Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy

Abstract

The long-term kinetics of T cell production following highly active antiretroviral therapy (HAART) were investigated in blood and lymph node in a group of HIV-infected subjects at early stage of established infection and prospectively studied for 72 wk. Before HAART, CD4 and CD8 T cell turnover was increased. However, the total number of proliferating CD4 ؉ T lymphocytes, i.e., CD4 ؉ Ki67 ؉ T lymphocytes, was not significantly different in HIV-infected (n ‫؍‬ 73) and HIV-negative (n ‫؍‬ 15) subjects, whereas proliferating CD8 ؉ Ki67 ؉ T lymphocytes were significantly higher in HIV-infected subjects. After HAART, the total body number of proliferating CD4 ؉ Ki67 ؉ T lymphocytes increased over time and was associated with an increase of both naive and memory CD4 ؉ T cells. The maximal increase (2-fold) was observed at week 36, whereas at week 72 the number of proliferating CD4 ؉ T cells dropped to baseline levels, i.e., before HAART. The kinetics of the fraction of proliferating CD4 and CD8 T cells were significantly correlated with the changes in the total body number of these T cell subsets. These results demonstrate a direct relationship between ex vivo measures of T cell production and quantitative changes in total body T lymphocyte populations. This study provides advances in the delineation of the kinetics of T cell production in HIV infection in the presence and͞or in the absence of HAART.

Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4 + and CD8 + T cell turnover in HIV-infected patients

“…Our results are consistent with a number of studies finding 2-to 6-fold higher CD4 ϩ and CD8 ϩ T cell proliferation in subjects with HIV or simian immunodeficiency virus infection (9)(10)(11)(12)(13)(15)(16)(17)(18)(19), suggesting a global activation of the immune system caused by HIV͞simian immunodeficiency virus replication. Our longitudinal studies showing declines in both fractional and absolute T cell proliferation after initiation of HAART and increases after cessation of HAART in parallel to changes in viral load clearly show that T cell proliferation is directly correlated with viral replication.…”

“…Our longitudinal studies showing declines in both fractional and absolute T cell proliferation after initiation of HAART and increases after cessation of HAART in parallel to changes in viral load clearly show that T cell proliferation is directly correlated with viral replication. These results are supported by some studies with Ki-67 (10,17), however, other studies have data to the contrary (14,15,18,19), and suggest that HIV replication blocks the ability of new CD4 ϩ T cells to regenerate. A major reason for these discrepancies may be the inherent differences between longitudinal as opposed to crosssectional studies.…”

“…Studies of lymphocyte turnover derived through analysis of immediate changes in CD4 ϩ T cell counts in the blood after highly active antiretroviral therapy (HAART) also led to estimates of high rates of CD4 turnover (2)(3)(4), although others have suggested that lymphocyte redistribution may be the major cause for CD4 increases immediately after HAART (5)(6)(7)(8). Measurements of lymphocyte proliferation using Ki-67, BrdUrd, and 2 H-glucose have yielded varying results (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19); however, the general consensus is that T cell proliferation is increased in HIV͞simian immunodeficiency virus-infected subjects. Variations in these studies may be caused by the difference in sample numbers, cross-sectional versus longitudinal studies, patient cohort composition, and whether one is measuring the absolute or fractional level of cell division.…”

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

“…This conclusion is supported by the fact that successful ART treatment, and consequent control of HIV-1 replication, results in a drop in proliferating T cells, despite slow recovery of CD4 + T cells, indicating that increased CD8 + T cell proliferation is driven by HIV-1 replication (41-43). This conclusion is further supported by the fact that the increased turnover of T cells observed during chronic HIV-1 infection is driven by HIV-1-associated immune activation (41,44,45), and this increased T cell turnover is observed in blood and lymph nodes of HIV-1 patients (44,(46)(47)(48)(49). Furthermore, CD8 + T cells show evidence of increased proliferation during HIV-1 infection (50).…”

RACK1 inhibits colonic cell growth by regulating Src activity at cell cycle checkpoints

“…For the analysis of Ki-67 expression (Fleury et al, 2000), 10 6 asynchronous HT-29 transfectants were fixed in 70% ethanol, collected by low-speed centrifugation, resuspended in phosphate-buffered saline (PBS) containing fluorescein isothiocyanate (FITC)-conjugated anti-Ki-67 or mouse IgG1, and incubated for 30 min at room temperature in the dark according to the manufacturer's protocol (Pharmingen) before staining with propidium iodide (PI; Sigma, St Louis, MO, USA). Cells (10 4 ) were analysed by FACScan cell sorting (Becton Dickinson, San Jose, CA, USA).…”