Analysis of host-virus interactions in AIDS with anti-gp120 T cell clones: Effect of HIV sequence variation and a mechanism for CD4⁺ cell depletion

The primary human T cell response to HIV was analyzed by isolating from seronegative donors T cell clones specific for HIV gp120. T cell epitopes restricted by different MHC elements were identified within gp120, and synthetic peptides were used to address the fundamental problem of how HIV sequence variability affects T cell recognition. Even one conservative substitution can drastically reduce recognition; thus the interaction of gp120 epitopes with T cell receptors and MHC is precise and poorly cross-reactive. Importantly, a subset of CD4⁺ gp120-specific clones manifest cytolytic activity and lyse uninfected autologous CD4⁺Ia⁺ T cells in the presence of gp120 in a process that is strictly dependent upon CD4-mediated uptake of gp120 by T cells. Assuming gp120 is shed from HIV-infected cells in vivo, this novel CD4-dependent autocytolytic mechanism may contribute to the profound depletion of CD4⁺ cells in AIDS.