Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1.

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes.

Influence of inhibitory killer immunoglobulin-like receptors and their HLA-C ligands on resolving hepatitis C virus infection.

An estimated 2%-3% of the world's population is chronically infected with hepatitis C virus (HCV) and this is a major cause of liver disease worldwide. Following acute infection, outcome is variable with acute HCV successfully resolved in some individuals (20%-30%), but in the majority of cases the virus is able to persist. Co-infection with human immunodeficiency virus has been associated with a negative impact on the course of HCV infection.

Model structure of human APOBEC3G.

Background: APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination. APOBEC3G has two cytosine deaminase (CDA) domains; the catalytically inactive amino-terminal domain of APOBEC3G (N-CDA) carries the Vif interaction domain. There is no 3-D structure of APOBEC3G solved by X-ray or nuclear magnetic resonance.

Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection.

Background: The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections.

Objectives: To determine whether single-nucleotide polymorphisms (SNPs) in TLR2-4 and TLR7-9 influenced the natural course of HIV-1 infection.

Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals.

To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles.

Silencing of both beta-TrCP1 and HOS (beta-TrCP2) is required to suppress human immunodeficiency virus type 1 Vpu-mediated CD4 down-modulation.

The human immunodeficiency virus type 1 (HIV-1) Vpu protein interacts with CD4 within the endoplasmic reticula of infected cells and targets CD4 for degradation through interaction with beta-TrCP1. Mammals possess a homologue of beta-TrCP1, HOS, which is also named beta-TrCP2. We show by coimmunoprecipitation experiments that beta-TrCP2 binds Vpu and is able to induce CD4 down-modulation as efficiently as beta-TrCP1.

Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection.

Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations.

Genomics meets HIV-1.

Genomics is now a core element in the effort to develop a vaccine against HIV-1. Thanks to unprecedented progress in high-throughput genotyping and sequencing, in knowledge about genetic variation in humans, and in evolutionary genomics, it is finally possible to systematically search the genome for common genetic variants that influence the human response to HIV-1. The identification of such variants would help to determine which aspects of the response to the virus are the most promising targets for intervention.

Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation.

Background And Objective: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.

Genetic, ethnic, and gender differences in the pharmacokinetics of antiretroviral agents.

Variable antiretroviral therapy (ART) drug response likely reflects the combined influence of environment, underlying disease, concurrent drugs, and genetics. Gender exerts modest or negligible effects on ART disposition, and it is expected to have limited clinical implication, although it should be accounted for in large population studies. Ethnic denominations have, with the notable exception of efavirenz, no clear influence on ART disposition.

Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection.

Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.

Role of common human TRIM5alpha variants in HIV-1 disease progression.

Background: The retroviral restriction factor tripartite motif protein (TRIM)5alpha, is characterized by marked amino acid diversity among primates, including specific clusters of residues under positive selection. The identification of multiple non-synonymous changes in humans suggests that TRIM5alpha variants might be relevant to retroviral pathogenesis. Previous studies have shown that such variants are unlikely to modify susceptibility to HIV-1 infection, or the course of early infection.

The integrase interactor 1 (INI1) proteins facilitate Tat-mediated human immunodeficiency virus type 1 transcription.

Integration of human immunodeficiency virus type 1 (HIV-1) into the host genome is catalyzed by the viral integrase (IN) and preferentially occurs within transcriptionally active genes. During the early phase of HIV-1 infection, the incoming viral preintegration complex (PIC) recruits the integrase interactor 1 (INI1)/hSNF5, a chromatin remodeling factor which directly binds to HIV-1 IN. The impact of this event on viral replication is so far unknown, although it has been hypothesized that it could tether the preintegration complex to transcriptionally active genes, thus contributing to the bias of HIV integration for these regions of the genome.

Consistent effects of TSG101 genetic variability on multiple outcomes of exposure to human immunodeficiency virus type 1.

Tumor susceptibility gene 101 (TSG101) encodes a host cellular protein that is appropriated by human immunodeficiency virus type 1 (HIV-1) in the budding process of viral particles from infected cells. Variation in the coding or noncoding regions of the gene could potentially affect the degree of TSG101-mediated release of viral particles. While the coding regions of the gene were found to lack nonsynonymous variants, two polymorphic sites in the TSG101 5' area were identified that were associated with the rate of AIDS progression among Caucasians.

Are plasma levels valid surrogates for cellular concentrations of antiretroviral drugs in HIV-infected patients?

Total plasma concentrations are currently measured for therapeutic drug monitoring of HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). However, the pharmacological target of antiretroviral drugs reside inside cells. To study the variability of their cellular accumulation, and to determine to which extent total plasma concentrations (TPC) correlate with cellular concentrations (CC), plasma and peripheral blood mononuclear cells (PBMCs) were simultaneously collected at single random times after drug intake from 133 HIV infected patients.

Host polymorphism in steps of the HIV-1 lifecycle after entry and other genetic variants influencing HIV-1 pathogenesis.

