# Howard University Research Center for Minority Health and Health Disparities

> **NIH NIH U54** · HOWARD UNIVERSITY · 2023 · $218,050

## Abstract

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...

## Key facts

- **NIH application ID:** 10874154
- **Project number:** 3U54MD007597-35S1
- **Recipient organization:** HOWARD UNIVERSITY
- **Principal Investigator:** William M. Southerland
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $218,050
- **Award type:** 3
- **Project period:** 1997-09-30 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874154

## Citation

> US National Institutes of Health, RePORTER application 10874154, Howard University Research Center for Minority Health and Health Disparities (3U54MD007597-35S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10874154. Licensed CC0.

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