HIV-associated dementia: New insights into disease pathogenesis and therapeutic interventions

Remarkable progress was made in recent years in the therapeutics of HIV-l-a ssociated dementia (HAD) and in unraveling the complex pathophysiology that follows viral invasion of the central nervous system (CNS). Viral replicat ion in and outside of the CNS was significantly reduced in HIV-I infected s ubjects by new potent antiretroviral therapies. This has resulted in partia l repair of cellular immune function with improvement in, and the preventio n of, neurologic deficits associated with progressive HIV-1 disease. In reg ard to HAD pathophysiology, it is now known that CNS damage induced by HIV- 1 infection occurs indirectly. Neuronal loss is mediated through immune act ivation and viral infection of mononuclear phagocytes (MPs) (brain macropha ges and microglia). Cellular and viral factors secreted by brain MPs produc e, over time, neuronal damage and drop out. Viral growth in the brain appea rs necessary, but not sufficient, to produce cognitive and motor impairment s in affected individuals. Indeed, the best predictor for neurologic impair ment following HIV-1 infection is the absolute number of immune-competent m acrophages; not the level of viral production in affected brain tissue. As yet, an understanding of macrophage-related neurodegeneration has not trans lated into significant improvements in the treatment of this devastating co mplication of HIV disease. Nonetheless, adjunctive antiinflammatory and neu roprotective therapies are being developed. New ideas regarding HAD neuropa thogenesis, and implications for the diagnosis and treatment of HAD are sum marized in this article.