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

The initial idea that high amounts of cytopathic virus produced everyday ca n drive high CD4(+) T cell production seemed logical and explained the prog ressive CD4(+) T cell depletion observed in HIV-infected subjects. It was h ypothesized that the CD4(+) T lymphocyte production was increased up to 70- fold in HIV-infected subjects. Determination of the CD4(+) T cell productio n 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 representativ e of the lymph node T cells; and (2) the lack of estimates of CD4(+) T lymp hocyte turnover in healthy HIV-negative subjects. Several immunologists hav e expressed caution regarding the assumptions used in modeling CD4(+) T cel l dynamics. Recent findings clearly show that blood is not representative o f lymphoid tissues. Indeed, when blood and lymph node compartments are cons idered together, we find that HIV-infected subjects naive to antiretroviral treatment have similar or lower CD4(+) T cell production, as compared to h ealthy subjects. This observation suggests an impaired T cell renewal capac ity in HIV-1 infected patients. Furthermore, the initial rise observed in b lood CD4(+) T cells of patients under HAART might not necessarily reflect n ewly 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 r edistribution from peripheral tissues. to blood and not T cell proliferatio n. In addition, immunophenotyping shows that the T cell increases during ea rly HAART therapy are restricted to memory populations. In contrast, the na ive T cell population does not immediately respond to HAART, their numbers in blood increase only after weeks of therapy. Based on those results, ther e is no evidence for an increased CD4(+) T cell production in HIV-infected subjects and therefore, CD4(+) T cell depletion cannot be explained by exha ustion of T cell renewal due to virus-induced cell destruction. After initi ation of HAART, naive CD4(+) T cell number slowly increases over a six mont h 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 o f the disease and therapy may indeed allow for T cell reconstitution.