Variable immortalizing potential and frequent virus latency in blood-derived T-cell clones infected with human T-cell...

Human T-cell leukemia virus type I (HTLV-I)-infected T cells expanded in vitro by single-cell cloning provide a unique system for investigating virus-cell interactions in nonimmortalized T cells. By analysis of clones generated randomly from the blood of virus carriers, we confirm that CD4 T cells are the major reservoir of HTLV-I in vivo and show that most infected cells contain a single integrated provirus. Contrary to the situation in HTLV-I immortalized cell lines, the HTLV-I provirus was found to be transcriptionally silent in a high proportion of randomly generated T-cell clones and could not be reactivated by mitogenic stimulation. The spontaneous proliferation previously documented in HTLV-I-infected T-cell clones was not observed in silently infected cells, and therefore correlates directly with the expression of tax and other viral genes. The only cytokine mRNA found to be significantly elevated in the virus-producing clones was interleukin-6; however, receptor-blocking experiments argue against a role for IL-6 in the virus-induced cell proliferation. We observed a striking variation in the ability of individual HTLV-I-producing clones to immortalize fresh peripheral blood lymphocytes. This ability did not correlate with the levels of viral mRNA expression, gag p24 production, spontaneous proliferation, or tax-transactivation, possibly suggesting a role for host cell factors as determinants of viral infectivity or immortalization. Studies to elucidate the basis of this phenotypic heterogeneity should enhance our understanding of viral spread and pathogenesis.