PROJECT ABSTRACT The first few months of HIV infection, broadly referred to as “early HIV infection,” are characterized by elevated viral loads and increased per-virion infectivity, resulting in higher transmission rates compared to the subsequent chronic infection period. Modeling studies have estimated that transmission during early infection disproportionately contributes to population-level HIV incidence: members of our team estimated that HIV transmission during the first five months of infection accounted for 38% of incident infections in 2010 in Lilongwe, Malawi, while a recent model from eSwatini estimated that transmission during the first three months of infection accounted for 15% of incident infections. Both studies concluded that to end the HIV epidemic, transmission during early infection must be addressed. The pre-seroconversion or “acute” phase, which represents the first several weeks of early infection, is characterized by the highest viral loads and infectivity. Detection of acute HIV infection (AHI) requires RNA or antigen testing, which is difficult to implement in many settings. Members of this study team have shown that sexually transmitted infections (STI) clinics are consistently high-yield settings for AHI detection and that an intervention (iKnow - NCT02467439) integrating AHI screening, assisted partner notification, and social contact referral in STI clinics can efficiently identify undiagnosed cases of HIV. The iKnow team assembled one of the largest documented cohorts of persons with AHI in Africa (n=115) between 2015 and 2019 at Bwaila STI clinic in Lilongwe, Malawi. Using questionnaire, household GPS, and phylogenetic data from the iKnow study, the proposed project will examine the prevention potential of AHI-focused interventions that are anchored in STI clinics and supplemented by geographically- and demographically-guided interventions in communities. Specifically, we will: 1) investigate the characteristics of persons and places associated with AHI; 2) test for spatiotemporal clustering of AHI cases and determine whether spatiotemporal AHI clusters were formed through phylogenetically linked transmission events; and 3) model the population-level impact on HIV incidence of interventions focusing on acute and early HIV infection. These analyses will provide novel insights into HIV transmission dynamics and inform interventions against transmission during acute and early HIV infection. To support the completion of this project and the applicant’s development into an independent investigator, the proposed training plan includes close mentorship by global experts in phylogenetics, phylogeography, mathematical modeling, and HIV prevention, as well as external coursework and readings. The applicant will develop scientific communication skills through manuscript writing and presentations to the PANGEA HIV consortium.