10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 35
R. Draenert¹ , Y. Tang¹, C. Verrill¹, A. Wurcel^1,2, M. Boczanowski¹, A. Rathod¹, M. Addo¹, B. Walker^1
1Partners AIDS Res Ctr, Boston, MA and ²Lemuel Shattuck Hosp, Jamaica Plain, MA

BACKGROUND: CD8 T-cell responses are thought to be critical for control of HIV infection. While these responses have been extensively studied in long-term non-progressors and patients (pts) with acute HIV infection, the extent and function of CD8 T-cell responses in chronically HIV-1 infected individuals in later stages of disease progression has not been well characterized with the more sensitive assay techniques now available.

METHODS: We studied a cohort of chronically HIV-1 infected, untreated individuals with late stage HIV infection. The mean viral load was 186,271 cp/ml (range 4,210 to > 750,000 cp/ml) and the mean CD4 count 141/ul (range 0 to 629/ul). Screening for CD8 T-cell responses by interferon-gamma Elispot assay was performed using a set of overlapping peptides spanning all expressed HIV-1 proteins. Flow cytometry was used for intracellular cytokine staining (ICS) and phenotypic analysis. Selected viral regions were sequenced based on RT-PCR from patient plasma.

RESULTS: Of the 30 persons tested, all but one had detectable CD8 T-cell responses (mean 20, range 0-56). By comparison to 25 persons who successfully controlled viremia without antiviral therapy, there was a substantial overlap in both breadth and magnitude of responses. However, breadth and magnitude in these persons with late stage disease correlated with viral load (inversely) and CD4 count, albeit weakly (r = -0.67, p = 0.01 and r = 0.65, p = 0.009, respectively). So far, sequence analysis of 13 single responses showed no evidence of escape mutation for 9 of them. Most of the HIV specific CD8 T-cell responses included a low percentage of mature effector cells of the CD45RA⁺CCR7- phenotype (0%-15%). However, in some persons, and for some epitopes, mature effector cells ranged as high as 38%.

CONCLUSIONS: Unexpectedly broad and strong IFN-gamma⁺ CD8 T-cell responses persist despite progressive chronic HIV infection with high viral loads and low CD4 counts. The lack of viral escape coupled with defects in full maturation suggest that in vivo defects in CD8 T-cell function play a major role in lack of efficacy in this cohort.

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