The overall objective of this proposal is to test the hypothesis that lymphocyte functional maturation is suppressed in infants with congenitally acquired HIV+ infection and that this deregulation is directly associated with increased levels of prostaglandin E2, PGE2. Despite major advances in HIV viruses molecular biology, key information on host interaction has been elusive. While measurement of CD4+ T cell count has been shown to have significant validity in adults, this is not the case for HIV+ infants. Opportunistic infections can develop in children with normal T lymphocyte subset number and in the absence of an inverted CD4/CD8 ratio. In our patient population 28% of HIV+ infants have developed an AIDS defining illness before the CD4/CD8 ratio fell below 1.0 and 18% before a fall in CD4+ T cells below 1000 occurred. Thus the basis of vulnerability to infection cannot be only quantitative loss of CD4+ T cells in HIV+ infants. Preliminary data show that infants with conserved CD4+ T cells, can have low or absent NK cell activity. Comparison with age matched non exposed infants showed significantly reduced NK cell activity (p<.01) and reduced response to interferon (p<0.01). In parallel studies, we found elevated serum levels of prostaglandin E2, PGE2, a known negative regulator of NK cell activity and correlation with reduced expression of the Interleukin-2, IL-2 receptor in response to IL-2 in vitro. Infants showed expansion of CD8+ T cells coexpressing CD38+, a normal fetal phenotype that appears to have suppressor activity.
The specific aims of this proposal are: 1) To study alterations in the cytokine network, specifically Interleukin-2, IL-2, and interferon(gamma), INF(gamma), in relationship to serum levels of prostaglandin E2, PGE-2. 2) To evaluate the prognostic significance of NK cell activity in HIV exposed neonates as ability to kill K562 and U937 in comparison with killing of the chronically HIV infected U1 cell lines. 3) To examine the role of expanded CD8+ T cells as possible suppressors of lymphocyte functional development. These studies appear to identify a critical network of interactions which normally develops postnatally.
| Cunningham-Rundles, Susanna; Ahrn, Siv; Abuav-Nussbaum, Rachel et al. (2002) Development of immunocompetence: role of micronutrients and microorganisms. Nutr Rev 60:S68-72 |
