Abstract
Common CCR5-∆32 and HLA alleles only explain a minority of the HIV long-term non-progressor (LTNP) and elite controller (EC) phenotypes. To identify rare genetic variants contributing to the slow disease progression phenotypes, we performed whole exome sequencing (WES) on seven LTNPs and four ECs. HLA and CCR5 allele status, total HIV DNA reservoir size, as well as variant-related functional differences between the ECs, LTNPs, and eleven age- and gender-matched HIV-infected non-controllers on antiretroviral therapy (NCARTs) were investigated. Several rare variants were identified in genes involved in innate immune sensing, CD4-dependent infectivity, HIV trafficking, and HIV transcription mainly within the LTNP group. ECs and LTNPs had a significantly lower HIV reservoir compared to NCARTs. Furthermore, three LTNPs with variants affecting HIV nuclear import showed integrated HIV DNA levels below detection limit after in vitro infection. HIV slow progressors with variants in the TLR and NOD2 pathways showed reduced pro-inflammatory responses compared to matched controls. Low-range plasma levels of fibronectin was observed in a LTNP harboring two FN1 variants. Taken together, this study identified rare variants in LTNPs as well as in one EC, which may contribute to understanding of HIV pathogenesis and these slow progressor phenotypes, especially in individuals without protecting CCR5-∆32 and HLA alleles.
Highlights
HIV infection results in a diverse clinical spectrum regarding disease progression and the development of progressive cellular immunodeficiency
We identified several interesting variants in genes encoding molecules involved in HIV entry and inward trafficking, HIV transcription, cell homeostasis, sensing, and inflammation
An important and unexpected finding was the presence of rare genetic variants in all long-term non-progressors (LTNPs) examined but only in one of four elite controllers (ECs), which may suggest a different genetic background and pathogenesis distinguishing these two different HIV disease phenotypes
Summary
HIV infection results in a diverse clinical spectrum regarding disease progression and the development of progressive cellular immunodeficiency. Some of the rare extreme phenotypes are known as elite controllers (ECs) and long-term non-progressors (LTNPs), whereas most HIV-infected individuals progress relatively fast without treatment and are termed non-controllers (NCs). HIV-1 disease progression has been correlated with microbial infection and innate immune activation. Based on studies of natural primate hosts controlling Simian immunodeficiency virus it has been hypothesized that downregulation of IFN and IFN stimulated gene (ISG) responses during the transition from acute to chronic infection may be essential for the non-progressing phenotypes of natural primate hosts and human ECs and LTNPs14,16. By investigating variants in whole exomes at the individual level, we here demonstrate that HIV slow progressors, in particular LTNPs, harbor rare variants in genes predicted to influence HIV-infectivity and replication, as well as in genes involved in mounting immune responses to HIV and microbial pathogens
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