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.
Background and Aims HLA Class I alleles are linked to spontaneous control of HCV and HIV-1, but for HCV the roles of particular alleles and corresponding CD8+ T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcome of HCV and determine associated key T cell responses. Methods In a cohort of HCV individuals we determined HLA Class I alleles, HCV outcome, T-cell responses, and examined sequence data for mutational changes within key epitopes. Results Carriage of HLA-B*57 was associated with a higher rate of viral clearance [RR=2.0, 95% C.I. 1.2–3.4] while HLA-B*08 was associated with a lower rate [RR=0.34, 95% C.I. 0.1–0.9]. Two HLA-B*57 restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B*57 harbored HCV strains with a high frequency of mutations in key residues. HLA-B*57-mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution towards less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B*57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B*57-mediated immune pressure. Conclusions Our data indicate a role of HLA-B*57-restricted CD8+ T cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B*57. The finding that HLA-B*57-mediated antiviral immunity is associated with control of both HIV-1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses.
Patients who have undergone total hip or knee replacement (THR and TKR, respectively) are at high risk of venous thromboembolism. We aimed to determine the time courses of both the incidence of venous thromboembolism and effective prophylaxis. Patients with elective primary THR and TKR were enrolled in the multi-national Global Orthopaedic Registry. Data on the incidence of venous thromboembolism and prophylaxis were collected from 6639 THR and 8326 TKR patients. The cumulative incidence of venous thromboembolism within three months of surgery was 1.7% in the THR and 2.3% in the TKR patients. The mean times to venous thromboembolism were 21.5 days (sd 22.5) for THR, and 9.7 days (sd 14.1) for TKR. It occurred after the median time to discharge in 75% of the THR and 57% of the TKA patients who developed venous thromboembolism. Of those who received recommended forms of prophylaxis, approximately one-quarter (26% of THR and 27% of TKR patients) were not receiving it seven days after surgery, the minimum duration recommended at the time of the study. The risk of venous thromboembolism extends beyond the usual period of hospitalisation, while the duration of prophylaxis is often shorter than this. Practices should be re-assessed to ensure that patients receive appropriate durations of prophylaxis.
Background We sought to use data captured in the electronic health record (EHR) to develop and validate a prediction rule for virologic failure in patients being treated for HIV infection. Methods We used EHRs at two Boston tertiary care hospitals, Massachusetts General Hospital and Brigham and Women's Hospital, to identify HIV-infected patients who were virologically suppressed (HIV RNA ≤400 copies/mL) on antiretroviral therapy between 1/1/05 and 12/31/06. We used a multivariable logistic model with data from Massachusetts General Hospital to derive a one-year virologic failure prediction rule. The model was validated using data from the Brigham and Women's Hospital. We then simplified the scoring scheme to develop a clinical prediction rule. Results The one-year virologic failure prediction model, using data from 712 Massachusetts General Hospital patients, demonstrated good discrimination (c-statistic 0.78) and calibration (χ2 =6.6, p =0.58). The validation model, based on 362 Brigham and Women's Hospital patients, also showed good discrimination (c-statistic 0.79) and calibration (χ2 =1.9, p =0.93). The clinical prediction rule included seven predictors, Sub-optimal Adherence, CD4 count <100/μL, Drug and/or Alcohol Abuse, Heavily ART Experienced, Missed ≥1Appointment, Prior Virologic Failure, and Suppressed ≤12 months, and appropriately stratified patients in the validation dataset into low, medium and high risk groups, with one-year virologic failure rates of 3.0%, 13.0% and 28.6%. Conclusions A risk score based on seven variables available in the EHR predicts HIV virologic failure at one year and could be used for targeted interventions to improve outcomes in HIV disease.
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