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Antiretrovirals target host proteosomes For those aged 25-44, HIV dropped from the leading cause of death in 1995 to third and fifth leading causes of death in 1996 and 1997 respectively. The age-adjusted HIV death rate of 5.9 deaths per 100,000 is the lowest rate since 1987; the first year mortality data were available for the disease. This dramatic reduction in AIDS related deaths has largely been due to the advent of anti-retroviral agents which prolong AIDS-free HIV infection as well as life-expectancy once AIDS has developed. Despite the success of HIV therapies, there is still a demand for molecules with reduced toxicity and susceptibility to drug resistance. Antiviral drugs such as indinavir, lamivudine and zidovudine have traditionally been thought of as reverse transcriptase inhibitors however recent evidence suggests that these molecules may also target host proteasomes. Proteosomes constitute the degradative machinery of the ubiquitin/adenosine triphosphate-dependent proteolytic pathway, which is involved in many cell functions, including immune response and apoptosis, and in HIV maturation and infectivity. This recent finding has a number of consequences. Firstly, a number of anti-virals toxicity may in part be due to this proteosome activity. Secondly, since proteosomes are known to play a role is preventing HIV maturation and infectivity, screening for antivirals with optimized proteosome and antiviral activity could lead to the development of improved therapeutics. Finally, drug resistance occurs as a result of spontaneous HIV-1 mutation; targeting host proteins as well as the virus itself can reduce the problems of resistance. In view of this data it is important to determine whether the rational development of antiretrovirals with optimized proteosome activity would be beneficial (through improved efficacy and decreased drug resistance susceptibility) or detrimental (through increased toxicity). Armed with this information it should be possible to build assays measuring proteosome activity into screening architectures thus improving existing therapies. Link to journal abstract:
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