Abstract

E-mail Abstract Author Add To Itinerary Session Search Abstracts Program

Session 70 Poster Session Thymic Function and Immune Reconstitution Session Time: 4:30-6:30 pm Room 4E-F

507-M. Dynamics of Lymphocyte Activation, Proliferation, and Death in HIV-1 Infection R. M. Ribeiro*1, H. Mohri2, D. Ho2, and A. S. Perelson1 1Los Alamos Natl. Lab., NM and 2Aaron Diamond AIDS Res. Ctr., Rockefeller Univ., New York, NY Background: A consequence of HIV-1 infection is the loss of CD4+ T cells. Several hypotheses have been proposed to explain T-cell depletion, including decreased production of T cells, increased death, or both. We used deuterated glucose labeling of T cells and modeling to show that T-cell production is not impaired and that the death rate of CD4+ T cells is increased. Methods: We analyzed data generated by in vivo D-glucose labeling of dividing lymphocytes, in 4 healthy and 7 HIV-1-infected individuals, of whom 5 were studied again after initiating HAART. To analyze the data, we developed a model for the dynamics of resting and dividing cells, which allowed us to estimate T-cell activation, proliferation, and death rates. Results: The model fits the data, showing that in HIV-1 infection, CD4+ T-cell proliferation, death, and activation rates are increased. These rates decrease after short-term HAART (1-2 months) and tend to normalize with long-term HAART (8-12 months). We obtain different results for CD4+ and CD8+ T cells. In the dividing cell population, the death rate of CD4+ T cells in HIV-1-infected individuals is increased in relation to healthy subjects (medians 0.11/day vs. 0.04/day, p=0.07), but in CD8+ T-cells this rate is not statistically different (0.03/day vs. 0.05/day, respectively). These findings are consistent with a virus-induced component in the death of CD4+ T cells. The activation rate is increased in the CD4+ T cells of infected patients (0.0051/day) vs. healthy individuals (0.0019/day, p=0.012), but such an increase is not seen in the CD8+ T-cell population (p=0.13). In contrast, the fraction of CD4+ dividing cells is not increased in infected individuals (p=0.23), indicating that these cells die too fast to allow any build-up. We also found a correlation between the estimated fraction of dividing T-cells and independent measurements of the percentage of Ki-67+ cells (p<0.007); and an inverse correlation between the fraction of dividing cells and baseline CD4+ cell count (p<0.02). Conclusions: Our results support the idea that increased activation, proliferation, and death during HIV-1 infection are the causes of CD4+ T-cell depletion. In the dividing CD8+ T-cell population, the proliferation and death rates are not different in HIV-1-infected and healthy individuals; however, the average turnover of these cells is increased in the former, because there is a larger fraction of activated CD8+ T cells.

©2002 9th Conference on Retroviruses and Opportunistic Infections