Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.

An intracellular drug interaction does not explain the suboptimal viral response in patients treated with the nucleoside-only regimen of TDF, ABC, and 3TC.

Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10 6 cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10 6 cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.Use of the combination of the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) didanosine (ddI) and tenofovir (TFV; given as the oral prodrug TFV disoproxil fumarate [TDF]) as part of antiretroviral treatment regimens for HIV infection has remained controversial due to reported pharmacokinetic and pharmacodynamic drug-drug interactions. Coadministration results in up to a 60% increase in ddI plasma exposure (as measured by the area under the concentrationtime curve [AUC] at steady state) with no change in the TFV AUC (24). There is evidence that the mechanism for this pharmacokinetic interaction is the inhibition of the purine nucleoside phosphorylase (PNP)-dependent phosphorolysis of ddI by phosphorylated metabolites of TFV (36). When it is coadministered with TDF, it is therefore recommended that the ddI dose be reduced from 400 to 250 mg once a day, that more vigilant safety monitoring for ddI-associated toxicities be undertaken, and that virologic and immunologic responses be followed more closely (Videx package insert; Bristol-Myers Squibb).Despite viral suppression, patients on TDF and non-dosereduced ddI have been reported to have paradoxical CD4 ϩ cell declines (4, 32, 33) or reduced CD4 ϩ cell recovery (30). Administration of non-dose-adjusted ddI and TDF has also been associated with an increased incid...