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HIV adaptation to the genetic polymorphism of the host

Mallal, S. (2003) HIV adaptation to the genetic polymorphism of the host. In: 10th Conference on Retroviruses and Opportunistic Infections, 10 - 14 February 2003, Boston, U.S.A.

Abstract

Background: Host genetics influence the clinical outcomes of HIV disease at multiple levels: establishment of infection, HIV viral load, CD4 T-cell decline, specific OIs and malignancies, and response to and complications of therapy. The exposure variable of interest may be the same in all patients (pts), as in the example of drugs, or polymorphic and adaptive, as in HIV and to a variable extent other pathogens. At one end of the spectrum abacavir hypersensitivity can be considered an experiment of man in which a fixed exposure predictably causes a serious clinical syndrome in the presence of the HLA B57 haplotype. In contrast HIV is highly polymorphic and rapidly adapts at both an individual and population level to host polymorphisms.

Methods: We studied HLA, KIR and chemokine receptor genotypes in 249 patients sequentially enrolled in the Western Australian HIV Cohort study since 1996. Of these, 175 pts have had full-length HIV genome sequencing, viral load, and CD4 T-cell measurements on samples taken before ART was started. HLA allele associations with viral polymorphisms were identified. The proportion of HLA A,B,C or DR associated polymorphic HIV residues adapted to the relevant HLA allele present was then calculated (e.g., non-consensus amino acid at HIV positions with positive HLA associations or consensus amino acid at positions with negative associations) to give an estimate of the degree of HIV adaptation to the HLA restricted responses.
Results: On univariate analyses of all 249 pts HLA B*5701 (0.6 log viral load, p = 0.01), B*2705 (0.5, p = 0.05), Bw4-80I (0.4, p = 0.01), CCR5 32bp deletion (0.5, p = 0.008), CCR5 C59353T (0.3, p = 0.05) were associated with lower viral load and the KIR haplotype 3DS1-2DS5 was associated with rapid progression from seroconversion to a CD4 < 30% (RR = 3.2, p = 0.002) but not higher viral load (p = 0.64). Less HIV adaptation to HLA restricted immune responses was associated with low viral load on univariate analysis (n = 175, p = 0.02). On multivariate analysis of 175 patients less HIV adaptation was more strongly associated with low viral load than HLA type alone: HLA B*5701 (p = 0.4), B*2705 (p = 0.78), Bw4-80I (p = 0.39), CCR5 32bp deletion (p = 0.01), CCR5 C59353T (p = 0.12) and less adaptation (p = 0.04).

Conclusions: These findings suggest that host genetic effects may be underestimated if the polymorphic and adaptive nature of the organism is not taken into account.

Publication Type: Conference Item
Murdoch Affiliation: Centre for Clinical Immunology and Biomedical Statistics
Conference Website: http://www.retroconference.org/2003/
Notes: Impact of Host Genetics on Clinical Outcomes Symposium
URI: http://researchrepository.murdoch.edu.au/id/eprint/15633
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