International Studies of the Acquired Immune Deficiency Syndrome (AIDS)

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

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, viral latency, and characterize the different molecular strains of HIV for infectiousness and progression of disease both on and prior to antiretroviral therapy. 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, and that Ugandan women have a significantly smaller replication-competent (RC) LVR compare to Ugandan men. We also found in this cohort that switching to dolutegravir (DTG)-based ART caused a temporary but significant spike in the RC-LVR. We have continued this study by examining the immunological and cellular effects of DTG both ex vivo and in vitro. In addition, we published two novel studies with collaborators from Uganda and South Africa, respectively, that identified the ability of HIV Nef to downregulate MHC-I as a possible driver for HIV persistence. We are continuing this work by examining possible novel interventions to disrupt Nef’s ability to block MHC-I downregulation. We are also 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 variability. Lastly, we are working with Dr. Eli Boritz, at the VRC, to examine 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 autologous antibody and CTL escape mutations on the size and make-up of the reservoir, as well as using a cross-subtype IPDA assay to examine the latent reservoir in South African women. Lastly, we are using a novel HIV p24 Tracer assay and site-directed next-generation sequencing to examine the reservoir in South African HIV+ to HIV+ kidney transplant recipients. In addition, we continued our work examining 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 published (highlighted below), and we have finished data collection for the sister study examining HIV+ to HIV+ liver transplantation. This work will be submitted for publication this fall. In South Africa, we expanded our larger kidney project to examine HIV-related kidney disease in the Eastern Cape, and the role of ApoL1 high-risk alleles in both recipient and donors on transplantation outcome. 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 long COVID, also known as Post-COVID conditions (PCCs). Little is known about treatment, inflammation, and PCC, though it’s impact varies greatly geographically. COVID-19 and PCC severity is positively associated with the presence of specific autoantibodies (AAbs), particularly anti-interferon alpha (aIFNα), antinuclear antibodies (ANAs), anti-cardiolipin (aCL), and anti-beta 2 glycoprotein 1 (aβ2GP1). Despite these associations, AAb dynamics across populations remain underexplored, which is particularly relevant given the marked differences in COVID-19 outcomes between regions. For example, COVID-19 mortality has been significantly lower in East Africa compared to the United States. We identified 224 patients from the Johns Hopkins Hospital Emergency Department (United States) and 117 participants from the Rakai Community Cohort Study (Uganda) who demonstrated serologic evidence of SARS-CoV-2 infection. For both groups, we measured aIFNα, ANAs, aCL, and aβ2GP1 at timepoints prior to and following evidence of infection to evaluate changes in autoantibody prevalence. Before evidence of SARS-CoV-2 infection, ANA prevalence was significantly higher in Rakai subjects compared to Baltimore subjects (44% vs 25%, p<0.001). The most striking ANA-related difference was for anti-Ku (22% vs 3%, p<0.001). In contrast, aIFNα, aCL, and aβ2GP1 were infrequently detected in both groups. We observed no significant induction of any tested AAbs following SARS-CoV-2 infection. Our findings indicate that AAb prevalence differs substantially between these two populations, independent of recent SARS-CoV-2 infection. This divergence raises the possibility that population-specific or environmental factors can significantly shape AAb profiles.