15th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 3-6, 2008

Conf Retrovir Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 21bLB)

Nichole Klatt ^1,2, E Shudo³, A Ortiz¹, J Engram¹, S Gordon^1,2, B Lawson², J Else², J Schmitz⁴, A Perelson³, and G Silvestri^1
1Univ of Pennsylvania, Philadelphia, US; ²Yerkes Natl Primate Res Ctr, Emory Univ, Atlanta, GA, US; ³Los Alamos Natl Lab, NM, US; and ⁴Beth Israel Deaconess Med Ctr, Boston, MA, US

BACKGROUND: While CD8+ T cell responses appear to be important in controlling virus replication during HIV/simian immunodeficiency virus (SIV) infection, the role of these responses in protecting from disease progression remains controversial. The failure of a cytotoxic T lymphocyte (CTL) -inducing, AdHu5-based AIDS vaccine in a large phase IIb clinical trial emphasizes the importance of better understanding the role of HIV/SIV-specific CTL responses. In this study, we sought to determine the in vivo effect of CD8+ T cells on the average lifespan of infected cells during SIV infection of rhesus macaques, by treating 2 groups of animals (i.e., CD8+ T cell depleted or controls) with potent ART.

METHODS: We treated 2 groups of 5 SIV_mac239-infected rhesus macaques with PMPA [(R)-9-(2-phosphonylmethoxypropyl)adenine] and emtricitabine (FTC) (30 mg/kg each for 30 days) starting at day 63 post inoculation; 1 group of animals was CD8+ T cell depleted (OKT8F monoclonal antibody, 5 mg/kg/day for 3 days) immediately prior to initiation of ART. The life span of infected cells in vivo—in the presence and absence of CD8+ T cells—was estimated by fitting the observed 2-phase viral decline to a mathematical model.

RESULTS: Treatment with OKT8F induced severe depletion of CD8+ T cells in all examined tissues (99.84% in blood and >95% in mucosal tissues) with a nadir observed 6 days after treatment. Antiretroviral therapy caused a rapid and significant decline in viral load, with an observed reduction in the range of 2 to 3 logs in 9 out of 10 animals. The mathematical model indicated that for the 9 responding animals d, the death rate of productively infected CD4+ T cells was the same for the two groups and m, the death rate of long-lived cells, was not significantly different between the groups regardless of CD8+ T cell depletion.

CONCLUSIONS: During pathogenic SIV_mac239 infection of rhesus macaques the in vivo lifespan of infected cells is similar in the presence or absence of CD8+ T cells. These data suggest that CTL do not have a major impact in determining the lifespan of infected cells during pathogenic SIV infection of rhesus macaques.

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2008-02-03
21bLB

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