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Background: A recent analysis of mutational patterns within Gag revealed independently evolving groups of residues (termed sectors) whose mutations are collectively coordinated. Of these sectors, sector 3 is the least tolerant of multiple simultaneous mutations and therefore is proposed to be the most vulnerable to a targeted immune attack. We hypothesized that coordinated CTL targeting of sector 3 residues is associated with immune control. Methods: We completed a comprehensive evaluation of Gag-specific responses in a cohort of 9 Long-term non-progressors (LTNPs, VL 10,000 RNA copies/ml, untreated). A Gag peptide set of 11-mer peptides overlapping by 10 amino acids was generated to reflect all variants found in at least 5% of clade B sequences in the LANL HIV Sequence Database. This peptide set includes 1300 peptides and covers all 500 amino acids of Gag. All study subjects were screened for responses to all peptides by IFN-γ/IL-2 FluoroSpot. Results: We observed a trend in the preferential targeting of sector 3 residues by LTNPs (p=0.07). This trend was not observed for any other sector or in total breadth of responses. Supporting the importance of sector 3 targeting, we found a significant positive correlation in our cohort between the relative proportion of sector 3 responses and CD4 count (r=0.49, p=0.04). We found no significant differences between LTNPs and HIV-Progressors in either the targeting of conserved 11-mers or overall Gag epitope variant recognition. Interestingly, LTNPs demonstrated higher levels of variant recognition than HIV-progressors when considering only the variable regions containing sector 3 residues. Conclusion: We found that preferential targeting of sector 3 residues distinguished Gag-specific responses between LTNPs and HIV-progressors, and that coordinated targeting of sector 3 residues may require cross-reactive responses. Additional investigations are ongoing to elucidate the role of sector 3 targeting in immune control of HIV.

High frequency responses were elicited against clade A (T1 95.8%, T2 100%, T3 97.4%, T4 100%), clade B (T1 95.8%, T2 95.0%, T3 92.1%, T4 96.3%), clade C (T1 92%, T2 76%, T3 76%, T4 78%), and Con S (T1-4 100%). There were no significant between-group differences in response frequency or magnitude. The majority also had responses to V1V2 clade A (T1 100%, T2 87.8%, T3 83.8%, T4 85.2%) and clade B (T1 58.3%, T2 65.9%, T3 54.1%, T4 51.9%). The mean fluorescent intensity was higher in T2 vs T1 (p=0.005) for clade A V1V2. No significant differences were observed between other groups.

Background Vaccinees in the Step Trial who were Ad5 seropositive at baseline had a trend toward increased HIV infection [2.3fold increased incidence (CI:1.2–4.3)] (Lancet, 2008; 372(9653): 1881–93). To further explore the relationship between HIV and Ad5, we investigated evidence of incident Ad5 infection and whether HIV infection was associated with increases in Ad5 neutralizing antibody (nAb) titer in the absence of vaccination.