TAs the AIDS pandemic enters its third decade, an end is still not in sight to the devastating disease. According to the World Health Organization, at least 42 million people are infected with HIV worldwide, and each day 16,000 more join the list. These statistics, horrifying as they are, almost certainly underestimate the actual number of cases. In August 2001, for example, China’s deputy health minister announced that his country’s AIDS population is not confined to a few individuals in a few social groups, as had been claimed, but is widespread and affects 600,000. Others say the estimate is closer to 1.5 million. If the current rate of infection continues in China, that number will swell to 10 million by 2005 and 20 million by 2010. HIV has ravaged Africa, with more than 19 million already deceased, 4 million of them under the age of 15.

While in many parts of the world, AIDS and HIV infection are spiraling out of control, some drugs have cut the death rate by 50 percent since their introduction in 1996. But this therapy—called highly active antiretroviral treatment or HAART—has introduced sociological and biological challenges, such as lack of availability and viral resistance.

As individuals, families, communities, and nations endure the heartbreaking effects of HIV, researchers are combating the virus at the cellular and molecular levels, a challenge that requires an understanding of how the virus infects human cells.

Like many viruses, HIV is streamlined in structure, just a nucleic acid (RNA) wrapped in a protein coat with sugars jutting from its surface, or envelope. HIV attaches to a cell of the immune system by binding to first one receptor, called CD4, and then contorting as it binds to a second receptor, called CCR5. The most common target is a type of white blood cell called a CD4 T cell. This binding fuses the viral envelope with the cell membrane, and the virus slips inside. Then, a viral enzyme, reverse transcriptase, converts the viral RNA into DNA, which then inserts into the host cell’s DNA. The cell then uses the stowaway viral instructions to produce the proteins that HIV requires to make more of itself. Soon, new viral particles bud from the commandeered cell. This goes on for some time. The person might experience an acute illness early on, but it will be years in most cases until the immune system begins to falter irreversibly.

Gradually, the viruses diversify, and variants that can evade immune attack come to predominate. This is natural selection at work, favoring the virus. For two to 15 years, while the person enjoys relatively good health, a battle rages within as HIV mutates into a force that will ultimately overcome the immune system—unless drugs slow the course. But just as HIV’s genome changes in ways that enable it to resist the mounting immune response, so too can it mutate to yield variants that find their way around the series of HAART drugs used to fight the virus.

“HIV so far has been able to resist anything,” explains Bolognesi. “There are so many viral variants that the chance that one can overcome a specific drug inhibition is certainly there. We now combine a number of different inhibitors that operate under different mechanisms, so the chance that HIV replicates and spawns a variant that is resistant to all are low.” Such resistance is likely to develop and persist when a patient does not take enough of the drug to completely suppress viral replication, allowing new variants to arise.

A mathematical model based on the rise of drug-resistant HIV infection in San Francisco, published in the September 2001 issue of Nature Medicine, reveals that resistance usually occurs within individuals as their resident viruses mutate, rather than a person contracting a resistant strain of virus from another person. That means that resistance is a natural consequence of viral evolution, and therefore hard to avoid. Different drugs are desperately needed, because once the virus develops resistance to one drug from existing classes, cross-resistance to other inhibitors aimed at the same target is likely.

Jesse Treu ’68 General partner, Domain Associates, one of the largest venture capital firms in the United States focused exclusively on the health-care business.

“Our recent analysis shows that it is absolutely critical for new and better drugs to be developed and used to treat HIV. It is essential that the new drugs be extremely effective in viral suppression, which will minimize the probability of resistance,” says Sally Blower, a professor in the department of biomathematics at the UCLA AIDS Institute and lead author of the study. The computer program predicts that by 2005, 42 percent of HIV infections in San Francisco will be resistant to the current generation of drugs.

Developing a more effective way to fight HIV infection is where T-20, Trimeris, and Rensselaer enter the picture.

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