• Isabella Zanella, Emanuele Focà, Melania Degli-Antoni, Francesco Castelli, and Eugenia Quiros-Roldan.
• Department of Molecular and Translational Medicine, University of Brescia, Clinical Chemistry Laboratory, Cytogenetics and Molecular Genetics Section, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy.
• Medicine (Baltimore). 2021 Nov 12; 100 (45): e27732e27732.

RationaleHIV elite controllers represent a rare subset of persons living with HIV, able to spontaneously control viral replication without antiviral therapy. HLA-B∗57 and HLA-B∗27 alleles are associated to efficient polyfunctional CD8+ T-cell response and are overrepresented in elite controllers but these alleles alone incompletely explain spontaneous HIV replication control in these subjects. Further mechanisms involved in innate and adaptive immune response and host genetics may contribute to this control. In this context, the homeostatic iron regulator (HFE) gene encodes a major histocompatibility complex-class-I-like molecule involved in both innate immunity, acting also through autophagy regulation, and iron homeostasis, strictly related to immune functions and susceptibility to infections.Patient ConcernsHomozygousity for the p.His63Asp (H63D) variant in the HFE gene was identified in an 80-year-old HIV-infected woman with spontaneous control of viral replication.DiagnosisHIV-1 RNA was undetectable in patient's serum with a routine assay and an ultra-sensitive assay (<1 copy/mL) during the 30 years follow-up. CD4+ and CD8+ T cell counts were stable and normal during all this period.InterventionsThe patient had a history of absence of any physical ailment and no antiviral therapy has been prescribed during the 30 years of follow-up. The subject did not harbor HLA-B∗57 and HLA-B∗27 alleles. HFE gene was sequenced by Sanger, as part of a larger study on a cohort of HIV infected patients, aged >65 years and screened for polymorphisms in genes belonging to several pathways involved in neuroinflammation.OutcomesThe woman had CD4+ and CD8+ T cell normal values and spontaneously controlled serum HIV-1 RNA levels for 30 years.LessonsWe assume that the interplay between the HFE H63D variant in homozygosity and innate immunity, perhaps through autophagy regulation, could play a role in HIV-1 replication control in our patient. This hypothesis needs to be explored in in vitro and in vivo studies. Understanding mechanisms involved in spontaneous control of HIV-1 replication remains indeed a challenge due to its possible implications for HIV cure research.Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.

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