HLA-B⁎27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope

Background & Aims: HLA-B⁄27 is associated with spontaneous HCV genotype 1 clearance. HLA-B⁄27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B⁄27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B⁄27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope. Methods: Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B⁄27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B⁄27:02 and 05. Results: The NS5B2820 epitope is only restricted by the HLA-B⁄27 subtype HLA-B⁄27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B⁄27 subtype B⁄27:05. Indeed, the epitope is very dominant in HLA-B⁄27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B⁄27:02+ chronically infected patients. Conclusions: The NS5B2820 epitope is immunodominant in the context of HLA-B⁄27:02, but is not restricted by other HLA-B⁄27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines.

Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing.

OBJECTIVES It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. METHODS This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. RESULTS Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35-5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76-6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12-5.18, P = 0.024). A dose-effect relationship between virological failure and mutational load was found. CONCLUSIONS Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.

Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation.

AIM The optimal duration of dual antiplatelet therapy (DAPT) following the use of new generation drug-eluting stents is unknown. METHODS AND RESULTS The association between DAPT interruption and the rates of stent thrombosis (ST) and cardiac death/target-vessel myocardial infarction (CD/TVMI) in patients receiving a Resolute zotarolimus-eluting stent (R-ZES) was analysed in 4896 patients from the pooled RESOLUTE clinical programme. Daily acetylsalicylate (ASA) and a thienopyridine for 6-12 months were prescribed. A DAPT interruption was defined as any interruption of ASA and/or a thienopyridine of >1 day; long interruptions were >14 days. Three groups were analysed: no interruption, interruption during the first month, and >1-12 months. There were 1069 (21.83%) patients with a DAPT interruption and 3827 patients with no interruption. Among the 166 patients in the 1-month interruption group, 6 definite/probable ST events occurred (3.61%; all long DAPT interruptions), and among the 903 patients in the >1-12 months (60% occurred between 6 and 12 months) interruption group, 1 ST event occurred (0.11%; 2-day DAPT interruption). Among patients with no DAPT interruption, 32 ST events occurred (0.84%). Rates of CD/TVMI were 6.84% in the 1-month long interruption group, 1.41% in the >1-12 months long interruption group, and 4.08% in patients on continuous DAPT. CONCLUSION In a pooled population of patients receiving an R-ZES, DAPT interruptions within 1 month are associated with a high risk of adverse outcomes. Dual antiplatelet therapy interruptions between 1 and 12 months were associated with low rates of ST and adverse cardiac outcomes. Randomized clinical trials are needed to determine whether early temporary or permanent interruption of DAPT is truly safe. CLINICAL TRIALSGOV IDENTIFIERS NCT00617084; NCT00726453; NCT00752128; NCT00927940.

Short- and long-term skeletal relapse after mandibular advancement surgery

This study analyzes short- and long-term skeletal relapse after mandibular advancement surgery and determines its contributing factors. Thirty-two consecutive patients were treated for skeletal Class II malocclusion during the period between 1986 and 1989. They all had combined orthodontic and surgical treatment with BSSO and rigid fixation excluding other surgery. Of these, 15 patients (47%) were available for a long-term cephalography in 2000. The measurement was performed based on the serial cephalograms taken preoperatively; 1 week, 6 months and 14 months postoperatively; and at the final evaluation after an average of 12 years. Mean mandibular advancement was 4.1 mm at B-point and 4.9 mm at pogonion. Representing surgical mandibular ramus displacement, gonion moved downwards 2 mm immediately after surgery. During the short-term postoperative period, mandibular corpus length decreased only 0.5 mm, indicating that there was no osteotomy slippage. After the first year of observation, skeletal relapse was 1.3 mm at B-point and pogonion. The relapse continued, reaching a total of 2.3 mm after 12 years, corresponding to 50% of the mandibular advancement. Mandibular ramus length continuously decreased 1 mm during the same observation period, indicating progressive condylar resorption. No significant relationship between the amount of initial surgical advancement and skeletal relapse was found. Preoperative high mandibulo-nasal plane (ML-NL) angle appears to be associated with long-term skeletal relapse.

Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes

AIMS: We investigated whether myeloid-related protein 8/14 complex (MRP8/14) expressed by infiltrating monocytes and granulocytes may represent a mediator and early biomarker of acute coronary syndromes (ACS). METHODS AND RESULTS: Immunohistochemistry of coronary thrombi was done in 41 ACS patients. Subsequently, levels of MRP8/14 were assessed systemically in 75 patients with ACS and culprit lesions, with stable coronary artery disease (CAD), or with normal coronary arteries. In a subset of patients, MRP8/14 was measured systemically and at the site of coronary occlusion. Macrophages and granulocytes, but not platelets stained positive for MRP8/14 in 76% of 41 thrombi patients. In ACS, local MRP8/14 levels [22.0 (16.2-41.5) mg/L] were increased when compared with systemic levels [13.4 (8.1-14.7) mg/L, P = 0.03]. Systemic levels of MRP8/14 were markedly elevated [15.1 (12.1-21.8) mg/L, P = 0.001] in ACS when compared with stable CAD [4.6 (3.5-7.1) mg/L] or normals [4.8 (4.0-6.3) mg/L]. Using a cut-off level of 8 mg/L, MRP8/14 but not myoglobin or troponin, identified ACS presenting within 3 h from symptom onset. CONCLUSION: In ACS, MRP8/14 is markedly expressed at the site of coronary occlusion by invading phagocytes. The occurrence of elevated MRP8/14 in the systemic circulation prior to markers of myocardial necrosis makes it a prime candidate for the detection of unstable plaques and management of ACS.

Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy

BACKGROUND: The CD4 T cell count recovery in human immunodeficiency virus type 1 (HIV-1)-infected individuals receiving potent antiretroviral therapy (ART) shows high variability. We studied the determinants and the clinical relevance of incomplete CD4 T cell restoration. METHODS: Longitudinal CD4 T cell count was analyzed in 293 participants of the Swiss HIV Cohort Study who had had a plasma HIV-1 RNA load <1000 copies/mL for > or =5 years. CD4 T cell recovery was stratified by CD4 T cell count 5 years after initiation of ART (> or =500 cells/microL was defined as a complete response, and <500 cells/microL was defined as an incomplete response). Determinants of incomplete responses and clinical events were evaluated using logistic regression and survival analyses. RESULTS: The median CD4 T cell count increased from 180 cells/microL at baseline to 576 cells/microL 5 years after ART initiation. A total of 35.8% of patients were incomplete responders, of whom 47.6% reached a CD4 T cell plateau <500 cells/microL. Centers for Disease Control and Prevention HIV-1 disease category B and/or C events occurred in 21% of incomplete responders and in 14.4% of complete responders (P>.05). Older age (adjusted odds ratio [aOR], 1.71 per 10-year increase; 95% confidence interval [CI], 1.21-2.43), lower baseline CD4 T cell count (aOR, 0.37 per 100-cell increase; 95% CI, 0.28-0.49), and longer duration of HIV infection (aOR, 2.39 per 10-year increase; 95% CI, 1.19-4.81) were significantly associated with a CD4 T cell count <500 cells/microL at 5 years. The median increases in CD4 T cell count after 3-6 months of ART were smaller in incomplete responders (P<.001) and predicted, in conjunction with baseline CD4 T cell count and age, incomplete response with 80% sensitivity and 72% specificity. CONCLUSION: Individuals with incomplete CD4 T cell recovery to <500 cells/microL had more advanced HIV-1 infection at baseline. CD4 T cell changes during the first 3-6 months of ART already reflect the capacity of the immune system to replenish depleted CD4 T lymphocytes.