are effective in reducing viral replication in vivo. Additionally, we have shown that these transductants efficiently decrease the size of the HIV reservoir. Combined, our results indicate that cell therapy-based approaches targeting the minimally polymorphic HLA-E molecules can provide a robust therapeutic effect in vivo, reducing the intact proviral DNA load in HIV-infected T cells. HLA-E based cell therapy, with its "universal" nature, holds significant potential as a novel approach to curing HIV.