New insights on CD4+ T cell turnover in HIV-1 infection

The initial idea that high amounts of cytopathic virus produced everyday can drive high CD4(+) T cell production seemed logical and explained the progressive CD4(+) T cell depletion observed in HIV-infected subjects. It was hypothesized that the CD4(+) T lymphocyte production was increased up to 70-fold in HIV-infected subjects. Determination of the CD4(+) T cell production was based on the kinetics of CD4(+) T cell recovery following initiation of highly-active antiretroviral therapy (HAART). However, this analysis was limited by: (1) the assumption that blood CD4(+) T cells are representative of the lymph node T cells; and (2) the lack of estimates of CD4(+) T lymphocyte turnover in healthy HIV-negative subjects. Several immunologists have expressed caution regarding the assumptions used in modeling CD4(+) T cell dynamics. Recent findings clearly show that blood is not representative of lymphoid tissues. Indeed, when blood and lymph node compartments are considered together, we find that HIV-infected subjects naive to antiretroviral treatment have similar or lower CD4(+) T cell production, as compared to healthy subjects. This observation suggests an impaired T cell renewal capacity in HIV-1 infected patients. Furthermore, the initial rise observed in blood CD4(+) T cells of patients under HAART might not necessarily reflect newly formed CD4(+) T cells. Indeed, the rapid increase in CD4(+) T cells in the blood observed shortly after initiation of HAART is caused by T cell redistribution from peripheral tissues. to blood and not T cell proliferation. In addition, immunophenotyping shows that the T cell increases during early HAART therapy are restricted to memory populations. In contrast, the naive T cell population does not immediately respond to HAART, their numbers in blood increase only after weeks of therapy. Based on those results, there is no evidence for an increased CD4(+) T cell production in HIV-infected subjects and therefore, CD4(+) T cell depletion cannot be explained by exhaustion of T cell renewal due to virus-induced cell destruction. After initiation of HAART, naive CD4(+) T cell number slowly increases over a six month period followed by a stabilization. The mechanism of renewal of CD4(+) T cells is, thus, still intact in HIV-infected subjects in the early stages of the disease and therapy may indeed allow for T cell reconstitution.