Human herpesvirus-6 (HHV-6), the etiologic agent of roseola, is ubiquitous, establishes latency in the host, and can infect a variety of immunocompetent cells, with CD4+ T lymphocytes being the targets in which it replicates most efficiently. The present study was undertaken to learn more about specific immunobiologic effects of HHV-6 infection on T-lymphocyte functions. Our data demonstrate that infection of peripheral blood mononuclear cells (PBMC) by HHV-6 results in suppression of T-lymphocyte functions, as evidenced by reduced interleukin-2 (IL-2) synthesis and cellular proliferation. In fact, HHV-6-infected PBMC secreted 50% less IL-2 than mock-infected cells after mitogenic stimulation with OKT3 antibody or phytohemmaglutinin (PHA). The inhibition of IL-2 by HHV-6 was also observed in enriched T-cell cultures, suggesting a direct effect of this virus on this cell type. Messenger RNA (mRNA) analysis by reverse-transcriptase polymerase chain reaction (PCR) indicated that HHV-6 diminishes IL-2 mRNA levels in mitogen-stimulated peripheral blood T cells. These results were also confirmed by Northern blot using the leukemic T-cell line Jurkat. This inhibitory effect of HHV-6 did not require infectious virus, as the use of UV-irradiated HHV-6 produced similar results. Moreover, HHV-6-infected PBMC showed up to an 85% reduction in their mitogen-driven proliferative response, as compared with sham-infected cells. Proliferation of both CD4+ and CD8+ T cells was affected by HHV-6. Taken together, our data show that infection of T cells by HHV-6 results in immune suppression characterized by a downregulation of IL-2 mRNA and protein synthesis accompanied by diminished cellular proliferation.