305 Dynamics of Virus-specific CD8+ T-cell Immunity and Viral Escape during Acute and Chronic HIV-1 Infection J. Cao*1,2, J. McNevin1, Y. Liu2, H. Zhao2, I. Genowati2, J.I. Mullins2, M.J. McElrath1,2 1Fred Hutchinson Cancer Res Ctr, Seattle, WA and 2Univ of Washington, Seattle
Background: Virus-specific CD8+ T-cells largely mediate control of HIV-1 replication during acute and chronic infection. HIV-1 can override the immune pressure by mutation of the CD8+ T-cell epitope sequences so that specific CD8+ T-cells no longer recognize the infected cells.
Method: To determine the interaction between HIV-1 replication and the host T-cell immunity, we analyzed HIV-1-specific IFN-gamma-secreting CD8+ T-cell responses and viral epitope sequences in T-cells and plasma from an antiretroviral-naive patient starting at 9 days and extending through 3 yrs of infection.
Results: High frequencies of HLA-Cw12-restricted Tat-specific and HLA-B51 restricted Vpr-specific CD8+ T-cells dominated the initial response to HIV-1 infection. Rapid escape mutations developed and remained fixed within both these epitopes. Coincident with the decline of these acute CD8+ T-cell responses and establishment of the viral set point, new responses emerged to determinants within gag, nef, env, pol and vif. The viral sequences of these epitopes at the time when responses first arose were identical to the sequences during acute infection, but immune escape developed in some of these epitopic regions over time. The development of escape mutations within the T-cell epitopes was not solely determined by the functional avidity of the response. Interestingly, in 1 case the dominant escape mutation was only transient.
Conclusions: In summary, our results provide evidence for the selection of viral escape to HIV-1 specific CD8+ CTL immune pressure during acute as well as chronic infection. Furthermore, we demonstrate the dynamics of the CD8+ T-cell response with establishment and maintenance of viral setpoint in the absence of antiretroviral treatment.
