Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, antiretroviral toxic neuropathy has become a common peripheral neuropathy among HIV/AIDS patients leading to discontinuation of antiretroviral therapy, for which the underlying pathogenesis is uncertain. This study examines the role of neurofilament (NF) proteins in the spinal dorsal horn, DRG and sciatic nerve after NRTI neurotoxicity in mice treated with zalcitabine (2',3'-dideoxycitidine; ddC). ddC administration up-regulated NF-M and pNF-H proteins with no effect on NF-L. The increase of pNF-H levels was counteracted by the silencing of HuD, an RNA binding protein involved in neuronal development and differentiation. Sciatic nerve sections of ddC exposed mice showed an increased axonal caliber, concomitantly to a pNF-H up-regulation. Both events were prevented by HuD silencing. pNF-H and HuD colocalize in DRG and spinal dorsal horn axons. However, the capability of HuD to bind NF mRNA was not demonstrated, indicating the presence of an indirect mechanism of control of NF expression by HuD. RNA immunoprecipitation experiments showed the capability of HuD to bind the BDNF mRNA and the administration of an anti-BDNF antibody prevented pNF-H increase. These data indicate the presence of a HuD - BDNF - NF-H pathway activated as a regenerative response to the axonal damage induced by ddC treatment to counteract the antiretroviral neurotoxicity. Since analgesics clinically used to treat neuropathic pain are ineffective on antiretroviral neuropathy, a neuroregenerative strategy might represent a new therapeutic opportunity to counteract neurotoxicity and avoid discontinuation or abandon of NRTI therapy.

A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC(50) values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.

The unique nature of the replication cycle of the retroviruses, including HIV, offera number of possible targets for chemotherapeutic agents. These are RNA viruses which have the capacity to make DNA copies through their characteristic enzyme, reverse transcriptase, encoded in the pole region of the viral genoma. Reverse transcription is an attractive target for therapeutic intervention as this event is uniquelly associated with retroviruses. Dideoxynucleoside analogues can compete with endogenous nucleosides that are the natural substrate for reverse transcriptase or may be incorporated intro the growing chain of proviral DNA and terminate elongation. Reverse transcriptase inhibition is the principal mechanism of action of zidovudine (AZT) and related nucleosides, dideoxyinosine (ddl) and dideoxycitidine (ddC), which all attach to reverse transcriptase to the same site. This review will discuss current approaches to the antiretroviral therapy in AIDS patients. Several well controlled clinical trials have established both the efficacy and toxicity of AZT in patients with AIDS and severe ARC and it was shown that this drug decreased the incidence and severity of opportunistic infections, with the highly significant reduction in early mortality. The efficacy of newer reverse transcriptase-inhibiting nucleoside derivatives will be discussed too, as well as the issue of combination therapies.