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Elevated Vascular Cell Adhesion Molecule-1 in AIDS Encephalitis Induced by Simian Immunodeficiency Virus

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Elevated Vascular Cell Adhesion Molecule-1 in AIDS Encephalitis Induced by Simian Immunodeficiency Virus American Journal ofPathology, Vol. 141, No. 5, November 1992 Copyright © American Association ofPathologists Short Communication Elevated Vascular Cell Adhesion Molecule-1 in AIDS Encephalitis Induced by Simian Immunodeficiency Virus Vito G. Sasseville,* Walter A. Newman,t nervous system, and this expression may, at least in Andrew A. Lackner, Mary 0. Smith,11 part, influence monocyte and lymphocyte recruit- Niels C. G. Lausen,* Dawson Beallt and ment to the central nervous system during the devel- Douglas J. Ringler* opment of AIDS encephalitis. Moreover, measure- From the Harvard Medical School, New England Regional ment of soluble VCAM-1 in CSF may assist in the Primate Research Center, Southborough, Massachusetts, clinical assessment of animals or people with AIDS. Otsuka America Pharmaceutical, Inc.,t Rockville, Maryland, (AmJPathol 1992, 141:1021-1030) New Mexico State University,* New Mexico Regional Primate Research Laboratory, Holloman Air Force Base, New Mexico, and the University of California,1I California Regional One of the most devastating manifestations of HIV-1 in- Primate Research Center, Davis, California fection involves an inflammatory disease of the central nervous system (CNS), referred to as AIDS encephalitis, AIDS encephalopathy, HIV encephalitis, or AIDS demen- AIDS encephalitis is a common sequela to HIV-1 in- tia complex.1" This disorder is characterized by multifo- fection in humans and simian immunodeficiency vi- cal gliosis and parenchymal infiltrates of multinucleate rus (SlVmac) infection in lenti- macaques. Although giant cells and macrophages.1 2.4 Many of the macro- viral-infected macrophages comprise parenchymal phages comprising these infiltrates contain HIV-1 protein, inflammatory infiltrates in affected brain tissue, the viral nucleic acid transcripts, and mature virions.35 8 In mechanisms responsible for leukocyte trafficking to addition, as these histologic changes are not associated the central nervous system in AIDS are unknown In with secondary opportunistic pathogens, it is believed this study, we investigated the expression of various that HIV encephalitis represents a primary lentiviral dis- endothelial-derived leukocyte adhesion in proteins ease manifestation. SIVmac-induced AIDS encephalitis. Encephalitic Not all patients infected with HIV-1 develop enceph- brains from SIVmac-infected but not un- macaques, alitis. Approximately 50% of patients infected with HIV-1 inflamed brains from other SlVmac-infected ani- have histologic evidence of AIDS encephalitis at the time mals; were found to express abundant vascular cell of postmortem examination.1' 2'49 Similarly, approxi- adhesion molecule-i (VCAM-1) protein on the ma- mately 50% of rhesus monkeys experimentally infected jority of arteriolar, venular, and capillary endothe- with simian immunodeficiency virus (SlVmac) develop lial cells. Soluble VCAM-1 concentrations in cerebro- an encephalitis similar to that seen in humans with spinal fluid (CSF) from encephalitic animals were increased approximately 20-fold above those from Supported by Public Health Service awards Al 29855, Al 25644, RR animals without AIDS encephalitis. Expression of 00168, RR 00169 and 5T32RR07000 from the National Institutes of other endothelial-related adhesion molecules, in- Health. A. Lackner was supported by a Public Health Service special cluding E-selectiny P-selectin, and intercellular adhe- emphasis research career award in laboratory animal science from the sion molecule-I (ICAM-1), was not uniformly asso- National Center for Research Resources (RR 0039). Accepted for publication July 24, 1992. ciated with AIDS encephalitis. Thus, the presence of Address reprint requests to Dr. Douglas J. Ringler, Harvard Medical VCAM-1 in both brain and CSF was uniformly asso- School, New England Regional Primate Research Center, P.O. Box 9102, ciated with SlVmac-induced disease of the central Southborough, MA 01772-9102. 1021 1022 Sasseville et al AJP November 1992, Vol. 141, No. 5 AIDS.""12 SlVmac and HIV-1 share extensive sequence expression of E-selectin and VCAM-1 on resting endot- homology and have similar genomic organization, mor- helium. 