Thursday, April 3, 2025
4/3/2025
Understanding the mechanism of tropism specific immune restriction in HIV infection - 1 PROJECT SUMMARY/ABSTRACT 2 HIV/AIDS remains a significant public health issue, with an estimated 39 million individuals currently living with 3 HIV globally, of whom only 76% are on combination antiretroviral therapy (cART). cART suppresses, but does 4 not eliminate, HIV and is associated with its own burden of lifelong treatment. Thus, there is a pressing need 5 for research to advance the field towards a novel cure for HIV. In the proposed research study, we aim to 6 address this through a unique perspective, by focusing on how the human immune system naturally restricts a 7 specific subset of HIV. HIV tropism is defined by coreceptor use after initial CD4 binding by the virus envelope 8 protein. During the early clinical stages of HIV infection, a subset of HIV which uses the CCR5 coreceptor, 9 termed R5-tropic virus, is dominant, while another HIV subset which uses the CXCR4 coreceptor, termed and 10 X4-tropic virus, is restricted and does not emerge until progression to late clinical disease stages, when the 11 immune system has been impaired. We propose to identify the molecular mechanisms that control the natural, 12 immune-mediated restriction of X4-Tropic virus. Using primary CD4 T cells, in vivo analyses in humanized 13 mouse models, experimental knockout of candidate genes, and analyses of banked patient specimens that 14 predate the widespread use of cART, the candidate will (1) characterize the molecular mechanisms that drive 15 restriction of X4-Tropic viral replication in the presence of R5-Tropic virus, and (2) characterize the mechanism 16 underlying the emergence of X4-Tropic virus during the late clinical disease stages. The overall goal of the 17 proposed study is to gain an understanding of how our immune system naturally restricts X4-Tropic viral 18 replication and how this restriction is lost in late-stage disease. This knowledge will be foundational to future 19 studies that will aim to develop novel treatments for HIV that empower the immune system to restrict R5-tropic 20 virus during early clinical stages in the same manner in which it naturally restricts productive X4-tropic viral 21 replication. The enclosed proposal includes a five year career development plan which focuses on improving 22 knowledge and skills related to the study of immune mediated restriction of X4-tropic viruses and includes a 23 comprehensive mentoring and didactic plan that will ensure the candidate’s successful transition to an 24 independent career in basic and translational HIV research focused on the host-pathogen interface. The 25 candidate is supported by expert mentors and has committed institutional support, with a promotion to 26 Instructor planned prior to the commencement of the K08 award period and 75% research time protected 27 during the award period. The proposed mentorship team, including a primary mentor who is a renowned HIV 28 researcher with prior experience in identifying novel immune mechanisms of HV reservoir clearance, will 29 support the candidate in developing key knowledge and skills. Successful completion of the proposed K08 30 training goals and specific aims will maximize the candidate’s chances of success in an independent research 31 career.
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