Abstract
Azidothymidine (AZT) is a synthetic, chain-terminating nucleoside analog used to treat HIV-1 infection. While AZT is not actively transported across the blood brain barrier, it does accumulate at high levels in cerebrospinal fluid, and subsequently diffuses into the overlying parenchyma. Due to the close anatomical proximity of the neurogenic niches to the ventricular system, we hypothesize that diffusion from CSF exposes neural stem/progenitor cells and their progeny to biologically relevant levels of AZT sufficient to perturb normal cell functions. We employed in vitro and in vivo models of mouse neurogenesis in order to assess the effects of AZT on developing and adult neurogenesis. Using in vitro assays we show that AZT reduces the population expansion potential of neural stem/progenitor cells by inducing senescence. Additionally, in a model of in vitro neurogenesis AZT severely attenuates neuroblast production. These effects are mirrored in vivo by clinically-relevant animal models. We show that in utero AZT exposure perturbs both population expansion and neurogenesis among neural stem/progenitor cells. Additionally, a short-term AZT regimen in adult mice suppresses subependymal zone neurogenesis. These data reveal novel negative effects of AZT on neural stem cell biology. Given that the sequelae of HIV infection often include neurologic deficits—subsumed under AIDS Dementia Complex (Brew, 1999)—it is important to determine to what extent AZT negatively affects neurological function in ways that contribute to, or exacerbate, ADC in order to avoid attributing iatrogenic drug effects to the underlying disease process, and thereby skewing the risk/benefit analysis of AZT therapy.
Highlights
AZT (3′-azido-3′-deoxythymidine; AZT, zidovudine or Retrovir) is a synthetic, chain-terminating thymidine analog in which the 3′-hydroxyl group is replaced with an azido group
We have examined the effect of AZT on the biology of neural stem cell (NSC) and neural progenitor cell (NPC)
Using both in vitro and in vivo models we found that AZT administration is associated with severe perturbations in both proliferative capacity and neurogenesis
Summary
AZT (3′-azido-3′-deoxythymidine; AZT, zidovudine or Retrovir) is a synthetic, chain-terminating thymidine analog in which the 3′-hydroxyl group is replaced with an azido group. AZT is converted intracellularly into active AZT-triphosphate (AZT-PPP) which competes with the natural substrate—deoxythymidine triphosphate (dTTP)—for incorporation into elongating viral DNA chains by HIV reverse transcriptase (RT). Once added to a DNA chain, AZT prevents further addition of nucleotides by impeding 5′-3′ phosphodiester linkages via its 3′azido group. AZT has been used in the treatment of HIV infection, alone, or in combination with other antiviral agents as a part of Highly Active Antiviral Therapy (HAART). The present recommendations for adult patients call for 500–600 mg AZT/day. This dose is approximately equivalent to 10 mg/kg/day, and results in a steady-state serum AZT concentration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
