Epidemiologic studies uncover patterns between immunologic/genetic phenotypes and disease states, identifying potential novel mechanisms of infectious diseases pathogenesis.
Host genetic predictors of plasma Interleukin-1 Beta (IL-1β) during treated HIV disease
There has been no genomewide association studies evaluation host genetic predictors of IL-1β during treated HIV disease. However, there is some evidence for a link between host genomics and IL-6 from multiple large epidemiologic studies in the general population and recently in a smaller group of people with HIV (PWH). Our lab is using samples from the U.S. Military HIV Natural History Study to perform whole genome sequencing to determine potential novel mechanisms by which individuals have high IL-1β levels after ART initiation.
Plasma cytokine Interleukin-1 Beta (IL-1β) associations with vascular events during treated HIV
Despite antiretroviral therapy (ART), people with HIV (PWH) experience higher rates of morbidity and mortality vs. age-matched HIV negative controls which may be driven by chronic inflammation due to persistent virus. Inflammasome activation leading to proinflammatory cytokine production, such as interleukin(IL)-6 (one of the strongest predictors of mortality in PWH on ART) may be a major driver of this risk. We performed a case-cohort study of 1,002 PWH on ART from the U.S. Military HIV Natural History Study to determine whether inflammasome activated signaling cytokines (IL-1β, IL-6, IL-18) levels predict incident vascular events in PWH on ART. A total of 200 “cases” of PWH on ART who experienced any vascular event (VE) during follow up were included, and cohort controls (PWH on ART without VE) were selected by modified incidence density sampling (1:4 matching). The U.S. Military HIV Natural History Study is a longitudinal cohort study, initiated in 1985 and includes over 8,000 U.S. military recruits followed since the time of HIV diagnosis.Participants were individuals with laboratory confirmed HIV-1 infection and ART-mediated viral suppression (>1 year) at the time of plasma sampling. Primary exposure is plasma inflammasome pathway cytokines (IL-1β, IL-6, and IL-18). Primary outcome was incident vascular event (VE), a composite measure including coronary artery disease (CAD), myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolus (PE), stroke/cerebrovascular accident (CVA), and peripheral arterial disease (PAD).
COVID-19 Host Immune Response Pathogenesis (CHIRP) Cohort Study
The COVID-19 pandemic has caused devastating morbidity and mortality worldwide. However, the virus itself does not seem to explain the person-to-person variability in clinical course (ranging from asymptomatic carriage to severe lethal respiratory disease, as well as long-term inflammatory sequelae). Variation in host genetics and host-specific immune responses likely play a major role in determining the severity of COVID-19. We are performing in-depth sampling of blood, sputum, nasal swab, saliva, urine, and stool to apply advanced single cell immunogenetic approaches to predict the specific immune cells and inflammatory pathways that determine severity of COVID-19. Our preliminary data from the CHIRP study demonstrates that convalescing COVID+ individuals mount robust T cell responses against SARS-CoV-2, suggesting an important role for T cells in viral clearance. These data will inform the safety of designing COVID clinical trials aimed at modulating these pathways.
GWAS of Immune Recovery in HIV+ Ugandans
CD4+ T cell recovery after antiretroviral therapy (ART) initiation follows 2-3 phases of recovery. There have been no genomewide association studies evaluating host genetic predictors of CD4 recovery during treated HIV disease. Our lab has collected pre-ART and post-ART suppressed samples from HIV-infected Ugandans to perform genomewide genotyping and CD4+ T cell quantification to determine potential novel mechanisms by which individuals vary in immune recovery after ART initiation.
Host Genetic Predictors of HIV Latency: Whole Exome Sequencing
HIV cure has emerged as an important research priority. A key challenge in HIV eradication strategies is the “HIV reservoir,” i.e., the cells in which HIV persists despite antiretroviral therapy (ART). Studies are now underway to understand how the HIV reservoir is established and how cells harboring HIV may be eradicated. For this study, we have generated custom whole exome sequencing and peripheral blood-based measures of the HIV reservoir (cell-associated total DNA and unspliced RNA) to discover potential host genetic mutations that determine the HIV reservoir size.
