Lack of viral escape and defective in vivo activation of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes in rapidly progressive infection

Human immunodeficiency virus type 1 (HIV-1)-specific immune responses over the course of rapidly progressive infection are not well defined. Detailed longitudinal analyses of neutralizing antibodies, lymphocyte proliferation, in vivo-activated and memory cytotoxic T-lymphocyte (CTL) responses, and v iral sequence variation were performed on a patient who presented with acut e HIV-1 infection, developed an AIDS-defining illness 13 months later, and died 45 months after presentation. Neutralizing-antibody responses remained weak throughout, and no HIV-1-specific lymphocyte proliferative responses were seen even early in the disease course. Strong in vivo-activated CTL di rected against Env and Pol epitopes were present at the time of the initial drop in viremia but were quickly lost. Memory CTL against Env and Pol epit opes were detected throughout the course of infection; however, these CTL w ere not activated in vivo. Despite an initially narrow CTL response, new ep itopes were not targeted as the disease progressed. Viral sequencing showed the emergence of variants within the two targeted CTL epitopes; however, v iral variants within the immunodominant Env epitope were well recognized by CTL, and there was no evidence of viral escape from immune system detectio n within this epitope. These data demonstrate a narrowly directed, static C TL response in a patient with rapidly progressive disease. We also show tha t disease progression can occur in the presence of persistent memory CTL re cognition of autologous epitopes and in the absence of detectable escape fr om CTL responses, consistent with an in vivo defect in activation of CTL.