Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors
Ángel Bayón-Gil, Inmaculada Hernández, Judith Dalmau, Juan C. Nieto, Víctor Urrea, Lidia Garrido-Sanz, Ginevra Caratù, Maria C. García-Guerrero, Cristina Gálvez, María Salgado, Itziar Erkizia, Fernando Laguía, Patricia Resa‐Infante, Marta Massanella, Raúl Tonda, Jordi Morata, Kai Ying Hong, Jane Koshy, Aaron R. Goldman, Leila B. Giron, Mohamed Abdel‐Mohsen, Holger Heyn, Javier Martínez‐Picado, María C. Puertas
Abstract
Background Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4 + T cell counts despite uncontrolled viral replication—a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies. Methods We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors. Findings Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4 + T cell apoptosis. Conclusions In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis. Funding The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH). Most people with HIV need lifelong antiretroviral treatment to keep the virus under control and prevent the development of immunodeficiency. However, in rare cases, no immune damage is observed in the absence of treatment and despite high levels of the virus. Researchers at IrsiCaixa have performed an integrated multiperspective analysis using cutting-edge technologies, revealing that most of these individuals have a genetic mutation that hinders viral infection of their cells. Additionally, other peculiarities of their immune system, such as a moderated chronic inflammatory response to the presence of the virus and preservation of equilibrium in their intestinal mucosa, play a complementary role. These results highlight the potential of modulating chronic inflammation to improve the health status of people with HIV. • VNPs are a rare group of people with HIV who do not exhibit CD4 + T cell depletion • Protection from HIV pathogenesis is driven by a complex combination of mechanisms • Heterozygosity for the CCR5Δ32 coreceptor confers genetic predisposition • Moderated gut disruption, T cell activation, and IFN responses jointly contribute The mechanisms enabling evasion from HIV-1 pathogenesis in VNPs are poorly understood. Here, Bayón-Gil et al. perform a comprehensive multiomics characterization, which reveals an intricate multifactorial mechanism including genetic predisposition to a lower infection rate, moderation of chronic immune activation, and preservation of intestinal homeostasis, jointly contributing to pathogenesis resistance.