PROJECT SUMMARY/ABSTRACT: Despite the many options for HIV treatment and prevention, an efficacious and safe vaccine remains a key component in efforts to end the pandemic. Natural killer (NK) cells play a crucial role in anti-viral immune responses. Not only have they have been shown to play a critical role in host protection through direct targeting of virally infected cells and also via NK-mediated antibody dependent cellular cytotoxicity. However, recent studies suggest a more encompassing role for NK cells since they can develop into long-lived memory cells and acquire antigen specificity. Thus, there is a need to elucidate the cellular and molecular mechanisms regulating NK cell responses to natural HIV infection and HIV vaccination. The long-term goal of our research is to devise safe and effective vaccine strategies to counter this viral pandemic. To achieve this, we have focused on understanding the mechanisms that mobilize NK cells, with particular attention to inducing NK cell cytotoxicity. The objective of this proposal is to identify qualitative and quantitative features of NK cell activation and differentiation inducted by HIV natural infection and Adenovirus (Ad)-vectored-based vaccination. The overarching hypothesis is that both natural HIV infection and Ad-vectored HIV vaccination will induce the activation and maturation of NK cells and subsequent development of memory NK cells. Our rationale is that understanding the mechanisms regulating NK cell activation and functionality, in addition to the cellular and molecular mechanisms of antibody-mediated NK cell functions, in response to both natural HIV infection and vaccination, will be beneficial for establishing translational interventions against HIV and other viral infections. Our specific aims will test the following: Aim 1: Differentiate memory NK cell subsets and their potential impact on HIV disease progression and response to Ad26.Mos.HIV vaccination; and Aim 2: Map and compare memory NK cell epigenetic signatures in response to HIV natural infection and Ad26.Mos.HIV vaccination. Upon conclusion, our analysis will help to fill the current knowledge gap regarding NK cell memory development in responses to both natural HIV infection and HIV vaccination. This knowledge is important because we expect it to identify novel aspects of the immune system we can modulate to our advantage against viral pathogens, and ultimately use NK cells as part of future effective therapeutic vaccine strategies.

PROJECT NARRATIVE HIV is one of world’s most serious health problems, and despite all the available treatments and prevention options, a safe and efficacious vaccine remains the only way to end the pandemic. Our proposed studies aim to understand the cellular and molecular mechanisms regulating natural killer (NK) cell activity and function in responses to both natural HIV infection and HIV vaccination with a focus on memory and adaptive like responses. Upon conclusion, we will better understand how to harness NK cells to create more effective vaccine strategies.