Session Day and Time: Wednesday 1:30 - 3:30 pm
Room: Hall A
Background: HIV-1-specific cytotoxic T-lymphocytes (CTL) play an important role in suppressing viral replication, yet their presence in vivo ultimately fails to protect most chronically HIV-infected individuals from disease progression. CTL responses that are weak, narrowly-directed, or target variable regions of HIV-1 may not consistently suppress HIV-1 replication in vivo. A therapeutic vaccine that generates a stronger, more broadly-directed CTL response targeting conserved HIV-1 epitopes might improve immunologic control of HIV-1 replication. We evaluated baseline CTL responses to a panel of highly conserved, HLA class I supertype epitopes in HIV-1 that are expressed in an epitope-based DNA vaccine currently under clinical investigation.
Methods: IFN-g ELISpot responses to 21 individual HLA-A2(7), -A3(7), or -B7(7) supertype-restricted, conserved epitope peptides from HIV-1 Env, Gag, Pol, Nef, and Vpr were tested in PBMC from 53 HIV-infected subjects and 13 uninfected controls. HLA typing was performed on a subset of subjects.
Results: One (1) or more epitope peptides were recognized in 70% of HIV-1-infected subjects, and 20 of 21 epitopes were recognized by at least one subject. A trend toward lower magnitude responses was seen in HAART-suppressed compared to viremic subjects (p = 0.09), but no significant difference in breadth of recognition between the two groups was observed (median 1.0 vs 1.5 peptides, p = 0.385). The probability of a response to HLA-A2, -A3, or –B7 supertype epitopes given relevant allele expression was 0.64. Response probability dropped to 0.32 for epitopes recognized outside a given supertype and primarily involved A2- and A3-restricted epitopes.
Conclusions: The majority of class I supertype HIV-1 epitopes tested was recognized by HIV-1-infected subjects, suggesting that they represent natural epitopes. Despite epitope antigenicity, recognition was limited to a few epitopes in the majority of subjects. The magnitude of responses was lowest in HAART-treated subjects, those usually considered to be candidates for therapeutic vaccination. HLA type was a strong predictor of supertype-specific responses, but a number of subjects also responded to epitopes outside of their supertype. These results suggest that pre-existing HIV-specific CTL responses to conserved, cross-reactive HIV-1 epitopes might be augmented in both magnitude and breadth through therapeutic vaccine strategies.