Purpose Of Review: Dominant host factors modifying the susceptibility to HIV-1 include diversity in the major histocompatibility complex class I, and alleles of chemokine and chemokine receptor genes. Additional host factors, particularly those determining cell permissiveness to viral replication, are expected to play a significant role in HIV-1 pathogenesis.

Recent Findings: A growing number of publications (n = 32) propose new variants (n = 27) modifying HIV-1 susceptibility in genes (n = 17) needed for the viral lifecycle, in antiviral innate defense, and in a number of soluble and membrane proteins.

Stable virulence levels in the HIV epidemic of Switzerland over two decades.

Objective: To determine whether the virulence of HIV-1 has been changing since its introduction into Switzerland.

Design: A prospective cohort study of HIV-1 infected individuals with well-characterized pre-therapy disease history.

Methods: To minimize the effect of recently imported viruses and ethnicity-associated host factors, the analysis was restricted to the white, north-west-European majority population of the cohort.

Ritonavir-boosted atazanavir-lopinavir combination: a pharmacokinetic interaction study of total, unbound plasma and cellular exposures.

Objectives: To assess potential pharmacokinetic (PK) interactions between atazanavir (ATV, 300 mg, once daily) and lopinavir (LPV, 400 mg, twice daily), both boosted by ritonavir (RTV, 100 mg).

Design: Two-parallel groups, addition of LPV in patients receiving ATV (n=6), and addition of ATV in patients receiving LPV (n=7), with before/after comparisons.

Methods: Each group had two complete PK profiles before and 2 weeks after the addition of the second protease inhibitor (PI).

Patterns of evolution of host proteins involved in retroviral pathogenesis.

Background: Evolutionary analysis may serve as a useful approach to identify and characterize host defense and viral proteins involved in genetic conflicts. We analyzed patterns of coding sequence evolution of genes with known (TRIM5alpha and APOBEC3G) or suspected (TRIM19/PML) roles in virus restriction, or in viral pathogenesis (PPIA, encoding Cyclophilin A), in the same set of human and non-human primate species.

Results And Conclusion: This analysis revealed previously unidentified clusters of positively selected sites in APOBEC3G and TRIM5alpha that may delineate new virus-interaction domains.

Determination of the novel non-peptidic HIV-protease inhibitor tipranavir by HPLC-UV after solid-phase extraction.

An HPLC method previously described for the assay of amprenavir (APV), ritonavir (RTV), indinavir (IDV), saquinavir (SQV), nelfinavir (NFV), lopinavir (LPV), atazanavir (ATV), nevirapine (NVP) and efavirenz (EFV) can be also conveniently applied, with minor gradient program adjustment, for the determination of the novel non-peptidic HIV protease inhibitor tipranavir (TPV) in human plasma, by off-line solid-phase extraction (SPE) followed by HPLC coupled with UV-diode array detection (DAD). After viral inactivation by heat, the plasma is diluted with phosphate buffer (pH 7), and subjected to a SPE on a C18 cartridge. Matrix components are eliminated with a solution of 0.

Opinion paper. Resistance to new anti-HIV agents: problems in the pathway of drug registration.

Resistance data are now requested by the regulatory agencies as an integral part of the approval process of new antiretroviral drugs. We examined the means by which resistance data was gathered during pre-clinical and clinical Phases I, II and III of drug development, and how the public and academic experts access these proprietary data. The analysis identified various opportunities for improvement of the current process, in particular the need for standards in generating and reporting resistance data on new antiretroviral drugs, and the need to enforce warnings in the product labelling on the drug combinations that can potentially lead to resistance and treatment failure.

Update of the drug resistance mutations in HIV-1: Fall 2005.

The International AIDS Society-USA (IAS-USA) Drug Resistance Mutations Group is marking 5 years as an independent volunteer panel of experts focused on identifying key HIV-1 drug resistance mutations. The goal of the effort is to quickly deliver accurate and unbiased information on these mutations to HIV clinical practitioners. The October/November 2005 version of the IAS-USA Drug Resistance Mutations Figures replaces the version published in this journal in March/April 2005.

Use of a combined ex vivo/in vivo population approach for screening of human genes involved in the human immunodeficiency virus type 1 life cycle for variants influencing disease progression.

Humans differ substantially with respect to susceptibility to human immunodeficiency virus type 1 (HIV-1). We evaluated variants of nine host genes participating in the viral life cycle for their role in modulating HIV-1 infection. Alleles were assessed ex vivo for their impact on viral replication in purified CD4 T cells from healthy blood donors (n = 128).

Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia.

Background: Unconjugated hyperbilirubinemia results from Gilbert syndrome and from antiretroviral therapy (ART) containing protease inhibitors. An understanding of the interaction between genetic predisposition and ART may help to identify individuals at highest risk for developing jaundice.

Methods: We quantified the contribution of UGT1A1*28 and ART to hyperbilirubinemia by longitudinally modeling 1386 total bilirubin levels in 96 human immunodeficiency virus (HIV)-infected individuals during a median of 6 years.