Individualising HIV treatment—pharmacogenetics and immunogenetics

Abstract

Many human genes influence the natural history of HIV disease, by accelerating or slowing progression from infection to AIDS (panel). Host factors also contribute to differences in the response to antiretroviral treatment. The “one-size-fits-all” regimen of antiretroviral treatments results in important interpersonal variation in drug concentrations and differences in susceptibility to drug toxicity. Pharmacogenetics (analysis of the genetic basis for variation in the response to specific medications) and immunogenetics (analysis of the genetic basis for variation in the response to specific antigens) are now being used to probe into the complexities of HIV therapy. Tabled 1 Gene/genetic region Protein function Influence of polymorphism† Polymorphism or allele may not exert influence directly but through linkage disequilibrium with other alleles. MHC=major histocompatibility complex, PGP=P-glycoprotein. Susceptibility to infection CCR5 Chemokine receptor Decreased susceptibility to infection RANTES Chemokine Decreased susceptibility to infection Natural history CCR5 Chemokine receptor Delayed (Δ32), or accelerated (promoter) progression CCR2 Chemokine receptor Delayed progression CX3CR1 Chemokine receptor Controversial SDF1 Chemokine Controversial MIP-1α Chemokine Accelerated progression RANTES Chemokine Controversial Interleukin-10 Cytokine Accelerated progression MBL Manose-binding lectin Controversial Class I HLA MHC Accelerated progression (homozygosity) HLA-B*5701 MHC Delayed progression HLA-B*35 MHC Accelerated progression HLA-Cw*04 MHC Accelerated progression Response to treatment CCR5 Chemokine receptor Virological response MDR1 Drug transporter (PGP) Drug concentrations and immunological response CYP2D6 CYP450 isoenzyme Drug concentrations Treatment toxicity SREBP-1c Cholesterol/triglyceride regulator Hyperlipidaemia Haplotype HLA-B*5701, DR7, DQ3 MHC Hypersensitivity to abacavir † Polymorphism or allele may not exert influence directly but through linkage disequilibrium with other alleles. MHC=major histocompatibility complex, PGP=P-glycoprotein. Open table in a new tab Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavirGenetic susceptibility to abacavir hypersensitivity is carried on the 57·1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2·5% without inappropriately denying abacavir to any patient. Full-Text PDF