News and Publications

Pathogenesis of AIDS-Related CNS Dysfunction

H.S. Fox, Z. Chen, T. Horn, T. Lane, A. Miller-Wing, C. Phillipson, J. Tornwall, D. Watry, M. Zandonatti

We are using infection with simian immunodeficiency virus (SIV) in Rhesus macaques as a model of AIDS. Previously we selected a neurovirulent strain of SIV by serially transferring infected microglia in vivo. The passage resulted in enrichment of a unique env quasi species in the infected brains. Studies done in collaboration with J. Nelson, Oregon Health Sciences University, indicated that serial passage also expanded the tropism of the virus to allow infection of cerebrovascular endothelial cells.

A number of infectious molecular clones of SIV constructed from virus after the third serial passage of microglia are being analyzed in vitro. The goal is to use the clones for in vivo molecular virology studies of neuropathogenesis. In collaboration with R. Doms, University of Pennsylvania, we have been characterizing the interaction of the envelope proteins encoded by these clones with the coreceptor molecules of the host cell that are essential for HIV and SIV infectivity. Interestingly, these envelope proteins can mediate fusion with the CCR5 and GPR15 coreceptors in a CD4-independent fashion. Because neurons can express coreceptors, we are investigating signaling through these coreceptors as a potential mechanism for the neurovirulence of this strain of SIV.

The neurovirulent SIV also induces functional changes in the CNS, as indicated by behavioral and electrophysiologic testing by L. Gold and S. Henriksen, Department of Neuropharmacology. Monkeys have CNS functional abnormalities as early as 1 month after infection with the virus. Radiotelemetric methods have been developed to enable remote continuous monitoring of body temperature, movement, and the respective circadian rhythms of these parameters in the animals. Acute SIV infection induces an increase in body temperature that is overlapped by a decrease in movement. The hyperthermia can persist for approximately 2 months after infection. Motor activity returns to baseline levels after the acute infection and then decreases to 50% of preinfection levels at 3 months after infection. Both the neurophysiologic abnormalities and the pathologic changes described earlier can play a role in decreased cognitive performance.

These results of early detectable neurophysiologic abnormalities after infection make the SIV model ideal for testing new therapies aimed at preventing or arresting cognitive decline induced by HIV. Although recent therapeutic advances have reduced mortality from HIV, most of the new agents do not markedly penetrate the blood-brain barrier. The CNS may remain a reservoir, and damage to the CNS may continue during the treatment-prolonged course of infection. We are using antiretroviral drugs to determine if decreasing systemic viral load in SIV-infected monkeys can prevent, reverse, or ameliorate the CNS abnormalities caused by the infection. The results will help address the issue of whether reducing the level of virus in the CNS, by using drugs with good penetration of the blood-brain barrier and no toxic CNS effects, should be an additional goal of therapy.

We are also continuing reasearch in 2 additional areas. First, we have begun a detailed molecular study of the blood-brain barrier. Novel molecules have been detected that are expressed by the specialized endothelial cells of the barrier. One of these molecules, termed MBEC1, encodes a membrane protein that is homologous to the receptor for the enterotoxin of Clostridium perfringens and is developmentally regulated. Further characterization of this and other novel molecules detected should lead to a better understanding of the role of the blood-brain barrier in normal physiologic conditions and in disease.

Second, we have long been interested in the sexual dimorphism of autoimmunity. We have begun studies in which nonobese diabetic mice are used as a model of Sjögren's syndrome, an autoimmune disease that affects the salivary and lacrimal glands of postmenopausal women. We found that the expression of 2 chemokines, IP-10 and RANTES, is associated with lymphocytic infiltration of the lacrimal glands in these mice. Because chemokines are the main stimulus for leukocyte diapedesis, most likely these molecules contribute to site-specific and selective recruitment of lymphocytes into lacrimal glands, leading to the destruction of glandular structures.

PUBLICATIONS

Chen, Z., Zandonatti, M., Jakubowski, D., Fox, H.S. Brain capillary endothelial cells express MBEC1, a protein that is related to the Clostridium perfringens enterotoxin receptors. Lab. Invest. 78:353, 1998.

Fox, H.S., Gold, L., Henriksen, S., Bloom, F. Simian immunodeficiency virus: A model for neuroAIDS. Neurobiol. Dis. 4:265, 1997.

Gold, L.H., Fox, H.S., Henriksen, S.J., Buchmeier, M.J., Weed, M.R., Taffe, M.A., Huitron-Resendez, S., Horn, T.F.W., Bloom, F.E. Longitudinal analysis of behavioral, neurophysiological, viral and immunological effects of SIV infection in Rhesus monkeys. J. Med. Primatol., in press.

Lee, T., Laco, G.S., Torbett, B.E., Fox, H.S., Lerner, D.L., Elder, J.H., Wong, C.H. Analysis of the S3 and S3´ subsite specificities of feline immunodeficiency virus (FIV) protease: Development of a broad-based protease inhibitor efficacious against FIV, SIV, and HIV in vitro and ex vivo. Proc. Natl. Acad. Sci. U.S.A. 95:939, 1998.

Strelow, L.I., Watry, D.D., Fox, H.S., Nelson, J.A. Efficient infection of brain microvascular endothelial cells by an in vivo-selected neuroinvasive SIVmac variant. J. Neurovirol., in press.