Aminopeptidase substrate preference affects HIV epitope presentation and predicts immune escape patterns in HIV-infected individuals.

Viruses evade immune detection partly through immune-associated mutations. Analyses of HIV sequences derived from infected individuals have identified numerous examples of HLA-associated mutations within or adjacent to T cell epitopes, but the potential impact of most mutations on epitope production and presentation remains unclear. The multistep breakdown of proteins into epitopes includes trimming of N-extended peptides into epitopes by aminopeptidases before loading onto MHC class I molecules. Definition of sequence signatures that modulate epitope production would lead to a better understanding of factors driving viral evolution and immune escape at the population level. In this study, we identified cytosolic aminopeptidases cleavage preferences in primary cells and its impact on HIV Ag degradation into epitopes in primary human cell extracts by mass spectrometry and on epitope presentation to CTL. We observed a hierarchy of preferred amino acid cleavage by cytosolic aminopeptidases. We demonstrated that flanking mutations producing more or less cleavable motifs can increase or decrease epitope production and presentation by up to 14-fold. We found that the efficiency of epitope production correlates with cleavability of flanking residues. These in vitro findings were supported by in vivo population-level analyses of clinically derived viral sequences from 1134 antiretroviral-naive HIV-infected individuals: HLA-associated mutations immune pressures drove the selection of residues that are less cleavable by aminopeptidases predominantly at N-flanking sites, leading to reduced epitope production and immune recognition. These results underscore an important and widespread role of Ag processing mutations in HIV immune escape and identify molecular mechanisms underlying impaired epitope presentation.

Confusion regarding cervical cancer screening and chlamydia screening among sexually active young women.

OBJECTIVE: The American Congress of Obstetricians and Gynecologists (ACOG) recently recommended that cervical cancer screening begin at 21 years of age and occur biennially for low-risk women younger than 30 years. Earlier studies suggested that women may have limited understanding of the differences between cervical cancer screening and chlamydia screening. This study assessed the knowledge of chlamydia and cervical cancer screening tests and schedules in younger women. METHODS: A survey regarding knowledge of chlamydia and cervical cancer screening was administered to 60 younger women aged 18-25 years in an obstetrics and gynaecology clinic at an urban community health centre. RESULTS: The majority of respondents recalled having had a Pap smear (93.3%) or chlamydia test (75.0%). Although many respondents understood that a Pap smear checks for cervical cancer (88.3%) and human papillomavirus (68.3%), 71.7% mistakenly believed that a Pap smear screens for chlamydia. No respondent correctly identified the revised cervical cancer screening schedule, and 83.3% selected annual screening. Few respondents (23.3%) identified the annual chlamydia screening schedule and 26.7% were unsure. CONCLUSION: Many younger women in an urban community health centre believed that cervical cancer screening also screens for chlamydia and were confused about chlamydia screening schedules. As there is limited knowledge of the revised ACOG cervical cancer screening guidelines, there is a risk that currently low chlamydia screening rates may decrease further after these new guidelines are better known. Obstetrician gynaecologists and primary care providers should educate younger women about the differences between chlamydia and cervical cancer screening and encourage sexually active younger women to have annual chlamydia screening.

Systematic review of benefit designs with differential cost sharing for prescription drugs.

OBJECTIVES: To evaluate the effects of health insurance benefit designs that introduced or increased the price difference between prescription drugs representing potential clinical substitutes. STUDY DESIGN: Systematic review of peer-reviewed articles. METHODS: Using English-language articles listed in PubMed between 1980 and 2012, we identified articles meeting our inclusion criteria and minimum methodological standards. We compared findings regarding the immediate patient response, total spending, and health outcomes after implementing the price change. RESULTS: Among the 31 articles identified, the mechanisms varied for creating the price differential between prescription drug substitutes, though they most frequently involved tiered formularies (19) or reference pricing (10). While nearly all studies (29 of 31) reported on patient responses to price changes, only 5 articles comprehensively assessed patient price responses, total spending, and health outcomes. Several studies found that some patients switched to cheaper drugs, but out-of-pocket spending increased on average, suggesting that other patients continued using the more expensive drug (ie, cost shifting to patients). Few studies examined the degree of heterogeneity in behavior responses, especially between patient cohorts for whom the substitute drugs had varying value. Some studies observed long-term effects, but most had limited post intervention observation periods. CONCLUSIONS: Differential cost-sharing designs influence drug use behavior, but there is limited evidence on how these designs affect the overall value of received care. The existing literature provides limited guidance for policy makers or organizational leaders to design benefits. We offer suggestions for future studies to inform policy and practice.