The Influence of Cytokines and Chemokines on the Pathophysiology of HIV-1 Associated Cognitive-Motor Disorders

Abstract

In conclusion, with improved primary suppression of HIV-1 replication using triple drug combinations including a protease inhibitor, it is likely that HIV-1-infected patients will survive longer, as CDC data have already to some extent demonstrated. Longer patient survival is especially likely given the successes of Pneumocystis carinii pneumonia and Mycobacterium avium complex prophylaxis. However, the current FDA-approved anti-retroviral regimens do not penetrate well into the CSF or brain tissue. Hence, HIV-1 may continue to replicate relatively unencumbered in brain, especially given the relatively muted immunological response therein. As result, a current hypothesis is that a greater prevalence of these disorders is expected in the near future. Moreover, given the improved prophylaxis and treatment of several lethal complications of HIV-1 infection, it might be expected that the complaint of cognitivemotor impairment will be afforded a higher priority for intervention. It is likely that patients with HIV-1 infection will become more and more focused on maintenance of their functional status as opposed to survival alone in the coming years. Further, while indirect mechanisms of cell death may not be of prominent importance in the periphery, evidence accumulated thus far suggests that such mechanisms (e.g., apoptosis) may be more important in the brain. It might be expected, therefore, that future CNS-specific treatment developments will require a focus on adjuvant therapies used in conjunction with primary anti-retroviral combination therapies. The use of cytokines, monoclonal antibody to cytokines, soluble cytokine receptor, and down-modulators of cytokine secretion represent one category of such adjuvant therapies requiring further development. Current data suggest that the development of such therapies will require an investment in additional basic science research aimed at uncovering the relationship of cytokines and chemokines to neuronal cell death in tissue, as it has already been demonstrated that the effects of several cytokines differ with response to the pathogenesis of MCMD and HAD (more closely related to macrophage activation) versus the progression of disease in the periphery (more closely related to CD4+ T lymphocyte depletion). Hence, a CNS-specific pharmacopeia of anti-retroviral and combination therapy is required to deal with the potential onslaught of cognitivemotor dysfunction and disorders that currently looms as a possibility in the next decade of HIV/AIDS.