An antigenic threshold for maintaining human immunodeficiency virus type 1-specific cytotoxic T lymphocytes

Background: Using the lymphocytic choriomeningitis virus (LCMV) model in mi ce, a number of studies show that memory cytotoxic T-lymphocyte (CTL) respo nses are maintained in the presence of continuous antigenic stimulation. Ye t, other groups found that memory CTL specific for LCMV could last for a li fetime in mice without viral antigens. Thus, the extent to which an antigen is required for the maintenance of virus-specific CTL remains controversia l. In humans, very few studies have bren conducted to investigate the relat ionship between the quantity of antigen and the magnitude of CTL responses. Materials and Methods: We quantified CTL precursors (CTLp) using a limiting -dilution analysis (LDA) and CTL effectors (CTLe) using a new Major Histoco mpatibility Complex (MHC) class I tetramer technology in six long-term nonp rogressors (LTNPs) with human immunodeficiency virus type-1 (HIV-1) infecti on, as well as in eight patients whose viral loads were well suppressed by antiretroviral therapy. The viremia levels in these patients were measured using an reverse transcription polymerase chain reaction (RT-PCR) assay. Th e proviral DNA load in peripheral blood mononuclear cell (PBMC) was also me asured by PCR in four LTNPs. Results: The LTNPs had high levels of HIV-1-specific memory CTLp and CTLe, while maintaining a low plasma viral load. Despite also having low viral lo ads, patients whose plasma viremia was well-suppressed by effective therapy had low levels of CTLe. Conclusions: Our findings suggest that a complex, rather than a monotonic, relationship exists between CTL levels and HIV-1 viremia, including what ap pears to be an antigenic threshold for the maintenance of CTL at a measurab le level. Under conditions of "antigen excess,", CTLe levels correlate inve rsely with viral load. On the other hand, under conditions that are "antige n limited," the correlation appears to be direct.