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Problem statement: Infection with retroviruses such as human immunodeficiency virus type 1 (HIV-1) and human T cell leukemia virus type 1 (HTLV-1) have been shown to lead to neurodegenerative diseases such as HIV-associated d ementia (HAD) or neuroAIDS and HTLV-1- Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), respectively. Approach: HIV-1- induced neurologic disease is associated with an in flux of HIV-infected monocytic cells across the blood-brain barrier. Following neuroinvasion, HIV-1 and viral proteins, in addition to cellular mediators released from infected and uninfected cel ls participate in astrocytic and neuronal dysregulation, leading to mild to severe neurocogni tive disorders. Results: The molecular architecture of viral regulatory components including the Long T erminal Repeat (LTR), genes encoding the viral proteins Tat, Vpr and Nef as well as the envelope g ene encoding gp120 and gp41 have been implicated in 'indirect' mechanisms of neuronal injury, mechan isms which are likely responsible for the majority of CNS damage induced by HIV-1 infection. The neuropathogenesis of HAM/TSP is linked, in part, with both intra-and extracellular effectors functio ns of the viral transactivator protein Tax and like ly other viral proteins. Tax is traditionally known to localize in the nucleus of infected cells serving as a regulator of both viral and cellular gene expressio n. Conclusion/Recommendations: However, recent evidence has suggested that Tax may also accumulate in the cytoplasm and be released from the infected cell through regulated cellular secretion processes. Once in the extracellular environment, T ax may cause functional alterations in cells of the pe ripheral blood, lymphoid organs and the central nervous system. These extracellular biological acti vities of Tax are likely very relevant to the neuropathogenesis of HTLV-1 and represent attractive targets for therapeutic intervention. |
