SIV Infection Of Natural Hosts Provides New Insights Into HIV Disease Complexity

Don Sodora, Ph.D., a principal investigator in SBRI's Viral Vaccines Program who recently joined SBRI from the University of Texas, Southwestern Medical Center, is senior author on one of three papers that collectively show CD4 T-cell depletion, a critical symptom of AIDS, is likely a part of a multifaceted scenario that triggers disease rather than the only cause.

In an HIV-infected person, CD4 T-cells (white blood cells that play a central role in creating immunity) decline and, at a certain point, the person gets sick and dies. This rapid and dramatic loss of CD4 T-cells is considered to be a key determinant of AIDS disease. However, in natural hosts, like the sooty mangabey (an African monkey species), simian immunodeficiency virus (SIV) induced CD4 T-cell depletion can be comparable to that in humans, but the monkeys do not show clinical signs of AIDS. "Our assessment of these natural hosts like mangabeys offers insight into the disease and shows us that progression to AIDS likely results from the cumulative effects of HIV/SIV replication, CD4 T-cell depletion, generalized immune activation and non-CD4 T-cells depletion or dysfunction," said Sodora.

Sodora's paper provides evidence, using the sooty mangabey SIV natural host, that virally induced CD4 T-cell depletion, by itself, is not sufficient to induce AIDS in a natural host. "When we first observed the dramatic CD4 depletion in all the tissues we examined in these monkeys, we were concerned that they might begin to exhibit clinical signs of AIDS," said Jeffrey Milush, Ph.D., lead author on the paper. "But after more than six years, we are sure that CD4 depletion by itself does not necessarily result in progression to AIDS".

Sodora contributed to a second paper, with senior author Guido Silvestri, M.D., of the University of Pennsylvania. In a study of disease free SIV--infected sooty mangabeys, Silvestri proposes that these African monkeys preserve immune function despite a major loss of mucosal CD4 T-cells as a result of an evolutionary adaptation to reduce immune activation in response to virus replication.

The third of the three papers published this week in The Journal of Immunology, with Ivona Pandrea, M.D., Ph.D., and Cristian Apetrei, M.D., Ph.D., from Tulane University as lead authors, shows that a severe loss of intestinal CD4 T-cells in another natural host, the African green monkey, is also not predictive of SIV virulence.

"These three papers published together indicate that CD4 T-cell depletion is one part of a more complex scenario that results in the clinical signs identified as AIDS," Sodora said. "We hope that studies in these natural host models will lead to improved HIV vaccines or new therapeutics that might someday make HIV-infected people more like these disease-resistant sooty mangabeys."