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

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

Ivona Pandrea, C Coleman, T Gaufin, R Gautam, M Pattison, C Monjure, A Lackner, and C Apetrei
Tulane Natl Primate Res Ctr, Tulane Univ, Covington, LA, US

BACKGROUND: Immune activation levels were reported to be the best predictor of disease progression in HIV-infected patients. However, there is no direct proof that induction of immune activation during chronic HIV/simian immunodeficiency virus (SIV) infection increases viral replication and results in disease progression. African non-human primates do not progress to AIDS and show low levels of immune activation during SIV infection. To investigate if immune activation levels drive SIV replication and disease progression, we experimentally induced immune activation in SIV_agm-infected African green monkeys. All previous attempts to increase the levels of immune activation/viral replication in natural hosts of SIV have been unsuccessful.

METHODS: We treated 4 SIV_agm-infected African green monkeys with ONTAK (Denileukin Diftitox) during chronic infection (day 600 post-infection) to deplete CD4+CD25+ T regulatory cells (Treg). The drug was administered to each animal for 5 consecutive days. We administered 3 treatments every 2 months. The dynamics of viral load were measured by real-time polymerase chain reaction (PCR). Major T cell populations and subsets were measured by flow-cytometry and the dynamics of pro-inflammatory cytokines in plasma was quantified by Luminex.

RESULTS: ONTAK did not induce a reduction in the number or function of Treg in chronically SIV-infected African green monkeys. However, ONTAK administration induced a significant increase in immune activation in all animals during the 3 treatments, as illustrated by the increases in -DR and CD69 expression on both CD4+ and CD8+ T cells. Increased CD4+ T cell proliferation (Ki-67) was also observed, resulting in significant increases in the pool of peripheral CD4+ T cells. Furthermore, significant increases in the levels of pro-inflammatory cytokines were observed after ONTAK administration. These changes persisted for 3 weeks after the initiation of each treatment and resulted in significant increases (2 to 4 log) in viral load in all animals. The peak of viral load post-ONTAK treatment reached the same levels as observed during acute infection.

CONCLUSIONS: We report the first successful experiment aimed at inducing immune activation in a natural host of SIV. Also, our results provide for the first time compelling proof-of concept that induction of immune activation during chronic SIV infection results in significant increases in viral replication, thus supporting the concept that immune activation is a key factor in disease progression during HIV/SIV infection.

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2008-02-03
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