This application is submitted in response to notice NOT-OD-09-058 (NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) and requests a competitive supplement under ARRA 2009. Our parent grant has provided mechanism insight regarding the decrease in skeletal muscle protein synthesis produced by HIV-1 protease inhibitors such as indinavir and lopinavir (LPV). The long-term goal of the parent grant is to elucidate mechanisms by which LPV and other protease inhibitors produce muscle myopathy. While conducting the studies described in the parent application, we reported HIV-1 transgenic (Tg) rats, which are noninfectious and constitutively express 7 of 9 viral envelop proteins, exhibit muscle atrophy not attributable to decreased caloric intake or increased energy expenditure. We have now administered LPV to HIV-1 Tg rats for 3 months and the observed wasting was markedly greater than that seen in HIV-1 Tg rats without LPV. Furthermore, we have evidence that the co-existence of LPV and HIV-1 viral protein expression decreases muscle protein synthesis in the basal post-absorptive state. Finally, we also noted a marked glucose intolerance, insulin resistance and ectopic deposition of triglycerides in skeletal muscle of HIV-1 Tg rats administered LPV. Hence, it is clear there is a strong interaction between one or more the viral proteins (not the HIV-1 virus per se) and the protease inhibitor which produces a dramatic metabolic phenotype. It seems likely that examining the in vivo effects of protease inhibitors and other HAART drugs in the HIV-1 Tg rat provides a more clinically relevant model because of the drug-viral protein interaction. Therefore, the goal of this competing revision is to determine the mechanism by which the administration of LPV to HIV-1 Tg rats produces this complex metabolic phenotype - with the primary focus being on the changes in glucose and protein metabolism in muscle. Although related, such studies are beyond the direct scope of the parent grant. However, our provocative data warrant further investigation, and the proposed studies can be completed within a 2-yr period. This competing revision requests funds for four specific purposes: 1) Hiring an identified unemployed postdoctoral fellow;2) employing a high school chemistry teacher as a summer intern;3) purchase of HIV-1 Tg rats which are extremely expensive;and 4) purchase of supplies necessary for the fellow and intern to have a productive training environment and to successfully complete the designated studies within 2 years. Because the proposed studies were not part of the parent application sufficient unobligated funds are not available. We have been extremely productive during the initial years of the parent application, and the funds supplied in this competing revision will greatly accelerate our research in identifying the cellular and molecular basis for muscle atrophy and insulin resistance produced by protease inhibitors in HIV-infected individuals.
Muscle wasting and insulin resistance in those patients infected with HIV-1 often occur independent of AIDS and may be a direct result of the treatment of these individuals with HIV protease inhibitor drugs. Our studies using HIV-1 transgenic rats administered the commonly prescribed protease inhibitor lopinavir are designed to elucidate the mechanisms by which this class of drugs negatively impacts translational efficiency and insulin action in muscle. Such data are needed to both realize the full potential and avoid possible pitfalls of this drug class in long-term treatment of HIV infection.
