On stand by: host genetics of HIV control

Carrington, Marya , b; Bashirova, Arman A.a , b; McLaren, Paul J.c , d , e

doi: 10.1097/01.aids.0000432536.85335.c8
Editorial Review

The impact of host genetic variation on determining the differential outcomes after HIV infection has been studied by two approaches: targeting of candidate genes and genome-wide association studies (GWASs). The overlap in genetic variants that has been identified by these two means has essentially been restricted to variants near to the human leukocyte antigen (HLA) class I genes, although variation in the CCR5 locus, which was first shown to have an effect on HIV outcomes using the candidate gene approach, does reach significance genome-wide when very large samples sizes (i.e. thousands) are used in GWAS. Overall, many of the variants identified by the candidate gene approach are likely to be spurious, as no additional variants apart from a novel variant near the HLA-C gene have been consistently identified by GWAS. Variants with low frequency and/or low impact on HIV outcomes are likely to exist in the genome and there could be many of them, but these are not identifiable, given current GWAS sample sizes. Several loci centrally involved in the immune response, including the immunoglobulin genes, T-cell receptor loci, or leukocyte receptor complex, are either poorly covered on the GWAS chips or difficult to interpret due to their repetitive nature and/or the presence of insertion/deletion polymorphisms in the region. These loci warrant further interrogation, but genetic characterization of these regions across a range of individuals will first be required. Finally, synergistic interactions between loci may affect outcome after infection, as suggested by associations of specific, functionally relevant HLA and killer cell immunoglobulin-like receptor variants with HIV disease outcomes, and these require further consideration as well.

Author Information

aCancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland

bRagon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA

cSchool of Life Sciences, École Polytechnique Fédérale de Lausanne

dInstitute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland

eProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Correspondence to Mary Carrington, PhD, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, PO Box B, Bldg 560 Frederick, MD 21702, USA. Tel: +1 301 846 1390; fax: +1 301 846 6771; e-mail: carringm@mail.nih.gov

Received 1 May, 2013

Revised 25 June, 2013

Accepted 27 June, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.