Correction for founder effects in host-viral association studies via principal components.

Viruses such as HIV and Hepatitis C (HCV) replicate rapidly and with high transcription error rates, which may facilitate their escape from immune detection through the encoding of mutations at key positions within human leukocyte antigen (HLA)-specific peptides, thus impeding T-cell recognition. Large-scale population-based host-viral association studies are conducted as hypothesis-generating analyses which aim to determine the positions within the viral sequence at which host HLA immune pressure may have led to these viral escape mutations. When transmission of the virus to the host is HLA-associated, however, standard tests of association can be confounded by the viral relatedness of contemporarily circulating viral sequences, as viral sequences descended from a common ancestor may share inherited patterns of polymorphisms, termed 'founder effects'.

Viral adaptation to host immune responses occurs in chronic hepatitis B virus (HBV) infection, and adaptation is greatest in HBV e antigen-negative disease.

Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119).

Tissue-specific associations between mitochondrial DNA levels and current treatment status in HIV-infected individuals.

Background: Tissue mitochondrial DNA (mtDNA) levels have been proposed as a marker of nucleoside analouge reverse transcriptase inhibitor (NRTI) toxicity. However, clinical studies have yielded conflicting data regarding possible associations with mtDNA levels. This study examined mtDNA levels in matched samples of peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from a large Australian cohort to examine treatment, clinical, and demographic associations with mtDNA depletion.

Interferon-gamma responses to Candida recover slowly or remain low in immunodeficient HIV patients responding to ART.

Extended assessments of memory T-cell responses in HIV patients who have a satisfactory virological response to combination antiretroviral therapy (CART) have been limited by availability of longitudinal samples and of antigens to which most individuals (including HIV-negative controls) have been exposed. Studies of cytomegalovirus (CMV) show that interferon-gamma (IFN-gamma) responses never recover completely, but this may be antigen-specific. Here we present responses to Candida and CMV antigens analyzed using a statistical approach that derives overall trends from samples collected at variable time points.

Recovery of CD4+ T Cells in HIV patients with a stable virologic response to antiretroviral therapy is associated with polymorphisms of interleukin-6 and central major histocompatibility complex genes.

We investigated whether polymorphisms in genes associated with HIV disease progression and/or immune activation affect CD4+ T-cell recovery in HIV patients who began combination antiretroviral therapy (ART) with advanced immunodeficiency and achieved stable control of plasma viremia. Patients with CD4 T-cell counts <300 cells/microL (n = 33) and >400 cells/microL (n = 37) on ART were compared. A multiple case-control logistic regression associated carriage of BAT1(1,2) or interleukin (IL)6-174(2,2) with low CD4 T-cell counts (P = 0.

Interactive selective pressures of HLA-restricted immune responses and antiretroviral drugs on HIV-1.

HIV-specific cytotoxic T lymphocyte (CTL) responses mediated by human leukocyte antigen (HLA) recognition and antiretroviral drugs exert selection pressure on HIV-1 in vivo. The selection of CTL escape mutations strongly underpins the failure of CTL control in most untreated infections whilst drug-resistance mutations predict failure of drug control. These two evolutionary forces share common target residues in HIV-1 at which their selection effects could be synergistic or antagonistic, such that the propensity to develop drug resistance and virological treatment failure may be influenced by HLA type.

Randomized, controlled, 48-week study of switching stavudine and/or protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients.

Objective: HIV-1 protease inhibitors (versus no protease inhibitors) and stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of stavudine and/or protease inhibitor-containing regimens to combivir/abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients.

Design: The investigation was a prospective, randomized, controlled, open-label study.

Viral load detectability profiles for HIV infection.

The introduction of potent antiretroviral therapies for treatment of HIV infection typically results in a dramatic reduction in plasma HIV RNA concentration, often to levels undetectable by current measurement practices. However, although a high proportion of patients achieve 'undetectability', many then experience a return to a state of detectability at a later date. As evaluation of virologic response provides a useful measure of therapy efficacy, it is of interest to estimate the proportions of cases with undetectable viral load over time following commencement of treatment.

Estimation of the Doppler ultrasound umbilical maximal waveform envelope: II. Prediction of fetal distress.

Blood flow variables obtained via Doppler ultrasound (US) waveform estimation have been investigated for prediction of fetal distress. The umbilical flow was assessed using a number of waveform summary statistics in addition to the currently used resistance indices. We examined the relationship between umbilical artery waveform patterns and intrauterine growth restriction, preterm delivery and hypertensive disorders.

Estimation of the Doppler ultrasound maximal umbilical waveform envelope: I. Estimation method.

We developed a parametric method of estimating the Doppler ultrasound (US) umbilical maximal flow waveform envelope that is robust to varying levels of signal-to-noise ratio (SNR). The method differs from previously proposed estimation algorithms in that it does not incorporate preliminary removal or reduction of noise; thus, avoiding potential resulting biases. Instead, we relied on a multiple time series interpretation that facilitates a regression approach.

Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level.

Antigen-specific T cell immunity is HLA-restricted. Human immunodeficiency virus-type 1 (HIV-1) mutations that allow escape from host immune responses may therefore be HLA allele-specific. We analyzed HIV-1 reverse transcriptase sequences from a large HLA-diverse population of HIV-1-infected individuals.