MAVS Genetic Variation Is Associated with Decreased HIV-1 Replication In Vitro and Reduced CD4+ T Cell Infection in HIV-1-Infected Individuals.

Melissa Stunnenberg,Teunis B H Geijtenbeek,Neeltje A Kootstra,Sonja I Gringhuis,Karel A Van Dort,Lisa Van Pul,Joris K Sprokholt

doi:10.3390/v12070764

Melissa Stunnenberg, Teunis B H Geijtenbeek + Show 5 more

Open Access

https://doi.org/10.3390/v12070764

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Abstract

The mitochondrial antiviral protein MAVS is a key player in the induction of antiviral responses; however, human immunodeficiency virus 1 (HIV-1) is able to suppress these responses. Two linked single nucleotide polymorphisms (SNPs) in the MAVS gene render MAVS insensitive to HIV-1-dependent suppression, and have been shown to be associated with a lower viral load at set point and delayed increase of viral load during disease progression. Here, we studied the underlying mechanisms involved in the control of viral replication in individuals homozygous for this MAVS genotype. We observed that individuals with the MAVS minor genotype had more stable total CD4+ T cell counts during a 7-year follow up and had lower cell-associated proviral DNA loads. Genetic variation in MAVS did not affect immune activation levels; however, a significantly lower percentage of naïve CD4+ but not CD8+ T cells was observed in the MAVS minor genotype. In vitro HIV-1 infection of peripheral blood mononuclear cells (PBMCs) from healthy donors with the MAVS minor genotype resulted in decreased viral replication. Although the precise underlying mechanism remains unclear, our data suggest that the protective effect of the MAVS minor genotype may be exerted by the initiation of local innate responses affecting viral replication and CD4+ T cell susceptibility.

Highlights

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a lack of protective immunity against the virus [1]
We examined whether MAVS genetic variation affects T cell differentiation as reflected by the percentages of different CD4+ T cell populations comprised of naïve T cells (Tn ; CD45RA+ CD27+ CCR7+ ) and differentiated phenotypes defined as terminally differentiated effector memory cells (TEMRA; CD45RA+ CCR7− CD27− ), central memory (CM; CD45RA− CCR7+ CD27+ ), transitional memory (TM; CD45RA− CCR7− CD27+ ) and effector memory (EM; CD45RA− CCR7− CD27− ) T cells (n = 4)
We investigated whether innate and adaptive immune responses contribute to the protective effect of the MAVS minor genotype by comparing the immune activation levels and T cell phenotype and function with responses induced in individuals carrying the MAVS major genotype

Summary

Introduction

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a lack of protective immunity against the virus [1]. During HIV-1 infection, insufficient priming of naïve T cells occurs, which is partially explained by suboptimal functioning of dendritic cells (DCs) crucial in the induction of antiviral immunity [1,2,3,4,5,6]. DCs contain the ability to sense viral pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) [7]. PRR triggering induces innate antiviral responses, such as antiviral type I interferon (IFN) and cytokine responses, subsequently leading to induction of adaptive immunity via DC activation [16,17,18,19,20]. Viral RNA is sensed by sensors such as MDA5, RIG-I, and DDX3, of which the latter two play an important role in sensing of HIV-1 RNA [12,15,21,22]

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