Research Project
10135135
Sickle cell disease (SCD) is an inherited hemoglobinopathy that leads to sickling of red blood cells and the development of chronic hemolytic anemia. SCD patients have lower risk for HIV-1 infection, but its underlying molecular mechanisms are not well understood. We recently showed that changes in iron metabolism leads to upregulation of innate immune response and prevent ex vivo HIV-1 infection of PBMCs obtained from SCD patients. Our working hypothesis is that hemolysis-mediated upregulation of ferroportin expression and iron export in SCD leads to the inhibition of HIV-1 replication. We further hypothesize that macrophage processing of abnormal sickle hemoglobin leads to interferon-? production and stimulation of antiviral response. What is yet unclear is whether SCD or sickle cell trait triggers an overall antiviral state or whether HIV-1 is controlled at post infection stage. To answer these questions, we will investigate HIV-1+ SCD patients and cohort of HIV-1+ sickle cell trait individuals to include males and Africans. We will also utilize mouse model of SCD to analyze EcoHIV-1 infection in vivo. In Specific Aim 1, we will analyze HIV-1 restriction in HIV-1+ SCD individuals. We will analyze the effect of SCD on HIV-1 infection in SCD HIV-1+ patients recruited from Howard University and Montefiore clinics. We will analyze their hematological and virological parameters and test host genes expression using RNA-Seq analysis. We will analyze their HIV-1 phylogeny, HLA-B alleles and inflammation markers. In Specific Aim 2, we will determine the effect of sickle cell trait on HIV-1 infection in African Americans and Africans and viral load in African Americans from WIHS, Multicenter Cohort AIDS Study (MACS), and a Nigerian cohort. We will conduct multivariable analysis to determine the effect of the trait on viral load, relationship to CD4/CD8 counts and levels of proteins involved in iron metabolism and HIV-1 restriction. We will also conduct a case control study to analyze HIV-1phylogeny and the effect of iron and inflammation markers on HIV-1 progression. In Specific Aim 3, we will analyze molecular mechanisms of HIV-1 inhibition in SCD and sickle cell trait. We will analyze expression of host HIV-1 restriction factors in monocyte- derived macrophages treated with HbSS and HbAS hemoglobin and test selected factors in ex vivo HIV-1 infection of PBMCs derived from SCD patients and HIV-1+ sickle cell trait participants from WIHS and MACS cohorts. We will also test HIV-1 infection in SCD and trait mouse models using EcoHIV virus that infects mice and leads to the latent HIV-1 infection in T cells and macrophages.The proposed research will elucidate the molecular mechanisms of HIV-1 inhibition in the settings of SCD and sickle cell trait, which could lead to novel anti-HIV-1 therapeutics based on the concept of HIV-1 restriction mediated by hemolysis and interferon induction by sickle cell hemoglobin.
