Host genes important to HIV replication and evolution

Abstract

Recent years have seen a significant increase in understanding of the host genetic and genomic determinants of susceptibility to HIV-1 infection and disease progression, driven in large part by candidate gene studies, genome-wide association studies, genome-wide transcriptome analyses, and large-scale in vitro genome screens. These studies have identified common variants in some host loci that clearly influence disease progression, characterized the scale and dynamics of gene and protein expression changes in response to infection, and provided the first comprehensive catalogs of genes and pathways involved in viral replication. Experimental models of AIDS and studies in natural hosts of primate lentiviruses have complemented and in some cases extended these findings. As the relevant technology continues to progress, the expectation is that such studies will increase in depth (e.g., to include host whole exome and whole genome sequencing) and in breadth (in particular, by integrating multiple data types).

Figure 1.

Distribution of the protective alleles according to viral or clinical phenotypes. The bar graphs show the allelic distribution of three variants that have a genome-wide significant association with HIV-1 set point (left-hand-side graphs) and disease progression (right-hand-side graphs) in a population of 2362 HIV-infected individuals. The data on HCP5, a perfect tag of HLA*B57:01, illustrate the nature of the association between protective alleles and long-term nonprogression: although 31%–37% of elite controllers carry HLA*B57:01, only 6%–22% of HLA*B57:01 carriers are elite controllers. (Adapted, with permission, from Fellay et al. 2009; reprinted, with permission, from PLoS Genetics © 2009.)

Figure 2.

Schematic representation of the parallelism between human and nonhuman primate (NHP) models of HIV/SIV pathogenesis. EC, elite controllers; RP, rapid progressors; VNP, extreme viremic nonprogressors. (Adapted, with permission, from Guido Silvestri 2010.)

Figure 3.

Multilayer representation of HIV-1 clade B Gag. The various information layers align the sites under positive selective pressure (red), conservation scores (<90% conserved, black), the structured domains at the protein (dark blue), and viral RNA level (light blue) (Watts et al. 2009), the position of CTL (dark green), antibody (light green), and T helper epitopes (turquoise) compiled in the Los Alamos HIV database, and the Gag region overlapping with the viral protease (purple).