Health-related quality of life in the WA HIV Cohort: 2008

Quality of life (QOL) is an important outcome of HIV treatment and a priority in the management of HIV. A new Patient-Reported Outcomes (PRO) questionnaire to measure the QOL in people living with HIV/AIDS (PLWHA) from different cultures and language groups has been developed. The instrument, PROQOL-HIV, has undergone psychometric validation in 791 individuals from 8 countries including 99 people from the WA HIV Cohort Study

Prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the Western Australian HIV cohort study

Abacavir therapy is associated with significant drug hypersensitivity in ∼8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allelle. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701–negative recipients

Association between low 25(OH) vitamin D levels, antiretroviral therapy and metabolic profile in a cohort of treated ahd therapy naive HIV positive patients in Western Australia

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Impact of anti-retroviral therapy and pneumocystis carinii pneumonia prophylaxis on the pattern of AIDS illnesses and AIDS survival in the Western Australian HIV Cohort Study: 1983 - 1992

OBJECTIVE: To evaluate the impact of antiretroviral therapy (ART) and Pneumocystis prophylaxis use on (a) the incidence of Pneumocystis carinii pneumonia (PCP) and CD4+ T-cell counts at AIDS, (b) the patterns of AIDS illnesses and (c) survival after AIDS. DESIGN: Prospective, longitudinal, observational study of all 230 patients diagnosed with AIDS in Western Australia to 1 January 1993. RESULTS: Of 230 patients with AIDS, 74 (32%) had begun both ART and PCP prophylaxis before AIDS and 135 (59%) had received neither therapy before AIDS. Patients treated with ART and PCP prophylaxis were less likely than untreated patients to have PCP as the first AIDS diagnosis (treated 28% versus non-treated 60%, p = 0.0001 Fisher's exact test) and once this was taken into account were also less likely to have Kaposi's sarcoma (KS) (17% versus 42.5%, p = 0.0003). Following adjustment for the reduction in PCP and KS the distribution of other AIDS illnesses was similar in the treated and untreated groups. In multivariate models treatment with ART and PCP prophylaxis before AIDS was associated with reduction in PCP as the first AIDS illness (p Acquired Immunodeficiency Syndrome/*DRUG THERAPY/IMMUNOLOGY/ MORTALITY Antiviral Agents/*THERAPEUTIC USE Australia/EPIDEMIOLOGY AIDS-Related Opportunistic Infections/COMPLICATIONS/*PREVENTION & CONTROL Cohort Studies CD4 Lymphocyte Count Human Longitudinal Studies Pneumonia, Pneumocystis carinii/COMPLICATIONS/*PREVENTION & CONTROL Prospective Studies Survival Rate

P09-15. Selection of higher avidity HLA-restricted T cell responses as a viral adaptation strategy

Loss of immune reactivity due to HIV mutational escape is well described. Data generated from a large population-based study (n>800) suggested that certain CD8 T cell epitopes are created as a result of HIV adaptation and are associated with enhanced viral replication. Here we sought to investigate the HLA-restricted T-cell responses associated with seven such adaptations

Helicobacter pylori adaptation in vivoin response to a high salt diet

Helicobacter pylori exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori diversification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high salt diet or a regular diet for four months, using proteomic and whole genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high salt diet produced higher levels of proteins involved in iron acquisition and oxidative stress resistance. Several of these changes were attributable to a non-synonymous mutation in fur (fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high salt conditions and oxidative stress. We propose a model in which a high salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori-infected animals, and that these conditions along with the high intraluminal concentrations of sodium chloride lead to selection of H. pylori strains that are most fit for growth in this environment

A general method to eliminate laboratory induced recombinants during massive, parallel sequencing of cDNA library.

Massive, parallel sequencing is a potent tool for dissecting the regulation of biological processes by revealing the dynamics of the cellular RNA profile under different conditions. Similarly, massive, parallel sequencing can be used to reveal the complexity of viral quasispecies that are often found in the RNA virus infected host. However, the production of cDNA libraries for next-generation sequencing (NGS) necessitates the reverse transcription of RNA into cDNA and the amplification of the cDNA template using PCR, which may introduce artefact in the form of phantom nucleic acids species that can bias the composition and interpretation of original RNA profiles

HLA-Associated viral mutations are common in human immunodeficiency virus type 1 elite controllers

Elite controllers (EC) of human immunodeficiency virus type 1 (HTV-1) maintain viremia below the limit of detection without antiretroviral treatment. Virus-specific cytotoxic CD8+ T lymphocytes are believed to play a crucial role in viral containment, but the degree of immune imprinting and compensatory mutations in EC is unclear. We obtained plasma gag, pol, and nef sequences from HLA-diverse subjects and found that 30 to 40% of the predefined HLA-associated polymorphic sites show evidence of immune selection pressure in EC., compared to approximately 50% of the sites in chronic progressors. These data indicate ongoing viral replication and escape from cytotoxic T lymphocytes are present even in strictly controlled HTV-1 infection

Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

Idiosyncratic adverse drug reactions are unpredictable, dose independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkage between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells that required HLA-B*57:01 molecules for their function. However, the mechanism by which abacavir induces this pathologic T cell response remains unclear. Here we show that abacavir can bind within the F-pocket of the peptide-binding groove of HLA-B*57:01 thereby altering its specificity. This supports a novel explanation for HLA-linked idiosyncratic adverse drug reactions; namely that drugs can alter the repertoire of self-peptides presented to T cells thus causing the equivalent of an alloreactive T cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir, and that were recognized by T cells of hypersensitive patients. The assays we have established can be applied to test additional compounds with suspected HLA linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA linked hypersensitivities as well as guide the development of safer drugs

Ultra-deep sequencing reveals dynamics of drug Resistance-Associated variants in Hepatitis C viruses: Relevance to treatment outcome and resistance screening

Hepatitis C is a global health issue with approximately 3% of the worlds’ population estimated to be infected with the hepatitis C virus (HCV) Inefficiencies in treatment has led to development of direct-acting antivirals (DAAs) that specifically target HCV proteins involved in the virus’s lifecycle1. One of the major concerns arising from the use of the DAAs is the emergence of resistance-associated variants (RAVs) that affect the efficacy of the drugs. RAVs are generally associated with a fitness cost and the use of ultra-deep pyrosequencing technology has shown that in most treatment naïve subjects low frequency circulating strains carry RAVs2. The aim of the study was to investigate i) the clinical relevance of low frequency RAVs; ii) the persistence of RAVs and iii) compensatory mutations in a subset of subjects who had failed boceprevir (SCH503034; protease inhibitor)