HIV-1 Epitope Variability Is Associated with T Cell Receptor Repertoire Instability and Breadth.

Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier for effective immune control. Each epitope typically is targeted by multiple clones with distinct T cell receptors (TCRs). While the clonal repertoire may be important for containing epitope variation, determinants of its composition are poorly understood. We investigate the clonal repertoire of 29 CTL responses against 23 HIV-1 epitopes longitudinally in nine chronically infected untreated subjects with plasma viremia of <3,000 RNA copies/ml over 17 to 179 weeks. The composition of TCRs targeting each epitope varied considerably in stability over time, although clonal stability (Sorensen index) was not significantly time dependent within this interval. However, TCR stability inversely correlated with epitope variability in the Los Alamos HIV-1 Sequence Database, consistent with TCR evolution being driven by epitope variation. Finally, a robust inverse correlation of TCR breadth against each epitope versus epitope variability further suggested that this variability drives TCR repertoire diversification. In the context of studies demonstrating rapidly shifting HIV-1 sequences in vivo, our findings support a variably dynamic process of shifting CTL clonality lagging in tandem with viral evolution and suggest that preventing escape of HIV-1 may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways.IMPORTANCE Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier to effective immune control. The number of distinct CTL clones targeting each epitope is proposed to be an important factor, but the determinants are poorly understood. Here, we demonstrate that the clonal stability and number of clones for the CTL response against an epitope are inversely associated with the general variability of the epitope. These results show that CTLs constantly lag epitope mutation, suggesting that preventing HIV-1 escape may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways.

Determinants of participation in HIV clinical trials: the importance of patients' trust in their provider.

PURPOSE: To investigate the factors that contribute to willingness to participate in HIV clinical trials and to determine the impact of a brief intervention on willingness to participate. METHODS: 115 consecutive outpatients receiving HIV primary care participated in this prospective study. Each patient completed a questionnaire about clinical trials and met with a research assistant who discussed the purpose of clinical trials. After the educational intervention, participants completed a second questionnaire and responses from the two surveys were compared. RESULTS: 115 patients were enrolled (56% had previously enrolled in a clinical trial; 50% of whom were currently enrolled in a trial); 92% would consider participating in a future clinical trial. Increased patient trust in the provider was associated with increased willingness to participate in a trial. After the intervention, 94% indicated that they would be willing to be contacted about a clinical trial for which they may be eligible and 85% preferred to be contacted by their primary physician. CONCLUSIONS: Patients' trust in their provider may predict willingness to participate in clinical trial. Providing HIV-infected patients and their providers with information about HIV clinical trials at the site where they receive care may increase participation rates in HIV clinical trials.