Analysis of distinctive host immune factors in HIV+ Viremic Non-Progressors

Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut de Recerca de la Sida (IRSICaixa) [eng] Human Immunodeficiency Virus (HIV), which primarily targets CD4+ T cells and establishes a chronic infection leading to CD4+ T-cell depletion and immune failure, is the causative agent of Acquired Immunodeficiency Syndrome (AIDS). The HIV/AIDS pandemic has dramatically impacted society over the past few decades. Although the development of effective antiretroviral treatments has undoubtedly improved the quality of life of people with HIV, some treated individuals still suffer from persistent chronic immune activation or lack immune recovery. We need a better understanding of the complex interactions between the virus and the immune system to identify biological mechanisms that can be exploited to help these populations. In some rare cases of HIV infection, people can naturally prevent the progression of the disease. These extreme phenotypes of HIV infection provide interesting models of limited pathogenesis and are a source of inspiration for new therapeutic strategies. Among them, Viremic Non-Progressors (VNPs) maintain normal CD4+ T-cell counts despite uncontrolled viral replication, presumably thanks to protective immune characteristics that are not yet fully characterized. In this study, we aimed to generate a comprehensive understanding of this infrequent phenotype of HIV infection by comparing VNPs and HIV+ Progressors from multiple perspectives: quantification of infected cells in peripheral blood, immunophenotype, genomics, single-cell transcriptomics, metabolomics, and analysis of plasma biomarkers. We have observed that during chronic infection VNPs show lower frequency of HIV-infected cells in the periphery, which is associated with a reduced expression of the viral coreceptor CCR5 and a higher prevalence of CCR5Δ32 deletion in heterozygosity. Moreover, despite similar viremia, we found lower bystander CD4+ T-cell death in VNPs, while the CD8+ T-cell compartment displays a less differentiated, less activated, and less cytotoxic phenotype. These individuals also show reduced interferon responses at the chronic phase of the infection, preserved responsiveness to LPS in vitro, reduced plasma levels of zonulin (a biomarker of intestinal permeability), and altered tryptophan catabolism compared to Progressors. Taken together, adult VNPs may prevent disease pathogenesis through a complex multifactorial mechanism that includes reduced susceptibili