ABSTRACT
The human leukocyte antigens HLA-B27 and HLA-B57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B27 and HLA-B57 are unable to control HIV-1. Here we found that HLA-B27-restricted CD8(+) T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B57-restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.
Subject(s)
HIV Infections/immunology , HIV-1/immunology , HLA-B Antigens/immunology , HLA-B27 Antigen/immunology , Receptors, Antigen, T-Cell/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cells, Cultured , Epitopes, T-Lymphocyte/immunology , HIV Infections/blood , HIV Infections/virology , HIV Long-Term Survivors , Humans , Perforin/immunology , Virus Replication/immunology , gag Gene Products, Human Immunodeficiency Virus/immunologyABSTRACT
Background: There are limited studies examining caregiver distress when raising a child with inflammatory bowel disease (IBD). The aim of this study was to investigate the occurrence of symptoms of distress (anxiety, depression, and post-traumatic stress disorder [PTSD]) among parents with children with IBD and associations with disease severity, time from diagnosis, and demographic factors. Methods: We conducted a cross-sectional study with parents of children (2-17 years) diagnosed with IBD. There were 2 cohorts: (1) recently diagnosed cohort (<6 months from diagnosis); (2) established diagnosis cohort (>1 year from diagnosis). Parents completed measures of anxiety, depression, and PTSD, while children completed surveys on the symptoms of their IBD. Results: Fifty-two parents in the recently diagnosed cohort and 103 parents in the established diagnosis cohort completed surveys. For the entire cohort of parents, we found the mean scores on all measures of distress were within the normal ranges with 20%, 13%, and 8% of parents reporting moderate-to-severe symptoms of anxiety, depression, and PTSD, respectively. Symptoms of anxiety and depression were not significantly associated with time from diagnosis; symptoms of anxiety and PTSD were significantly associated with patients' IBD clinical activity. Conclusions: Parents with children with IBD are remarkably resilient to distress even soon after their child's diagnosis. Despite considerable resilience, routine brief caregiver screening for symptoms of anxiety during annual visits seems reasonable and feasible.