Central nervous system (CNS) pathology is an increasingly recognized consequence of HIV infection. Dementia is a complication of that pathology. Dementia increases the burden of the illness to the patient, caregiver, health care system and society. We know from experience with another dementing disorder, Alzheimer's disease, that strategies which might delay the onset of dementia can have a profoundly beneficial effect. It has been projected by some that even a short delay in onset can produce significant benefit on the national level. At the present time there is a paucity of CNS models for the study of the effects of HIV infection. One of the central objectives of this grant is to characterize the SCID mouse model of HIV CNS infection. By use of contemporary histological techniques, the present study will address basic questions of HIV CNS infection in the SCID mouse. Answers to these questions may have a direct bearing on improving treatment strategies. By understanding how HIV enters the CNS and what it infects in the CNS, existing antiviral therapies may be adapted in a more efficacious way. By use of the SCID mouse model the following questions pertaining to HIV infection of the CNS will be investigated. 1) What is the time course and subsequent CNS pathology produced in this model? 2) Does virus enter the CNS during viremic states or by migrating cells? 3) Do infected human macrophages or T cells induce gliosis in the SCID mouse brain? These aims will require a detailed analysis of the HIV infected reconstituted SCID mouse brain and will include an evaluation of altered synaptic connections, neuromorphologic analysis and an evaluation of stress protein production. Sensitive methods for viral detection and localization will also be used. By these varying histologic approaches it will be possible to investigate the pathophysiologic changes which accompany HIV infection in the SCID mouse. Future directions will examine the efficacy of this model for antiviral drug treatment of the CNS. For example, when should antiviral treatment be initiated to minimize CNS involvement?
