HIV-1 DOWN-REGULATES CD4 COSTIMULATION OF TCR CDS-DIRECTED TYROSINE PHOSPHORYLATION THROUGH CD4/P56(LCK) DISSOCIATION/

One consequence of HIV type 1 (HIV-1) infection is the gradual loss of responsiveness of T lymphocytes to Ags both in vitro and in vivo. It has been suggested that the underlying mechanism that contributes to t his T cell dysfunction before CD4(+) cell decline involves down-regula tion of surface receptors, alterations in intracellular redox status, interference by viral Ags, and later in infection, the absence or alte ration of specific cytokine production. In this report, we demonstrate that infection of the T-lymphocytic cell line H9 with the LAI isolate of HIV-1 results in profoundly altered regulation of CD4-induced cost imulation of TCR/CD3-directed signaling. TCR/CD3-induced tyrosine phos phorylation of the intracellular enzyme phospholipase-C gamma 1 and th e surface receptor/substrates CD5 and CD6 was unaffected by virus infe ction, whereas augmented responses normally observed after the co-liga tion of CD4 with TCR/CD3 on T lymphocytes were absent in HIV-1-infecte d H9 cells. Costimulation of TCR/CD3-induced signaling via MHC class I I molecules was also down-regulated in virally infected cells. TCR/CD3 and HLA-DR receptor expression remained intact in infected cultures f or at least 3 wk, whereas CD4 surface expression was gradually lost bu t maintained for up to 1 wk, suggesting that the absence of costimulat ion early in infection was not surface receptor density-dependent. In HIV-1-infected cells, CD4 was not physically linked with its associate d tyrosine kinase p56(lck) whereas normal levels of p56(lck) were read ily recovered from the cellular cytoplasm. Similar observations were n oted in cultures of H9 cells infected with a field isolate of HIV-1 ob tained from cultured PBMC from an infected donor. HIV-1 infection of T lymphocytes thus downregulates potentially critical early signal tran sduction events by a mechanism that appears to involve interference of CD4 receptor association with p56(lck). A potential outcome of these biochemical effects may include the limited responsiveness of infected T cells to antigenic stimulation observed during HIV-1 infection.