Effect of Fc Receptor Genetic Diversity on HIV-1 Disease Pathogenesis

Abstract

Fc receptor (FcR) genes collectively have copy number and allelic polymorphisms that have been implicated in multiple inflammatory and autoimmune diseases. This variation might also be involved in etiology of infectious diseases. The protective role of Fc-mediated antibody-function in HIV-1 immunity has led to the investigation of specific polymorphisms in FcR genes on acquisition, disease progression, and vaccine efficacy in natural history cohorts. The purpose of this review is not only to explore these known HIV-1 host genetic associations, but also to re-evaluate them in the context of genome-wide data. In the current era of effective anti-retroviral therapy, the potential impact of such variation on post-treatment cohorts cannot go unheeded and is discussed here in the light of current findings. Specific polymorphisms associating with HIV-1 pathogenesis have previously been genotyped by assays that captured only the single-nucleotide polymorphism (SNP) of interest without relative information of neighboring variants. With recent technological advances, variation within these genes can now be characterized using next-generation sequencing, allowing precise annotation of the whole chromosomal region. We herein also discuss updates in the annotation of common FcR variants that have been previously associated with HIV-1 pathogenesis.

Keywords: Fc receptors; HIV-1; disease association; next-generation sequencing; polymorphism.

Figure 1

Structure and polymorphism of the FCGR genes. (A) Approximate chromosomal locations of the FCGR gene complex containing 5 FCGR genes and the FCGR1A gene located at ~12 Mb centromeric to the FCGR cluster. In comparison, the KIR gene family is illustrated immediately to the right including adjacent genes (FCAR) and gene clusters. For both FCGR and KIR, alternative haplotypes identified in populations are illustrated with the colored bars depicting genes present in a subset of haplotypes and shaded bars depicting genes present in all haplotypes (framework genes). Figure depicting KIR has been reproduced with permission from the Oxford University Press (9). (B) The plots show the abundance of SNPs at each position of the indicated regions from chr1 and chr19, using data derived from the UCSC genome browser. (C) Approximate number of SNPs in both regions are listed including a summary from all chromosomes for comparison.

Figure 2

No association between FCGR2A or FCGR3A polymorphisms on HIV-1 set point viral load. Regional association plot highlighting the association between the FCGR2A (rs1801274) and FCGR3A (rs396991) polymorphisms and HIV-1 spVL across 395 exome sequenced patients (48). Color intensities represent the linkage disequilibrium (r²) of other SNPs in the region with rs1801287 and rs396991, respectively. The blue line indicates the estimated recombination rate in cM/Mb from The International HapMap Consortium (2007).

Figure 3

Polymorphism in FCGR2A (CD32a) does not associate with reservoir size. The rs1801274 SNP variant did not associate with levels of total or integrated HIV DNA, determined in N = 93 and N = 78 of the patients, respectively (55, 56).