Abstract & Commentary

A key host response to HIV infection

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine. Dr. Winslow is on the speaker's bureau for GSK and Cubist Pharmaceuticals, and is a consultant for Siemens Diagnostics.

Synopsis: A polymorphism in the CXCR6 chemokine receptor gene was found to be associated with long-term non-progression (LTNP) to AIDS in a cohort of French patients in which "elite controllers" were excluded.

Source: Limou S, et al. Multiple-cohort genetic association study reveals CXCR6 as a new chemokine receptor involved in long-term non-progression to AIDS. J Infect Dis. 2010;202:908-915.

The genomics of resistance to immunodeficiency virus (GRIV) Cohort was established in France in 1995 to generate a large database for genetic studies to identify host genes associated with rapid progression and long-term non-progression to AIDS. To reduce confounding by excess heterogeneity, the cohort was restricted to white people of European descent living in France. LTNPs were defined as patients with asymptomatic HIV infection who maintained consistent CD4+ lymphocyte counts > 500 in the absence of antiretroviral (ARV) therapy. Of the 248 individuals in the cohort who met the criteria for LTNP and had a viral load available, 186 had HIV RNA > 100 copies/mL. These latter patients were included in the analysis described in this paper.

The GRIV cohort and the control group were genotyped initially using a bead-chip method. A total of 283,637 single nucleotide polymorphisms (SNPs) could be tested for potential association with LTNP. After identification of a SNP in CXCR6 as being associated with LTNP, the coding region for this chemokine receptor was amplified by PCR and underwent complete sequencing by conventional dideoxynucleoside sequencing using dye terminators and an ABI DNA analyzer.

The SNP identified as being associated with LTNP in patients who were not "elite controllers" (rs2234358) lies within the CXCR6 gene on chromosome 3, which is only 422 kb from the CCR5 gene. The rs2234538 signal was replicated in three independent, additional cohort studies of white people of European descent (ACS, MACS, and USA HIV-1 cohorts). This SNP is located in the 3' untranslated region of CXCR6, and could influence gene expression, mRNA stability, mRNA regulation, or mRNA splicing.

Commentary

Large cohorts of HIV patients have provided some important early insights into the host genetic factors associated with immune response to a variety of pathogens. This latest SNP association with LTNP is independent of the well-known CCR2-CCR5 locus, is not linked to virologic control of HIV, and is not linked to HLA type. The finding of this additional association of a chemokine receptor with HIV progression is not surprising due to the now well-known effect of chemokine receptors on host response to a variety of pathogens. While CXCR6 has been shown to be a minor coreceptor for HIV-1, this particular SNP is not located in an exon, so its biological effect is postulated to be related to modulation of CXCR6 expression. This may, in turn, affect trafficking of effector T-cells and inflammation. Further research in this area is certain to continue to improve our understanding of host response to HIV infection.