ABSTRACT Increased iron stores correlate with rapid AIDS progression in HIV-1-infected patients, in iron-loaded thalassemia major patients, in HIV-positive patients administered with oral iron, and those with the haptoglobin 2-2 polymorphism. While in Caucasians iron overload is primarily driven by mutations in hemochromatosis (HFE) gene, in Africans and African Americans, ferroportin (FPN) Q248H gene variant (Rs 1156835, allele frequency of 2.2-13.4%) is associated with increased iron load FPN is the only known cellular iron export protein, that is negatively regulated by hepcidin, a short peptide secreted by the liver. HIV-1 infection inversely correlates with the expression levels of transferrin receptor, a surrogate marker of reduced intracellular iron. Iron chelators inhibit HIV-1 replication as shown by us and others. Thus, iron metabolism is intrinsically connected to the HIV-1 infection and disease progression. However, the mechanism of HIV-1 activation in iron-loaded cells is not fully understood and the effect of systemic iron load due to the FPN expression on HIV-1 infection in vivo has not been extensively studied. FPN Q248H is the only variant with high minor allele frequency (MAF=0.026) among all other known FPN mutations. In our preliminary study, we generated a knock-in FPN Q248H mice that had increased iron load in organs and higher levels of circulating iron. We therefore hypothesize that FPN Q248H mutation will increase iron load and exacerbate the response to HIV-1 infection in individuals with this mutation. We further hypothesize that males with FPN Q248H mutation are at risk of HIV-1 infection and may not be able to control the infection even under cART treatment. We will test these hypotheses in the cohort of HIV-1+ man and in FPN Q248H mouse model. In Aim 1, we will analyze the effect of FPN Q248H variant on HIV-1 infection in male African Americans from Multicenter Cohort AIDS Study (MACS) cohort. We will conduct multivariate analysis to determine the effect of the homozygote and heterozygote FPN Q248H mutation on viral load, relationship to the CD4+ and CD8+ counts, hematological parameters (hemoglobin, MCV, RBC counts) and behavioral variables (drug, opioid, alcohol, sexual partners, PrEP). In Aim 2, we will investigate the effect of FPN Q248H variant on HIV infection in FPN Q248H mouse model using EcoHIV virus that infects mouse T cells and macrophages. We will also analyze antiviral factors expressed in mouse splenic T cells and macrophages using RNA Seq analysis. The proposed study will be a collaboration between RCMI (Howard University) and DC CFAR (Georgetown University) Institutions. The study includes a mentorship plan for graduate students and Junior Investigators. The proposed study will establish the role of FPN Q248 mutation specific for African Americans in HIV-1 infection by behavioral, and molecular analyses. It will also test the effect of FPN Q248 mutation in novel mouse model. This study will help to b...