CD8+ T-cell exhaustion during chronic human immunodeficiency virus (HIV) infection is characterized by increasing expression of exhaustion markers on the cell surface that lead to decreased function, greatly diminishing immune responses and therapeutic vaccination efficacy. Blocking the activation of one such marker (PD-1) using a monoclonal antibody (aPD-1) can help reverse exhaustion. We hypothesized that dosing with aPD-1 would boost the immune system and decrease expression of certain exhaustion markers on CD8+ T-cells throughout infection in order to improve therapeutic vaccine responses. To investigate this hypothesis, we studied how exhaustion changed over time in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques treated with a combinatorial therapeutic regimen consisting of a conserved-elements vaccine to circumvent viral mutants, GS986 to reverse latency, CCR5 gene editing to prevent viral entry, aPD-1 to reverse T-cell exhaustion, and antiretroviral treatment. We characterized exhaustion in peripheral blood mononuclear cells (PBMC) with surface staining and flow cytometry, focusing on markers of exhaustion including PD-1, CTLA-4, LAG-3, TIGIT, and TIM-3 at various timepoints throughout SHIV infection and therapeutic vaccination. We observed higher CD8+ T-cell vaccine responses in animals receiving aPD-1, compared to animals that were vaccinated but not given aPD-1, suggesting aPD-1 dosing improved vaccine responses. We did not observe any significant correlation between PD-1 signaling and expression of other exhaustion markers, suggesting that blocking PD-1 does not reduce exhaustion by decreasing the expression of other exhaustion markers. However, we found a significant negative correlation between CD8+ T-cell vaccine responses and the expression of TIGIT (Spearman r= -0.75, p=0.007). As reduced TIGIT on CD8+ T-cells correlated with increased vaccine responses, there may be a role for dual TIGIT and PD-1 blockade in future studies. Defining the role of CD8+ T-cell exhaustion in therapeutic vaccine immunogenicity and efficacy is crucial to improving combinatorial immunotherapy towards a cure for HIV.

Currently, there is no clinical best practice in place to support and manage follow up care for previvors, individuals who have tested positive for one or more mutations that increase cancer risk. Patients and providers need support in making complex decisions about follow-up. This project aims to design ‘previvor plans’, modeled after survivorship care plans received by cancer survivors, to help inform and support previvors after they receive a positive test result. Content of the previvor plans includes recommendations for screening, prophylactic surgery, pharmacological interventions, and lifestyle changes based on national guidelines as well as resources to receive further education and support. This project is a part of a larger study which evaluates two different methods of engaging patients in genetic testing for cancer risk across 12 different primary care clinics. Each patient in the study who tests positive for a mutation that increases cancer risk receives a previvor plan tailored with resources and recommendations specific to their test results and location. Use of the plans will be evaluated through surveys and interviews of previvor patients. If successful, the creation of previvor plans will provide a tool which can be used by patients and their providers to manage follow up care after receiving a positive test result.