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

Using the lymphocytic choriomeningitis virus (LCMV) model in mice, a number of studies show that memory cytotoxic T-lymphocyte (CTL) responses are maintained in the presence of continuous antigenic stimulation. Yet, other groups found that memory CTL specific for LCMV could last for a lifetime in mice without viral antigens. Thus, the extent to which an antigen is required for the maintenance of virus-specific CTL remains controversial. In humans, very few studies have been conducted to investigate the relationship between the quantity of antigen and the magnitude of CTL responses.

We quantified CTL precursors (CTLp) using a limiting-dilution analysis (LDA) and CTL effectors (CTLe) using a new Major Histocompatibility Complex (MHC) class I tetramer technology in six long-term nonprogressors (LTNPs) with human immunodeficiency virus type-1 (HIV-1) infection, 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. The proviral DNA load in peripheral blood mononuclear cell (PBMC) was also measured by PCR in four LTNPs.

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 loads, patients whose plasma viremia was well-suppressed by effective therapy had low levels of CTLe.

Our findings suggest that a complex, rather than a monotonic, relationship exists between CTL levels and HIV-1 viremia, including what appears to be an antigenic threshold for the maintenance of CTL at a measurable level. Under conditions of "antigen excess,", CTLe levels correlate inversely with viral load. On the other hand, under conditions that are "antigen limited," the correlation appears to be direct.