bTo overcome the problem of HIV-1 variability, candidate vaccine antigens have been designed to be composed of conserved elements of the HIV-1 proteome. Such candidate vaccines could be improved with a better understanding of both HIV-1 evolutionary constraints and the fitness cost of specific mutations. We evaluated the in vitro fitness cost of 23 mutations engineered in the HIV-1 subtype B Gag-p24 Center-of-Tree (COT) protein through fitness competition assays. While some mutations at conserved sites exacted a high fitness cost, as expected under the assumption that the most conserved residue confers the highest fitness, there was no overall strong relationship between sequence conservation and replicative capacity. By comparing sites that have evolved since the beginning of the epidemic to those that have remain unchanged, we found that sites that have evolved over time were more likely to correspond to HLA-associated sites and that their mutation had limited fitness costs. Our data showed no transcendent link between high conservation and high fitness cost, indicating that merely focusing on conserved segments of HIV-1 would not be sufficient for a successful vaccine strategy. Nonetheless, a subset of sites exacted a high fitness cost upon mutation-these sites have been under selective pressure to change since the beginning of the epidemic but have proved virtually nonmutable and could constitute preferred targets for vaccine design.
A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-␥/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (P ؍ 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (P ؍ 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r ؍ 0.62, P ؍ 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r ؍ ؊0.38, P ؍ 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r ؍ 0.50, P ؍ 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies.
Purpose/Objective(s): There are many studies findings on patient positioning efficiency using SGRT. In our clinic, we have 80 patients in average per linear accelerator. Hence, we would like to further develop the positioning method by combining the functions from both LINAC and SGRT system to investigate its potential in positioning accuracy and setup time. Materials/Methods: There was 40 thoracic cancer patients were selected randomly and divided into 2 groups. Controlled group (Group A) with a total of 20 patients who were aligned based on skin marking. The patient was aligned to the CT reference plane by the therapists using hands. Then, the therapists did the manual calculations for each patient for the isocenter shifts. The other 20 patients, the experimental group (Group B), who were first aligned to the reference plane along their nipples across the vac-bag marking to ensure patient's position in longitudinal direction and patient was nicely fit into the vac-bag. Next, the therapist introduced the first step of auto-positioning and second step with 'move couch' function to the isocenter position. CBCT images were taken in both groups and shifts in translational and rotational were recorded. All systematic and random errors were analyzed as well as setup time.Results: Total of 208 and 199 CBCT images in group A and B were analyzed. The mean shifts errors for group A and B were 0.36cm, 0.27cm and 0.44cm (lat, lng and vrt) and 0.898, 0.988 and 0.768 (pitch, roll and rtn) and 0.23cm, 0.10cm and 0.16cm (lat, lng and vrt) and 0.638, 0.58 and 0.578 (pitch, roll and rtn) respectively. Group B is superior in positioning accuracy than Group A in all directions. The results also shown the average setup time for Group A and B were 118 second and 89 seconds respectively. It is statistical significance (P < 0.05). Conclusion: New positioning method using combination of auto-positioning by both LINAC and SGRT system has proven to improve our workflow efficiency and setup accuracy greatly. It eliminates the need of isocenter shift manual calculation, which substantially reduced the potential of human error-induced radiation incidence. This new positioning method is adapted in our clinic to replace the current patient positioning workflow.
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