Administrative Supplement for U54 AI170752 In the absence of an effective preventive vaccine or a cure, HIV-1 continues to be a major global health crisis. Having claimed 40.4 million lives so far with ongoing transmission in all countries globally, according to the World Health Organization, with some countries reporting increasing trends in new infections when previously on the decline. For the estimated 39.0 million people living with HIV at the end of 2022, highly active antiretroviral therapy (HAART) provides the best current hope for avoiding fatality due to the infection. While HAART has substantially reduced morbidity and mortality, it is not curative due to the formation of a very stable reservoir of latent virus in resting memory CD4+ T cells. The Duke Center for HIV Structural Biology (DCHSB) brings together a diverse team of scientists to focus on structural studies of the HIV-1 Envelope (Env) protein that provides new insights into dynamics of HIV-1 entry and fusion with the host membrane, the Env-initiated immune activation of B cell receptors, and the role of anti-Env antibodies in blocking viral rebound. This multicomponent application for an Administrative Supplement for U54 AI170752, will accelerate membrane protein technologies for HIV-1 Env studies, aimed at structural dissection of the mechanisms of antibody interactions to the Membrane Proximal External Region (MPER), understanding HIV-1 coreceptor tropism and elucidating the mechanism of a gp41 directed fusion inhibitor. The second component will add a Direct Detector Camera to our existing Tundra microscope to enable routine high resolution cryo-EM data acquisition for HIV-1 Env samples. The third component will acquire a Nanotemper Monolith X for robust equilibrium measurement of challenging biomolecular interactions with minimal sample consumption.

In this multicomponent application for an Administrative Supplement for U54 AI170752, the first component will accelerate membrane protein technologies for HIV-1 Env studies, aimed at structural dissection of the mechanisms of antibody interactions to the Membrane Proximal External Region (MPER), understanding HIV- 1 coreceptor tropism and elucidating the mechanism of a gp41 directed fusion inhibitor. The second component will add a Direct Detector Camera to our existing Tundra microscope to enable routine high resolution cryo-EM data acquisition for HIV-1 Env samples. The third component will acquire a Nanotemper Monolith X for robust equilibrium measurement of challenging biomolecular interactions with minimal sample consumption.