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.

Public Health Relevance

The proposed research is relevant to public health and specifically minority health and health disparities because it is aimed at understanding the molecular mechanism of HIV-1 infection in patients with Sickle Cell Disease. The proposed research is relevant to the NIH mission that pertains to a reduced disparities and vulnerability of the minority population to chronic diseases that include HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125005-07
Application #
10135135
Study Section
HIV Comorbidities and Clinical Studies Study Section (HCCS)
Program Officer
Ochocinska, Margaret J
Project Start
2014-05-05
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Howard University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
Khaibullina, Alfia; Adjei, Elena A; Afangbedji, Nowah et al. (2018) RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice. Haematologica 103:787-798
Ivanov, Andrey; Lin, Xionghao; Ammosova, Tatiana et al. (2018) HIV-1 Tat phosphorylation on Ser-16 residue modulates HIV-1 transcription. Retrovirology 15:39
Jerebtsova, Marina; Saraf, Santosh L; Soni, Simran et al. (2018) Urinary orosomucoid is associated with progressive chronic kidney disease stage in patients with sickle cell anemia. Am J Hematol 93:E107-E109
Jerebtsova, Marina; Saraf, Santosh L; Lin, Xionghao et al. (2018) Identification of ceruloplasmin as a biomarker of chronic kidney disease in urine of sickle cell disease patients by proteomic analysis. Am J Hematol 93:E45-E47
Lin, Xionghao; Ammosova, Tatyana; Kumari, Namita et al. (2017) Protein Phosphatase-1 -targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals. Curr Pharm Des 23:4122-4132
Sergueeva, Adelina; Miasnikova, Galina; Shah, Binal N et al. (2017) Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia. Haematologica 102:e166-e169
Ammosova, Tatiana; Washington, Kareem; Rotimi, Jamie et al. (2016) Protein Phosphatase-1 Regulates Expression of Neuregulin-1. Biology (Basel) 5:
Kumari, Namita; Ammosova, Tatiana; Diaz, Sharmin et al. (2016) Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease. Blood Adv 1:170-183
Ogunwuyi, Oluwaseun; Kumari, Namita; Smith, Kahli A et al. (2016) Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment. Infect Dis (Auckl) 9:21-32
Huang, Hanxia; Konduru, Krishnamurthy; Solovena, Veronica et al. (2016) Therapeutic potential of the heme oxygenase-1 inducer hemin against Ebola virus infection. Curr Trends Immunol 17:117-123

Showing the most recent 10 out of 24 publications