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'. Recognizing the correspondence between this problem and the confounding of case-control genome-wide association studies by population stratification, we adapt methods taken from that field to the analysis of host-viral associations. In particular, we consider methods based on principal components analysis within a logistic regression framework motivated by alternative formulations in the Frisch-Waugh-Lovell Theorem. We demonstrate via simulation their utility in detecting true host-viral associations whilst minimizing confounding by associations generated by founder effects. The proposed methods incorporate relatively robust, standard statistical procedures which can be easily implemented using widely available software, and provide alternatives to the more complex computer intensive methods often implemented in this area

The geology and geophysics of Kuiper Belt object (486958) Arrokoth

The Cold Classical Kuiper Belt, a class of small bodies in undisturbed orbits beyond Neptune, are primitive objects preserving information about Solar System formation. The New Horizons spacecraft flew past one of these objects, the 36 km long contact binary (486958) Arrokoth (2014 MU69), in January 2019. Images from the flyby show that Arrokoth has no detectable rings, and no satellites (larger than 180 meters diameter) within a radius of 8000 km, and has a lightly-cratered smooth surface with complex geological features, unlike those on previously visited Solar System bodies. The density of impact craters indicates the surface dates from the formation of the Solar System. The two lobes of the contact binary have closely aligned poles and equators, constraining their accretion mechanism

Response to HAART: Host genetic associations

No abstract availabl

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. These proportions depend on the rates of transition from detectability to undetectability and subsequent return to detectability, and may be related to covariates or risk factors, possibly differing in both transitions. We consider construction of detectability profiles as estimates of these proportions, based on parametric modelling of the component survival distributions. The method is applied to an examination of the effects of baseline CD4 T-cell lymphocyte counts on virologic response to therapy amongst patients of the Western Australian HIV Cohort Study

Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection

Background: Progressive subcutaneous fat wasting, fat accumulation, dyslipidaemia and insulin resistance in HIV-infected patients on antiretroviral therapy has been attributed to the long-term toxicity of HIV protease inhibitors (PI). More recently, fat wasting has been observed in patients who have never taken a PI, implicating an independent effect of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy. Objectives: To determine the relative contribution of NRTI and PI, as well as any other factors, to fat wasting in HIV-infected patients. Design: Longitudinal cohort study involving 277 participants of the Western Australian HIV Cohort Study. Methods: The time to onset of clinically apparent fat wasting in patients receiving different antiretroviral regimens was compared using standardized clinical criteria. Regional fat measured by dual energy X-ray absorptiometry (DEXA) in 161 patients was also compared. The average rate of percentage fat reduction was estimated in 70 patients who had consecutive DEXA scans at approximately 6-monthly intervals. Multiple confounding factors were considered in the analyses. Results: Progressive subcutaneous fat wasting, indistinguishable from that described in PI-treated patients, does occur in PI-naive, NRTI-treated patients. In patients taking triple combination antiretroviral therapy, age (relative risk = 1.052 per year;P  < 0.0001), white race (relative risk = 3.9;P  = 0.023), longer duration of dual NRTI therapy prior to addition of PI (relative risk = 1.021 per month;P  = 0.0046) and increased cumulative time on stavudine-containing regimens compared with time on zidovudine-containing regimens (relative risk = 1.085 per month;P  < 0.0001) are associated with increased risk of fat wasting. Stavudine increases the risk of fat wasting by 265% per year compared with zidovudine. However PI therapy is associated with faster progression to clinically apparent wasting compared with dual NRTI therapy without PI. The results of DEXA scanning supports these clinical data and suggest a non-linear decline in fat over time. Conclusions: NRTIs do have an independent contribution to fat wasting, but PI are the predominant influence and may act synergistically with NRTIs. NRTIs appear to predispose individuals to slowly progressive fat loss, which is markedly accelerated when a PI and NRTIs are combined. Of the NRTIs, stavudine leads to an earlier onset of clinically apparent fat wasting compared with zidovudine. Fat wasting associated with NRTI use may be a manifestation of mitochondrial toxicity, which may be exacerbated by PI use

Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy

Objective: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. Design: A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. Results: In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. Conclusions: Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia

Randomised, controlled, 48-week study of switching stavudine and/or protease inhibitors to Combavir/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. Subjects: The subjects included 37 HIV-1-infected individuals with stable undetectable HIV-1 loads who were taking a regimen containing either stavudine or zidovudine with lamivudine and a protease inhibitor. Intervention: Subjects were randomized to continue therapy or switch stavudine to zidovudine and protease inhibitor to abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and abacavir. Main Outcome Measures: Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed. Results: There was an average gain in fat mass of 0.009 kg/(leg[middle dot]mo) in switch patients versus a loss of 0.010 kg/(leg[middle dot]mo) in controls (p = .04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm[middle dot]mo) (p = .004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intra-abdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/abacavir maintained virological control in all but one case, and three (13.6%) of 22 individuals had adverse reactions to abacavir therapy. Conclusions: A switch to combivir/abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with stavudine and/or protease inhibitor

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. Methods: mtDNA was quantified by real-time polymerase chain reaction. Results were compared across patient treatment and demographic details using linear mixed models. Results: One hundred sixty-three PBMCs and 161 fat samples were available from 61 individuals. Current NRTI exposure was the major determinant of mtDNA levels. Both ddI (didanosine) and d4T (stavudine) exposures were associated with mtDNA depletion in fat (P <= 0.0001 vs. those not on NRTIs). DdI exposure (P = 0.003), but not d4T exposure (P = 0.5), was associated with mtDNA depletion in PBMCs. No association between patient demographics or time on current therapy and mtDNA was observed. Conclusions: Current NRTI exposure is the major determinant of tissue mtDNA, but the precise determinants are tissue specific. Both ddI and d4T exposure are associated with fat mtDNA depletion, whereas ddI exposure was the only observed association with mtDNA depletion in PBMCs

The immune response to HIV: The interplay between virus and host genetic factors

The immune response to HIV infection is complex involving multiple interactive pathways and components. These pathways are influenced by both virus and host genetic factors, which determine disease progression, complications and response to treatment. HIV virus evades the antigen specific T-cell immunity by undergoing mutations throughout its entire genome, which at a population level are both positively and negatively associated with particular HLA alleles. The extent to which this adaptation occurs influences viral load. These results provide evidence that host HLA is an important factor imprinting on viral evolution. Host genetic factors are also important predictors of clinical course and complications in established HIV infection. In cross-sectional and longitudinal studies of the WA HIV cohort, we have shown certain HLA and chemokine receptor alleles influence viral load set point. In addition, the presence of certain NK cell KIR genes influence outcome, particularly, in relation to rate of decline of CD4 cells. Those genes characteristic of the B group of KIR haplotypes were associated with a more rapid rate of decline. Host genetics can also influence responses to therapeutic agents. In an update of our initial observation that abacavir hypersensitivity shows a striking association with MHC markers of the 57.1 AH, we show that these markers have a useful clinical role while mapping, and in vitro studies have provided some insights into the possible pathogenic basis for this association

Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy

Background: To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log10 copies/mL). Methods: Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients. Results: Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses. Conclusions: We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens