421   IL-12 and Immune Activation in Early HIV Infection.

A. A. Byrnes*¹, D. Harris¹, B. Sabundayo¹, J. Margolick¹, and C. L. Karp¹.
¹Johns Hopkins Univ., Baltimore, MD and²Children's Hosp. Res. Fndn., Cincinnati, OH.

Background:Despite considerable literature on the immunology of chronic HIV infection, little is known about immunological events occurring in the very early stages of infection. Production of IL-12 is impaired in chronic HIV infection. As IL-12 is a cytokine central to the regulation of cellular immunity, this is thought to contribute to the immunosuppression associated with HIV infection. Both the underlying mechanism and the timing of the onset of IL-12 impairment have remained unclear. We examined the production of IL-12 and other immunoregulatory cytokines, along with a panel of non-specific immune activation markers, in early HIV infection (<1 year from seroconversion), both in the presence and in the absence of HAART.

Methods:PBMC and plasma were collected from 30 infected participants in the Acute Infection and Early Disease Research Project (AIEDRP), along with 12 healthy controls. IL-12 was measured both by FACS and in the supernatants of bacterially stimulated PBMC. IL-12, along with soluble markers of immune activation, was also measured in plasma. Comparisons between patients and controls were analyzed by the Mann-Whitney test; differences over time in the same donor were analyzed by the Wilcoxon signed rank test.

Results:In vitro production of IL-12 by PBMC (a) was not impaired in the subjects with early HIV infection and (b) did not change in the first 6 months of HAART. In fact, plasma IL-12 was significantly elevated in early HIV infection (p = 0.019). Most other soluble immune activation markers (sCD8,b2-microglobulin, neopterin, sIL- 2R, TNFRI, and TNFRII, but not sCD4) were also significantly upregulated in plasma prior to HAART (p < 0.05); only sCD8,b2-microglobulin, and neopterin normalized during HAART.

Conclusion:IL-12 production is not impaired in early HIV infection. The relevance of this fact to the likely mechanism(s) underlying IL-12 impairment later in disease will be discussed. In the context of the widespread immune activation of early HIV infection, HAART-mediated suppression of viral load appears to dissociate activation of CD8 T cells from that of other compartments of the immune system.