HIV/AIDS is a global pandemic with ~40 million individuals living with HIV infection, and approximately 45 million have died from AIDS worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV and its co-infections in developing countries, to determine the viral kinetics associated with transmission, and to characterize the different molecular strains of HIV for infectiousness and progression of disease. The major barrier to curing HIV infection is the persistence of HIV in latently infected resting CD4+ T cells. Previous work from our section and the ICER Uganda team found that the latent viral reservoir (LVR) in our Ugandan population is over 2-fold smaller than that of a previously reported American population. In addition, we also found that Ugandan women have a significantly smaller replication-competent LVR compare to Ugandan men. We are actively working on novel assays and analysis strategies to better examine the viral makeup of the latent reservoir. This work includes examining strategies for dating the HIV reservoir, and more comprehensive ways to assess reservoir clonality and diversity. In addition, Dr. Redd led an analysis of full-genome sequences from the Uganda reservoir, and the development and validation of a HIV subtype A/D IPDA assay for use in Africa. We are also continuing our ten-year longitudinal analysis of the LVR in our Ugandan cohort. As an extension of this work, our group and our long-term collaborators at the Rakai Health Science Program have become a critical partner for the the REACH Delaney HIV cure consortium. Lastly, we are working with Dr. Eli Boritz, at the VRC, to examine at the infected cell level transcriptomics of male and female Ugandans, and have begun a collaboration with Dr. Sharon Lewin, University of Melbourne, to develop and validate a non-subtype B version of their exciting CRSIPR-activator construct for HIV cure in Africa. We are also continuing our HIV latency work in South Africa with several ongoing studies examining the roles of Nef-mediated MHC-I downregulation and CTL escape mutations on the size and make-up of the reservoir, as well as validating a cross-subtype IPDA assay for use in South Africa. We also continued our work examining HIV-positive to HIV-positive (HIV+/HIV+) organ transplants in South Africa and the US. In particular, the HOPE in Action multicenter US-based clinical trial examining HIV+/HIV+ kidney transplants was recently completed, and it was found that HIV+/HIV+ transplantation is safe and the recipient outcomes are comparable with HIV-/HIV+ transplants. This work was recently accepted for publication in New England Journal of Medicine. In South Africa, we expanded our larger kidney project to examine HIV-related kidney disease in the Eastern Cape, as well as examined the effects of COVID-19 infection on our HIV+ to HIV+ kidney recipient cohort in Cape Town. COVID-19 has transitioned to an endemic infectious disease across the globe, and we have continued our work examining the immunology and virology associated with SARS-CoV-2 infection. We examined the role of pre-existing cross-reactive T cell responses in Ugandans pre-pandemic, and found that almost 90% of the cohort tested had cross-reactive responses. We also have continued our work examining antibody responses to SARS-CoV-2 infection, vaccination, and post-convalescent plasma treatment. Post-COVID conditions (PCCs) are common and have significant morbidity. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. One third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and anosmia (14.5%) being most common. In a multivariable analysis, female sex (adjusted odds ratio [AOR] = 2.69 [1.93–3.81]), older age (AOR = 1.32 [1.17–1.50]), and elevated baseline levels of IL-6 (AOR = 1.59 [1.02–2.47]) were independently associated with development of PCC. Furthermore, early CCP treatment (≤5 days after symptom onset) treatment had statistically significant lower odds of PCC. We characterized Emergency Department (ED) patients with high-titer syphilis infections (HTSIs) with the goal of defining a screening strategy that best identifies undiagnosed, untreated syphilis infections. Using unlinked, de-identified remnant serum samples from patients attending an urban ED, between 10 January and 9 February 2022, were tested using a three-tier testing algorithm, and sociodemographic variables were extracted from ED administrative database prior to testing. Patients who tested positive for treponemal antibodies in the first tier and positive at high titer (≥1:8) for nontreponemal antibodies in the second tier were classified as HTSI. Among 1951 unique patients tested, 23 (1.2% [95% CI 8%-1.8%]) had HTSI. Of those, 18 (78%) lacked a primary care physician, 5 (22%) were HIV positive, and 8 (35%) were women of reproductive age (18-49 years). Using a screening strategy that measured syphilis antibodies in patients with HIV, without a primary care physician, and women of reproductive age would have identified most patients with HTSI (21/23 [91%]). We conclude that a high prevalence of HTSI exists in an urban ED and propose a screening strategy to identify these individuals.