Therapeutics
Drug Discovery
HIV
The identification of viral and cellular drug targets is essential for fueling the drug development pipeline. Early drug discovery efforts concentrated on a relatively small number of viral targets: HIV reverse transcriptase (an enzyme that catalyzes the synthesis of viral DNA within infected cells from the RNA template carried by infectious virions) and HIV protease (an enzyme that cleaves and processes viral precursor proteins allowing virion maturation). Treatment regimens containing combinations of reverse transcriptase and protease inhibitors, commonly known as highly active antiretroviral therapy, or HAART, revolutionized the treatment of people with HIV by markedly lowering viral load and decreasing the incidence of AIDS-associated opportunistic infections. Many patients receiving HAART nevertheless suffer metabolic abnormalities and drug toxicities, have difficulty adhering to the complex drug regimens, and develop strains of HIV resistant to therapy.
Additional viral and cellular targets are now being extensively studied—and therapies targeting HIV integrase, various steps in the virus entry process, and virion maturation have been examined in clinical trials in recent years. Still in the early stages of preclinical investigation are potential inhibitors of Vif/APOBEC; ESCRT I, II, and III (virus assembly); and TRIM-5 alpha (virus uncoating).
Co-Infections
HIV-infected individuals without access to effective treatment regimens to combat their HIV infection commonly manifest diseases caused by co-infection with infectious agents such as Mycobacterium avium, Pneumocystis carinii, Cryptosporidium parvum, cryptococci, fungi, and human cytomegalovirus. Diseases caused by these pathogens are less common nowadays in AIDS patients receiving HAART; however, co-infection with hepatitis C virus (HCV) or tuberculosis (TB) has increased in incidence, especially in countries where the risk of co-infection is high. As a result of prolonged survival, greater numbers of HIV-infected individuals are exhibiting the long-term complications of HCV infection, namely end-stage liver disease and hepatocellular carcinoma. Infection by HCV in some instances has been shown to interfere with HAART regimens. TB can accelerate the progress of AIDS and is currently the leading cause of death in persons who are HIV positive.
NIAID Activities
- NIAID funds grants to identify and validate new targets critical to the replication of HIV and its co-infections.
- NIAID funds grants to discover new therapeutic agents to treat HIV and its co-infections.
- NIAID administers contracts that evaluate new therapeutic agents and strategies for potential activity in cell culture and in animal efficacy models.
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