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HIV/AIDS: The Global Pandemic Continues Unabated

Every 6 seconds, someone is newly infected with human immunodeficiency virus type 1 (HIV), and every 10 seconds someone dies from AIDS. Antiviral drugs currently target two key viral enzymes: reverse transcriptase and protease. When administered in combination, these drugs permit HIV-infected patients to survive the infection, but treatment is lifelong and comes at great cost, both financially and in terms of toxicity and the inevitable emergence of drug resistance. In particular, the high cost of these therapies has impeded distribution to impoverished areas of the world where HIV is hitting the hardest.

New Targets, New Drugs

The laboratory of Dr. Cheryl Stoddart in the Gladstone Institute of Virology and Immunology focuses on the evaluation of new anti-HIV drug candidates. It is a difficult mission. Failure of a drug at the preclinical stage is far more common than success. The discovery and development of new antiretroviral drugs to combat HIV infection is a dynamic process that is continuously fueled, at its most basic level, by studies of the interplay between HIV and its cellular host and by the identification of new molecular targets for therapy. The search for new drugs is also fueled at the clinical level by the manifold problems (tolerability, toxicity, and viral resistance) encountered with existing drugs. From their discovery as compounds with anti-HIV activity to their eventual licensing for the treatment of HIV infection, new antiretroviral drugs must overcome many hurdles, and it is often impossible to predict which compounds will make it all the way to approval for clinical use.

Estimated incidence of AIDS and deaths among adults and adolescents with AIDS, 1985–2002 in the United States. The introduction of HIV drugs targeting reverse transcriptase and protease dramatically changed the course of the disease in the United States. New therapies directed at additional targets are needed to continue this progress.

New Points of Attack

Many of the most promising HIV drugs now in preclinical and clinical development do not target specific viral enzymes. Instead, they act by disrupting specific protein–protein interactions that control early events (entry and uncoating) as well as late events (viral maturation) in the viral life cycle. The entry of HIV into a cell involves the attachment of the virion to surface CD4 receptors via the gp120 Env protein, the interaction of the conformationally altered gp120 protein with one of two chemokine coreceptors (CCR5 and CXCR4) for HIV, and gp41 Env–mediated fusion of virions to target cells. The latter step delivers the viral nucleocapsid—the viral genetic material shielded by a protein coat— to the cytoplasm. After uncoating, the viral genome is reverse transcribed, assembled into a preintegration complex, and transported to the nucleus for eventual replication and generation of viral progeny. Finally, at the other end of the viral life cycle, the main structural protein Gag must be cleaved at many precise sites and in a specific order for correct assembly, and thus maximal infectivity, of the nascent viral particle. The unveiling of these new targets has paved the way for new drug discovery, which is typically enabled by the design of target-based cellular assays suitable for high-throughput screening of tens of thousands of chemical compounds to identify those with promising antiviral activity.

Diagram of HIV particle showing the major structural and functional components. gp = glycoprotein.

The Devil Is in the Pharmacokinetics

The most elegantly designed assays and most state-of-the-art viral targets will not, however, guarantee a successful drug. There are many hurdles to cross. If the drug is to be administered orally, the ideal route, it must be absorbed from the gastrointestinal tract and be able to achieve and sustain blood levels 10 to 100 times higher than the concentration needed for activity in vitro. Moreover, the drug must do this in the absence of toxicity over prolonged periods (years) of drug administration. This is a tall order for any new drug, and the majority fail to pass this crucial stage of development.

Potential targets for drug interventions can be identified by examining the HIV life cycle. For example, an innate cellular restriction factor, TRIM5α, normally binds to the viral capsid and prevents uncoating. The viral capsid coat recruits an abundant cellular protein, cyclophilin A (small purple boxes), to prevent binding by TRIM5α. The drug candidate UNIL-025 binds cyclophilin A and prevents it from blocking the action of TRIM5α.

Recent Successes

Over the last 9 years, the Stoddart laboratory has evaluated more than 50 new compounds from over 30 different chemical classes. Six are currently in human clinical trials. Among those successes are these three promising new agents:

• SCH-C, a CCR5 antagonist that inhibits entry of HIV into the cell
• UNIL-025, a cyclophilin-binding inhibitor of HIV uncoating
• PA-457, an inhibitor of HIV capsid maturation

Summary

Basic science advances have been rapidly translated into new and promising classes of antiviral inhibitors. These new drugs include a CCR5 antagonist entry inhibitor that blocks attachment of HIV to the CCR5 coreceptor, an inhibitor of cyclophilin A, and an agent that prevents proper maturation of the virion. Despite these successes, it is essential that new (and existing) drugs be made available in impoverished areas of the world, particularly in Africa, India, and Asia, where the virus continues to spread unchecked and where poverty fuels the pandemic.