Publications

Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.

Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n = 379; average body mass index (BMI), 49.0 kg/m2] and lean (n = 378; average BMI, 19.5 kg/m2) individuals. In total, three rare non-synonymous variants were identified, only one of which, PYY Q62P, exhibited familial segregation with body mass. Through serendipity, previous studies based on cell culture revealed this precise variant to have altered receptor-binding selectivity in vitro. We further show, using mouse peptide injection experiments, that while the wild-type PYY peptide reduces food intake, the mutant PYY 62P had an insignificant effect in reducing food intake in vivo. Taken together, these results are the first to support that rare sequence variants within PYY can influence human susceptibility to obesity.

Current guidelines recommend that postmenopausal hormone therapy (HT) be used primarily for treatment of vasomotor and urogenital symptoms associated with the menopausal transition and that women use the lowest effective dose for the shortest time necessary. Vasomotor symptoms improve or resolve spontaneously within a few months to a few years of onset in the majority of women, suggesting that most women should be able to discontinue HT within a few years of starting treatment. Approximately 75% of women who try to stop are able to stop HT without major difficulty. However, some women who would like to stop HT are unable to do so, mainly owing to the development of vasomotor symptoms. Troublesome symptoms associated with stopping HT appear to be more common among women who start HT for treatment of symptoms, but they also are reported by women who started HT for other reasons, such as prevention of osteoporosis. Unfortunately, little information is available to guide physicians in helping women who have difficulty stopping HT. Many clinicians recommend slowly tapering HT or adding another drug for treatment of hot flashes, but the effectiveness of these approaches has not been evaluated. For women who cannot tolerate even a slow taper, the value of symptom relief likely outweighs any increased risks due to HT use.