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D Gabuzda
Dana-Farber Cancer Inst and Harvard Med Sch, Boston, MA
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Background: HIV infects the central nervous system and causes dementia and other neurologic disorders. The incidence of HIV-associated dementia (HAD) has declined significantly since the introduction of HAART. Nonetheless, most current antiretrovirals have relatively poor CNS penetration. Therefore, the CNS is a reservoir for long-term viral persistence and HAD continues to be a significant complication of HIV infection. Neuro-invasion of HIV occurs through the trafficking of infected monocytes across the blood-brain barrier. Perivascular macrophages and microglia are the primary cellular reservoir of HIV in the brain. Although HIV enters the CNS early in the course of infection, HAD typically occurs only after progression to AIDS. The loss of immune control associated with disease progression, increased immune activation, increased trafficking of activated and/or infected monocytes into the CNS, and late emergence of viral variants that impact CNS disease progression are all possible reasons why HAD typically occurs only in the late stages of HIV disease.
Methods: Mechanisms of virus entry into the CNS were investigated using molecular and cell biology approaches. HIV viruses in brain were analyzed to determine genetic and functional characteristics that underlie neurotropism and neurovirulence. Primary brain culture models were used for in vitro studies to elucidate mechanisms of neurodegeneration. Monocyte populations in peripheral blood from AIDS patients with HAD were characterized to investigate the role of monocyte viral reservoirs in the pathogenesis of HAD.
Results: Viruses with reduced CCR5/CD4 dependence and an increased CCR5 affinity may represent a pathogenic viral phenotype contributing to increased viral loads in the CNS, formation of multinucleated giant cells in brain, and neurodegenerative manifestations of AIDS. CD16+ monocytes trafficking into the brain may play an important role in establishing a long-lived reservoir of virus in the CNS and contributing to mechanisms of neurologic injury in HAD. Important parallels between pathogenic mechanisms in the central nervous system and immune system will be considered.
Conclusions: Understanding viral and host factors that lead to CNS infection and HIV-associated neurologic injury will provide a rational basis for optimal prevention and treatment of HAD.
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