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Session 26 Oral Abstracts
Retroviral Pathogenesis
Wednesday, 10 am - 12:30 pm
Presentation Time: 12:00 pm
Room 2005


129
Modeling T-cell Labeling with BrdU in SIV-infected Sooty Mangabeys
R M Ribeiro*1, M Di Mascio2, H M McClure3, R P Johnson4, A Kaur4, and A S Perelson5
1Univ. of Oxford, UK; 2NIAID, NIH, DHHS, Bethesda, MD, USA; 3Yerkes Natl. Primate Res. Ctr., Atlanta, GA, USA; 4New England Regional Primate Res. Ctr., Harvard Med. Sch., Southborough, MA, USA; and 5Los Alamos Natl. Lab., Los Alamos, NM

Background:  Sooty mangabeys are natural hosts of the simian immunodeficiency virus (SIV) that do not progress to AIDS despite sustained high viral loads. Understanding the dynamics of T-lymphocyte turnover in these animals may shed light on the mechanisms of CD4+ T-cell depletion in HIV-infected humans and SIV-infected rhesus macaques.

Methods:  For 2 weeks, 6 SIV-infected and 5 uninfected sooty mangabeys were given daily BrdU intraperitoneally. BrdU incorporation in T cells was measured frequently during the labeling (first 2 weeks) and the follow-up de-labeling phase (median 10 weeks). The percentage of BrdU-labeled T cells versus time was fitted using a model of T-cell dynamics, from which we estimated the average death rate of the T-cell population.

Results:  The median plasma viral load in the infected mangabeys was 1.1´105 copies/mL of SIV RNA (range 8.27´103 to 2´105). The model fitted the data well (see 2 examples for CD4+ cells in figure below), and we estimated the death rate and fraction of dividing cells. The mean death rate for both uninfected and infected CD4+ T cells was 0.01 day-1, and for CD8+ T cells it was 0.008 day-1 and 0.009 day-1, respectively. Using the Mann-Whitney U-test, there was no statistically significant difference in the average death rate of uninfected and infected monkeys, either in the CD4+ (p = 0.53) or the CD8+ (p = 0.41) T-cell subsets. There was a good correlation between the death rate estimated in CD4+ and CD8+ T cells (r = 0.78, p = 0.008), although the former were always higher.

 

  

 

Conclusions:  In contrast to hosts with pathogenic sequelae of lentiviral infection, CD4+ and CD8+ T-cell turnover, as measured by BrdU incorporation, is not increased in SIV-infected sooty mangabeys. This suggests that the natural host and virus have co-evolved so that viral infection does not increase average CD4+ T-cell death rate despite ongoing viral replication. Understanding how this equilibrium is achieved may be relevant for HIV infection.

Keywords: T-cell dynamics; natural host; BrdU labeling