Cells infected with the human immunodeficiency virus (HIV) show decreased expression of the 58-kilodalton T4 (CD4) antigen on their surface. In this study, the effect of HIV infection on the synthesis of T4 messenger RNA (mRNA) and protein products was evaluated in T-cell lines. Metabolically labeled lysates from the T4+ cell line Sup-T1 were immunoprecipitated with monoclonal antibodies to T4. Compared with uninfected cells, HIV-infected Sup-T1 cells showed decreased amounts of T4 that coprecipitated with both the 120-kilodalton viral envelope and the 150-kilodalton envelope precursor molecules. In four of five HIV-producing T-cell lines studied, the steady-state levels of T4 mRNA were also reduced. Thus, the decreased T4 antigen on HIV-infected cells is due to at least three factors: reduced steady-state levels of T4-specific mRNA, reduced amounts of immunoprecipitable T4 antigen, and the complexing of available T4 antigen with viral envelope gene products. The data suggested that the T4 protein produced after infection may be complexed with viral envelope gene products within infected cells. Retroviral envelope-receptor complexes may thus participate in a general mechanism by which receptors for retroviruses are down-modulated and alterations in cellular function develop after infection.

The proliferation of non-neoplastic

The bcl-2 and c-myc proto-oncogenes are brought into juxtaposition with the immunoglobulin heavy chain locus in particular B-cell lymphomas, resulting in high levels of constitutive accumulation of their messenger RNAs. Precisely how the products of the bcl-2 and c-myc genes contribute to tumorigenesis is unknown, but observations that c-myc expression is rapidly induced in nonneoplastic lymphocytes upon stimulation of proliferation raise the possibility that this proto-oncogene is involved in the control of normal cellular growth. In addition to c-myc, the bcl-2 proto-oncogene also was expressed in normal human B and T lymphocytes after stimulation with appropriate mitogens. Comparison of the regulation of the expression of these proto-oncogenes demonstrated marked differences and provided evidence that, in contrast to c-myc, levels of bcl-2 messenger RNA are regulated primarily through transcriptional mechanisms.

Aberrant expression of the c-myc gene results from nonrandom chromosomal translocations involving the transcriptionally active antigen receptor gene loci, in particular lymphocytic leukemias and lymphomas, and is believed to contribute to the etiology of these neoplasms. In addition to its expression in abnormal lymphocytes, increased accumulation of c-myc mRNA occurs rapidly in normal B-and T-lymphocytes after stimulation with appropriate mitogens. The mechanisms that mediate these mitogeninduced elevations in c-myc mRNA levels, however, have not been determined for normal B and T cells. By using enriched populations of B-and T-lymphocytes obtained from freshly isolated human tonsils and stimulated with Staphylococcus-A or with phytohemagglutinin, respectively, we observed marked elevations (20-40-fold) in the steady state levels of accumulated cmyc messenger RNA (mRNA) within I h of exposure of cells to mitogens; modest increases (three-to fivefold) in the relative rate of transcription of the c-myc gene through protein synthesisindependent (cycloheximide-insensitive) mechanisms; and rapid rates of degradation of mature c-myc mRNAs through protein synthesis-dependent (cycloheximide-sensitive) mechanisms. These findings corroborate previous studies in other cell types and provide evidence for both transcriptional and posttranscriptional control of c-myc proto-oncogene expression in normal human lymphocytes.

Here we demonstrate that CsA and DEX, at concentrations that markedly inhibited PHA-induced proliferation and IL 2 mRNA accumulation, partially diminished the expression of receptors for IL 2 on PBMC. This inhibition of IL 2 receptor expression occurred at a pretranslational level and involved a reduction in both high affinity and low affinity forms of the receptor. Although both CsA and DEX inhibited IL 2 receptor expression by about 50%, only CsA blocked the PHA-mediated induction of IL 2 responsivity in PBMC cultures. These data provide evidence that 1) CsA and DEX suppress the proliferation of T lymphocytes through distinct (though perhaps overlapping) mechanisms, 2) CsA (but not DEX) blocks the PHA-mediated induction of signals necessary for T cells to become capable of proliferating in response to IL 2, and 3) T cells regulate the expression of their genes for IL 2 and IL 2 receptors, at least in part, through independent mechanisms.