# Sickle Cell Disease and Sickle Cell Trait Protection Against HIV-1-infection in Africans and African Americans

> **NIH NIH R01** · HOWARD UNIVERSITY · 2020 · $718,249

## Abstract

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-β 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.

## Key facts

- **NIH application ID:** 10012487
- **Project number:** 2R01HL125005-06A1
- **Recipient organization:** HOWARD UNIVERSITY
- **Principal Investigator:** SERGEI NEKHAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $718,249
- **Award type:** 2
- **Project period:** 2014-05-05 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012487

## Citation

> US National Institutes of Health, RePORTER application 10012487, Sickle Cell Disease and Sickle Cell Trait Protection Against HIV-1-infection in Africans and African Americans (2R01HL125005-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10012487. Licensed CC0.

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