Animal Model Enables Researchers to Track the Evolution of HIV
Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.
Dr. Zandrea Ambrose
December 15, 2009—Successful treatment of HIV infection is often hampered by the development of mutated, drug-resistant strains of the virus. HIV mutates extremely rapidly because of its high rate of growth and the genetic errors it makes in the course of that growth, but the vast majority of these mutated viruses are incapable of replication.
However, sometimes a virus evolves that can out-compete the virus that initially infected the patient, due to changes that may render it less susceptible to attack by the immune system or antiretroviral drugs. These new drug-resistant viruses may also be more or less likely to be transmitted sexually. Highly active antiretroviral therapy (HAART) itself exerts “pressure” on HIV populations to evolve, leading to the natural selection of resistant viruses that may have any of the above characteristics. It is therefore crucial to understand how quickly and under which circumstances these drug-resistant viruses emerge, and whether they have any clinically relevant ramifications.
It is difficult to study the emergence of drug-resistant virus in people because of complicating factors such as the potential for repeat infections with new viral strains or imperfect HAART adherence, which is known to increase the rate at which drug resistance emerges. amfAR grantee Dr. Zandrea Ambrose, working at the University of Pittsburgh, with colleagues from the National Cancer Institute, Tufts University, and the Karolinska Institute in Stockholm, solved these problems by using an animal model that could better control for these possibilities and permit new studies of the evolution of HIV and HIV drug resistance.
Writing in the November issue of the journal Retrovirology, Ambrose and associates reported using a chimeric AIDS virus created in the laboratory by joining the outer envelope and other genes of the monkey AIDS virus, SIV, with the reverse transcriptase gene of the human AIDS virus, HIV. Nine different versions of this virus were injected into three monkeys. The researchers were then able to follow the fate of each of the nine virus subpopulations as they competed with each other for survival inside a single animal under three different conditions. Initially, the monkeys received no treatment, then they were treated with a single anti-HIV drug, and finally, they received a complete HAART regimen consisting of three different anti-HIV drugs.
When the monkeys were treated with a single drug, the non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva), viruses carrying mutations that rendered them resistant to efavirenz became dominant within about three months. However, during subsequent treatment with HAART, those viruses that were able to replicate during treatment with efavirenz alone were predominantly susceptible to more comprehensive anti-HIV therapy. This suggested that when a subject is being treated with a full complement of anti-HIV drugs, the presence or absence of at least some known drug-resistant mutations does not greatly influence which types of virus persist, in that drug-resistant virus does not necessarily overtake the original virus.
The authors concluded, “Our new method provided a valuable tool for studying HIV subpopulation emergence, persistence, and decline during ART.”
Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is vice president and director of research.