PROJECT SUMMARY/ABSTRACT Although modern therapies have dramatically improved the outlooks for people living with HIV they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, many people do not have access to these expensive medications - in particular those living in resource-limited settings. Furthermore, efforts to end the HIV epidemic have suffered from the lack of effective preventative or therapeutic vaccines – biomedical tools which have played critical roles in the elimination of other epidemics, such as smallpox. Recent years have seen important advances in harnessing the antibody arm of the immune system towards these aims, though substantial challenges still exist. The T-cell arm of the immune system, which specializes in the recognition and elimination of virus infected cells, holds great promise to contribute to these efforts, but has lagged behind in development. This can be attributed – in part – to substantial limitations in the suitability of currently available pre-clinical animal models for the study of T-cell responses. For example, the property of major histocompatibility (MHC) restriction means that the ways in which the virus- infected cells of a rhesus macaque will recognize a virus-infected cell differ from the way they would be recognized by a given human. The current proposal aims to build upon compelling preliminary results, in which we have observed that a relatively simple, but powerful, modification of a humanized mouse model solves many of the key issues that have limited utility to date. Namely, we present a mouse model that can be stably engrafted with immune cells (PBMC) from HIV-infected or uninfected adults, without inducing graft versus host disease (GvHD). The use of adult cells both avoids the need for fetal tissue. In this project, we will test whether HIV- specific T-cell responses arise naturally in this mouse model, and whether these play a role in suppressing viral replication. We will then test whether we are able to induce HIV-specific T-cell responses in uninfected animals using an mRNA vaccine technology, similar to that employed against COVID-19. Finally, we will test whether vaccine-induced responses can control viral replication. If successful, this will result in a novel small animal model in which we can rapidly test and optimize HIV vaccination strategies using a mRNA platform. We believe that this will facilitate the translation of optimal approaches to clinical trials.

PROJECT NARRATIVE Although HIV infection can be controlled by daily lifelong adherence to expensive antiretroviral ARV therapies, it cannot presently be cured, and there are no effective preventative or therapeutic vaccines. The development of such vaccines has been hampered by limitations in existing small animal models of HIV-infection, particularly with respect to their abilities to assess method of enhancing the T-cell arm of the immune system. This proposal aims to address this unmet need by building upon compelling preliminary data to validate a relatively simple, but potentially powerful, novel mouse model of HIV replication, in which to test and optimize vaccine strategies.