The impact of HIV-1 on neurogenesis: implications for HAND.

HIV-1 infection, in addition to its destructive effects on the immune system, plays a role in the development of neurocognitive deficits. Indeed up to 50% of long-term HIV infected patients suffer from HIV-associated neurocognitive disorders (HAND). These deficits have been well characterized and defined clinically according to a number of cognitive parameters. HAND is often accompanied by atrophy of the brain including inhibition of neurogenesis, especially in the hippocampus. Many mechanisms have been proposed as contributing factors to HAND including induction of oxidative stress in the central nervous system (CNS), chronic microglial-mediated neuroinflammation, amyloid-beta (Aß) deposition, hyperphosphorylated tau protein, and toxic effects of combination antiretroviral therapy (cART). In these review we focus solely on recent experimental evidence suggesting that disturbance by HIV-1 results in impairment of neurogenesis as one contributing factor to HAND. Impaired neurogenesis has been linked to cognitive deficits and other neurodegenerative disorders. This article will highlight recently identified pathological mechanisms which potentially contribute to the development of impaired neurogenesis by HIV-1 or HIV-1-associated proteins from both animal and human studies.

Efavirenz promotes ß-secretase expression and increased Aß1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND).

Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human "Swedish" mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aß) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Aß), and promoted increased ß-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aß - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aß generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aß phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aß promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aß peptide.