Neuropathogenesis of central nervous system HIV-1 infection.

Neuronal damage and death are consistent pathologic findings in the brains of patients with ADC, and multiple cell model systems have demonstrated neurotoxicity through the effects of HIV-1 infection in macrophages and microglia. Brain MRI studies (1H-MRS) indicate that reversible neuronal cell dysfunction occurs early during the course of HIV-1 infection, long before overt symptoms of ADC appear. Epidemiologic studies suggest that a high viral load in the CNS is a major risk factor for ADC and that HAART may significantly reduce, but not eliminate, the risk of developing ADC. Targeted adjunctive therapies administered early are likely necessary to maximize CNS protection against HIV, and rational approaches to such therapy are rapidly evolving through in vitro analysis of the mechanisms of HIV-associated neurotoxicity. Soluble factors released by infected cells may directly or indirectly damage neurons and induce apoptosis at the level of NMDA subtype of glutamate receptors, and NMDA receptor antagonists represent a major therapeutic option currently under intense clinical investigation. Likewise, drugs with antioxidant or free radical scavenging effects offer another rational approach to adjunctive therapy and are also under intense clinical scrutiny. Finally, agents that inhibit neuronal death-signaling pathways (e.g., p38 MAPK inhibitors) and that stimulate cell survival pathways (e.g., Akt/PKB) may represent the next investigational step in designing anti-ADC therapies.