CD46 Genetic Variability and HIV-1 Infection Susceptibility.

Carmen Serrano-Rísquez,Sergio Lo Caputo,Antonio Rivero,Antonio Rivero-Juárez,Mohamed Omar,Antonio Caruz,Mara Biasin,Juan Antonio Pineda,Mario Clerici,Francisco J Márquez,Luis Miguel Real,María Amparo Gómez-Vidal,Donald Forthal

doi:10.3390/cells10113094

Abstract

CD46 is the main receptor for complement protein C3 and plays an important role in adaptive immune responses. CD46 genetic variants are associated with susceptibility to several infectious and autoimmune diseases. Additionally, CD46 function can be subverted by HIV-1 to evade attack by complement, a strategy shared by viruses of other families. We sought to determine the association between CD46 gene variants and HIV-1 acquired through intravenous drug use (IDU) and sexual routes (n = 823). Study subjects were of European ancestry and were HIV-1 infected (n = 438) or exposed but seronegative (n = 387). Genotyping of the rs2796265 SNP located in the CD46 gene region was done by allele-specific real-time PCR. A meta-analysis merging IDU and sexual cohorts indicates that the minor genotype (CC) was associated with increased resistance to HIV-1 infection OR = 0.2, 95% CI (0.07–0.61), p = 0.004. The HIV-1-protective genotype is correlated with reduced CD46 expression and alterations in the ratio of CD46 mRNA splicing isoforms.

Highlights

The complement system is a fundamental part of the innate and adaptive immune system and is required for the elimination of pathogens, immune complexes, and apoptotic cells
Two individuals in the HIV-1 exposed seronegative (HESN) group were homozygous for CCR5 ∆32 and were excluded from subsequent analysis
No departure from Hardy– Weinberg equilibrium was observed in the intravenous drug use (IDU) (p = 0.3) or sexual (p = 0.4) HESN cohorts (Table 1)

Summary

Introduction

The complement system is a fundamental part of the innate and adaptive immune system and is required for the elimination of pathogens, immune complexes, and apoptotic cells. The core complement protein C3 is cleaved to C3b via the classical-lectin or the alternative pathways giving rise to the formation of active C3b convertases that trigger a massive conversion of C3b onto the adjacent pathogen surfaces [1]. Proteolysis of C3b to iC3b generates an opsonin that tags microbes for recognition and phagocytosis mediated by complement receptors expressed on phagocytes and lymphocytes [1,2]. This is a highly regulated process to avoid complement-mediated tissue injury. This activity is assisted by a set of other soluble inhibitors of complement activation present in the serum, such as CFH or C4BP

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