19,20'28'38'39 In contrast, ICAM-1 and P-selectin phology, and biologic properties.1315 Most importantly, are basally expressed on endothelium in many tis- SlVmac-infected macaques develop immunodeficiency sues.17'31'36 Inasmuch as leukocyte-endothelial adhe- and a clinical syndrome identical in many ways to AIDS in sion is requisite for vascular extravasation of leuko- humans. Thus, SlVmac-infected rhesus monkeys repre- cytes,40 homing of specific leukocyte cell types to the sent a useful model to study the pathogenesis of HIV CNS may be controlled by different endothelial expres- encephalitis and other AIDS-related sequelae. sion of these leukocyte adhesion molecules. We have previously suggested that in simian AIDS, In this study, we investigated the expression of leuko- the presence of viruses in vivo with replicative potential cyte adhesion molecules in SlVmac-induced AIDS en- for macrophages is essential, but not predictive, for the cephalitis. We found that encephalitic brains from SIV- development of SlVmac-induced AIDS encephalitis.16 mac-infected animals expressed abundant VCAM-1 pro- Thus, both viral and host parameters are likely involved in tein on the majority of parenchymal vessels. In addition, determining which patients ultimately progress to lentivi- concentrations of soluble VCAM-1 (sVCAM-1) in cere- ral-induced disease of the CNS. Understanding the brospinal fluid (CSF) from encephalitic animals were mechanisms responsible for the development of this dis- markedly elevated over those from animals without AIDS order has obvious important consequences. First, thera- encephalitis. These findings underscore the potential rel- peutic intervention studies can be directed to early cel- evance of VCAM-1 expression in the pathogenesis of lular events before clinical disease. Secondly, less inva- AIDS encephalitis. Furthermore, detection of elevated sive means of diagnosis of encephalitis may be possible sVCAM-1 in CSF may assist in the clinical diagnosis of by detecting the earliest host parameters or pathogenetic this manifestation in animals or people with AIDS. mechanisms involved in leukocyte trafficking in the brain. Thirdly, a better understanding of the mechanisms in- volved in AIDS encephalitis will likely broaden our under- Materials and Methods standing of other primary lentiviral disease manifesta- tions. Unfortunately, the sequence of events and mech- Animals and Virus anisms involved in the genesis of this disease remain largely unknown. Brain tissue from 37 rhesus monkeys (Macaca mulatta), HIV- and SlVmac-induced encephalitis share many one barbary macaque (M. sylvana), one pigtail macaque features in common with other inflammatory diseases. (M. nemestrina), and one cynomolgus monkey (M. fas- Leukocytes marginate and adhere to venular endothe- cicularis) was collected at death and used for immuno- lium, extravasate from the vascular lumen, and eventually histochemical analysis. Thirty-four of these animals were collect as perivascular and parenchymal inflammatory in- experimentally infected with SlVmac before death. The filtrates. In a number of inflammatory processes, endo- strain of SlVmac used for experimental infection, survival thelial activation and de novo endothelial production of time, age, and related animal data are contained within novel membrane proteins in the brain17'18 and other tis- Table 1. The procedures associated with the experimen- sues1923 precedes the formation of inflammatory infil- tal infection of many of these macaques with SlVmac trates. Some of these endothelial membrane proteins are have been described in detail previously.14'16'41X5 Ani- cell adhesion molecules, which have been shown to be mals were inoculated either intravenously or intramuscu- involved in the adhesion of leukocytes to cytokine- larly with uncloned SlVmac25i,154346 molecularly stimulated endothelium in vitro.19'2,28 Recent interest cloned SlVmac239,14'47,48 or an uncloned macrophage- has focused on four proteins, designated E-selectin, tropic variant of SlVmac239, termed SlVmac239/31614.16 P-selectin, intercellular adhesion molecule-1 (ICAM-1), (Table 1). All animals were shown to be persistently in- and vascular cell adhesion molecule-1 (VCAM- fected with SlVmac by multiple viral isolations from pe- 1).24 27,2319 These molecules have been shown to differ ripheral blood mononuclear cells, as previously de- in their leukocyte binding repertoire in vitro so that E-se- scribed,46 and/or a rise in serum antibody response lectin selectively promotes endothelial adhesion to poly- against SlVmac proteins.49 morphonuclear cells and memory T cells,27'32 P-selectin Normal brain tissue from five mature rhesus monkeys enhances endothelial attachment to polymorphonuclear and one cynomolgus monkey was also evaluated as a cells,33 VCAM-1 mediates monocyte, lymphocyte, baso- control (Table 1). These monkeys were serologically neg- phil, and eosinophil attachment,19'2426'34,35 whereas ative for SlVmac before death. ICAM-1 promotes the adhesion of all types of leuko- In addition, CSF was collected from 30 SlVmac- cytes.36'37 Differences in basal expression of these pro- infected rhesus monkeys at the time of death by lumbar teins exist, so that there is an absence, or at the most, little or cisternal puncture. All 30 CSF samples were obtained VCAM-1 in AIDS Encephalitis 1023 AJP November 1992, Vol. 141, No.
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