Understanding the mechanisms of neuronal regeneration and repair in the adult central nervous system is a vital area of research. Using a rhesus lentiviral
encephalitis model, we sought to determine whether recovery of neuronal metabolism after injury coincides with the induction of two important markers of synaptodendritic repair: growth-associated protein-43 (GAP-43) and
ephrin B3. We examined whether the improvement of neuronal metabolism with combined anti-retroviral
therapy (cART) after simian immunodeficiency virus (SIV)
infection in rhesus macaques involved induction of
GAP-43, also known as
neuromodulin, and
ephrin B3, both implicated in axonal pathfinding during neurodevelopment and regulation of synapse formation, neuronal plasticity, and repair in adult brain. We utilized magnetic resonance spectroscopy to demonstrate improved neuronal metabolism in vivo in adult SIV-infected cART animals compared to untreated and uninfected controls. We then assessed levels of
GAP-43,
ephrin B3, and
synaptophysin, a pre-synaptic marker, in three brain regions important for cognitive function, cortex, hippocampus, and putamen, by quantitative real-time RT-PCR and immunohistochemistry. Here we demonstrate that (1)
GAP-43 mRNA and
protein are induced with SIV
infection, (2)
GAP-43 protein is higher in the hippocampus outer molecular layer in SIV-infected animals that received cART compared to those that did not, and (3) activated microglia and infiltrating SIV-infected macrophages express abundant
ephrin B3, an important axonal guidance molecule. We propose a model whereby SIV
infection triggers events that lead to induction of
GAP-43 and
ephrin B3, and that short-term cART results in increased magnitude of repair mechanisms especially in the hippocampus, a region known for high levels of adult plasticity.