An early antigen-presenting cell defect in HIV-1-infected patients correlates with CD4 dependency in human T-cell clones.

We have used a defined panel of nine HIV peptide-specific T-cell clones (TLC) generated from a healthy volunteer to evaluate the antigen-presenting cell (APC) function of human immunodeficiency virus-1 (HIV- 1)-infected patients. Peripheral blood mononuclear cells (PBMC) from HLA-matched seropositive and uninfected volunteers were compared for their capacity to present peptide to TLC specific for the V3 loop of HIV- 1 envelope glycoprotein gp120, influenza haemagglutinin or the mycobacterial 19,000 MW antigen APC from uninfected volunteers (HIV- APC) invariably presented peptides to all TLC with comparable efficiency. In contrast using APC from HIV- 1-infected subjects (HIV+ APC) three patterns of responsiveness were observed. The first group of TLC was not stimulated by HIV+ APC even early in infection. The second responded to all APC comparably. The third and intermediate group, responded to APC from some clinically asymptomatic, but not acquired immune deficiency syndrome (AIDS), patients. The two additional TLC, derived from other donors and with specificity for non-HIV peptides, showed similar variation in response to HIV+ APC. The different patterns of response to HIV APC did not correlate with the fine specificity or cytokine phenotypes of the TLC. Neither was the defect due to decreased levels of expression of APC molecules involved in delivering the first or second signal required for T-cell activation APC mixing experiments showed no evidence of APC-derived inhibitory factor. Furthermore, the defect was independent of T cells or their products and was equally expressed in monocytes and dendritic cells. Instead, responsiveness was inversely related to the degree of CD4 dependency suggesting that the underlying mechanism was a CD4 APC-associated gp120 interaction. The early appearance of this defect in HIV- 1 infection co-incident with the loss of recall responses is consistent with a role for APC dysfunction in pathogenesis.