|
Ronald Ellis
Univ. of California, San Diego
The central nervous system (CNS) is a viral reservoir that is positioned to play a pivotal role in HIV population genetics and in the evolution of antiretroviral resistance. Divergent evolution of HIV in the CNS is favored by viral, immune, and pharmacologic compartmentalization. Env and pol genotypes in the brain and cerebrospinal fluid (CSF) have been shown to diverge from those in plasma and lymphoid tissue. Divergent env genotypes may be explained by differences in selective pressures related to restricted immunity and differing host cell populations (monocytes, microglia) in the CNS, while divergent pol genotypes may be explained by differences in compartmental selection pressures resulting from antiretroviral therapy. Molecular filtering and efflux pumps at the blood-brain and blood-CSF barriers substantially reduce antiretroviral drug penetration in CSF and brain, especially for protease inhibitors. Viral, immune and pharmacologic compartmentalization are further evidenced in vivo by differences in the kinetics of responses to antiretrovirals in CSF and plasma, especially in advanced HIV infection. Frank discordances of CSF and plasma responses to antiretroviral therapy are seen in some patients. Exchange of mutant viruses between the CNS and blood appears to be mediated by cellular trafficking that wanes with worsening immunosuppression, so that in patients with advanced disease, HIV may replicate autonomously in the CNS, independent of reinfection by HIV in the blood. A major challenge to current research is to formulate empirical approaches to the study of HIV replication, trafficking, and antiretroviral pharmacology in the CNS. A practical approach to investigating the pathogenesis of CNS HIV infection utilizes studies of cerebrospinal fluid HIV and antiretroviral levels. In conjunction with a better understanding of the brain-CSF interface, such studies may guide more effective antiretroviral treatment strategies.
Session 63. Symposium
Update on Epidemiology and Prevention
Wednesday, 2:00-4:00pm
Ballroom VIII-X
© 8th Conference on Retroviruses and Opportunistic Infections