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General and Virus-Specific Immune Augmentation Strategies
Tuesday, 1:30 - 3:30 pm
Background: Structured treatment interruptions after therapeutic vaccination can provide important information about the efficacy of vaccines and the role of CTL. In this study we interrupted HAART after vaccination with a MVA-BN-Nef vector (Modified Vaccinia Virus Ankara-Bavarian Nordic) and we correlated the CTL response to viral load and viral sequence variation.
Methods: We vaccinated 14 HIV-1+ patients on HAART were vaccinated at week 0, 4 and 16 with a nef expressing MVA-BN. HIV specific T-cells were monitored by g-IFN ELISpot. Structured treatment interruptions was performed 2 weeks after the third vaccination. nef genes were sequenced from plasma at peak viremia. Recognition of autologous nef was tested by IFN-g ELISpot using peptides and PBMC.
Results: As reported previously, MVA-BN-Nef vaccination was safe and immunogenic. After interruption of HAART viral load became detectable after 4 weeks (median, range 2 to 12 weeks) reaching a median peak of 54 000 copies/mLl (8400-500,000) after 6 weeks (median, week 4 to 22). After a median Structured treatment interruptions of 18 weeks (4-51w) HAART was resumed in 8 patients at a median viral load of 33,000 copies/mL (7000-120000). 6 patients still are off therapy after 64 weeks (median,week 57 to 76) with a median viral load of 4350 copies/mL (700-35000).
We performed a detailed analysis of CTL, viral load and nef sequences in all patients, which revealed a complex interaction depending on the number of CTL, the quality of epitopes and viral sequence variation. In 2 patients Nef-specific CTL activity transiently declined during peak viremia indicating a functional immunosuppression by HIV itself. Rebound peak viremia was prevented in a patient in whom MVA-BN-Nef had induced a very strong increase of Nef-specific CTL. In contrast, other patients could not prevent rebound viremia despite the presence of CTL, but subsequently they could decrease viremia in association with rising CTL frequencies or with recruitment of new CTL specificities. Sequence analysis of viral nef genes revealed in several patients the presence of potential CTL escape mutations.
Conclusions: Therapeutic vaccination with MVA-BN-Nef can improve HIV-1 specific immunity at least in a subset of patients. Our data indicate that the number of CTL, the quality of epitopes, the presence of escape mutations and presumably viral virulence factors are important parameters for the control of HIV-replication.
Keywords: MVA-BN-Nef; therapeutic vaccination; STI