Role of HIV-1 Tat and CC Chemokine MIP-1 alpha in the pathogenesis of HIV associated central nervous system disorders

Two syndromes affecting cognitive and motor function in the setting of AIDS have been described as HIV encephalopathy (HIVE) and progressive multifoca l leukoencephalopathy (PML). HIVE is characterized by the presence of micro glial nodules with accompanying astrocytosis. PML is a fatal demyelinating disease of the white matter induced by the human papovavirus JCV which caus es cytolytic destruction of glial cells. In addition to the effect of HIV-1 induced immune suppression, HIV may act directly as a co-factor for stimul ation of JCV replication in AIDS patients, in part due to Tat-induced activ ation of JCV gene transcription. Since Tat has been implicated in CNS patho genesis, we examined its localization in CNS specimens from HIV infected pa tients with HIVE and PML as well as controls. Based on the observation of C C chemokine induction in monocytes by Tat, we also examined the cellular lo calization of the CC chemokine Macrophage Inflammatory Protein-1 alpha (MIP -1 alpha) and its cognate receptor CCR-5 in these samples. In HIVE, Tat was primarily localized in astrocytes and microglia, within the nodular lesion s. In PML, a marked increase in the number of Tat positive astrocytes was o bserved. In both HIVE and PML, prominent expression of MIP-1 alpha. and CCR -5 was found within areas containing histopathological lesions. CCR-5 posit ivity of microglia was localized primarily to nodular lesions in HIVE. In P R IL, increased numbers of cells with monocyte/microglial morphology were o bserved relative to HIVE. The increased MIP-1 alpha positivity, and potenti ally other chemokines, may contribute to the pathogenesis of PML in the set ting of HIV infection. Tat may play an important role in the pathogenesis o f both HIV associated CNS disease states, acting indirectly through cytokin e and chemokine dysregulation.