Ferroportin Q248H mutation is associated with the less weight loss in persons with HIV-1

Abstract

Abstract Ferroportin (FPN) disease is a genetically predisposed iron overload driven by over 30 mutations in the FPN gene that increase FPN resistance to degradation by hepcidin. Most of the reported mutations have negligible frequencies, except for the FPN Q248H mutation, which is highly prevalent in Africans (frequency up to 13.4%). A high frequency of the FPN Q248H mutation may be due to a survival advantage and positive selection. Data from combined cohorts comprising over 18,000 African children demonstrated that the FPN Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but does not protect against malaria or bacteremia. We hypothesize that the FPN Q248H mutation might protect from HIV-1 infection and possibly other chronic viral infections which have a high burden in Africa, and, thus, be positively selected. Our previous studies showed that the FPN Q248H mutant has reduced sensitivity to hepcidin and facilitated more active iron export in the presence of hepcidin (Nekhai et al., Haematologica, 2013), and that FPN expression inhibits HIV-1 replication (Xu et al., Retrovirology, 2010). We hypothesize that the FPN Q248H mutation might reduce the comorbidities of chronic HIV infection. We genotyped the FPN Q248H mutation in 927 African American male participants from the Multicenter AIDS Cohort Study (MACS, age 26-48 years), including 479 persons with HIV (PWH) and 448 control persons without HIV-1 (PWOH). The FPN Q248H mutation was genotyped by single-nucleotide polymorphism (SNP) assay from Thermo Fisher (rs11568350 SNP ID) using DNA extracted from peripheral blood mononuclear cells. Longitudinal analysis of viral load (VL), CD4+ and CD8+ levels were assessed alongside body weight trends and stratified by the FPN Q248H mutation status. The baseline characteristics between FPN mutants(A/A or A/C) and wild type FPN (C/C) were compared using the Student's t-test. We used mixed-effect models to test the effect of FPN Q248H mutation on the change of CD4, CD8, and weight during the follow-up period in PWH. Models were adjusted for the confounding effect of antiretroviral therapy, the number of male sex partners, and illicit drug use. The frequency of the FPN Q248H mutation was 9.6% in PWH and 9.2% in PWOH. The baseline VL was higher in participants with FPN Q248H (A/A or A/C) mutations (β=0.14, p=0.74), whereas CD4 (β=-1.48, p=0.11), CD8 (β=-1.50, p=0.11), or CD4/CD8 (β=-0.02, p=0.63), levels were lower. The proportion with undetectable VL at the initial visit was higher among PWH with the FPN Q248H (A/A or A/C) mutation (14.3%) compared to WT FPN (C/C) (10.5%). In the 20-year follow-up, there was a statistically significant increase in CD4 (β=0.19, p<0.001), and CD8 (β=0.12, p<0.001), levels in PWH with FPN Q248H mutation compared to those with WT FPN, suggesting better control of HIV-1 infection. Analysis of the longitudinal changes in the body weight of PWH showed a significant increase in participants with the FPN Q248H mutation. PWH with WT FPN gained less than 2% of body weight, whereas PWH who had FPN Q248H mutation gained about 8% of body weight (P for interaction of time and mutation <0.001).PWOH gained about 10% of body weight during the 20-year follow-up period. The findings of this study indicate that PWH with FPN Q248H mutation maintain similar weight trajectories to PWOH as compared to the PWH with WT FPN. Weight loss is a serious complication of HIV infection that increases mortality risks. A substantial proportion of PWH in Sub-Saharan Africa is undernourished, and undernutrition contributes to an increased risk of mortality and other comorbidities. Protection from weight loss (cachexia) in people with chronic infections may contribute to the positive selection of the FPN Q428H mutation in Africa. Future studies will elucidate the mechanism of weight preservation and evaluate the role of iron metabolism modifying treatments in the management of chronic HIV-1 infection. ACKNOWLEDGMENTS: We acknowledge the Genomics Core Facility at the University of Utah for sample processing and genotyping and thank Michael Klein for his assistance. This work was supported by 1R01HL125005, U54MD007597, 2P30AI117970, U01-HL146241, U01-HL146201, U01-HL146204, U01-HL146202, U01-HL146193, U01-HL146245, U01-HL146242, U01-HL146205, U01-HL146203, U01-HL146192, U01-HL146194, UL1-TR000004, P30-AI-050409, P30-AI-050410 and P30-AI-027767.