Using light-sheet microscopy to examine interaction between HIV distribution and Fos-expressing neuronal ensembles in rat brains

National Institute On Drug Abuse

Investigators

Abstract

Despite the effectiveness of anti-retroviral therapy for HIV, infected cells harboring provirus within the central nervous system contribute to HIV-associated neurocognitive disorder (HAND). Brain-resident glial cell populations, primarily microglia, are infected by the virus and negatively impact the functionality and viability of surrounding neurons through a variety of mechanisms including pro-inflammatory cytokine release, neurotrophic dysregulation, aberrant glutamate homeostasis, and direct damage from viral protein production. Furthermore, it has been established that microglia harbor latent provirus, which can be activated by pro-inflammatory stimuli leading to productive viral replication and release. Microglia are also mobile within the nervous system particularly when they are activated by a variety of cytokines during inflammation; thus, microglia replication and release and their mobility can mediate the spread of HIV in brain. The immediate goal of this initial proposal is (1) to use our light-sheet microscopy method in rats to examine how HIV virus spreads throughout the brain and (2) how this spread is affected by repeated cocaine administration. Light-sheet microscopy allows unbiased observation of HIV viral spread over the entire brain, rather than the usual biased assessment of only a few chosen brain areas. An unbiased assessment allows us to determine not only how HIV spreads throughout the entire brain but also to identify previously unknown infected regions. We are currently testing the best provirus for use in this project.