MERIT Award Recipient: John M. Coffin, Ph.D.
Retroviruses are unique among infectious agents in that they can readily evolve into different niches. This ability is critical to their ability to cause a wide variety of diseases - from cancer to AIDS and many others - to infect different host species including humans and different kinds of cells within their host, and to evade both the immune response and the action of antiviral drugs. Our research goal is to understand the mechanisms and consequences of some of these evolutionary processes. We are focusing on the following specific questions:
- How can retroviruses evolve to use different cell surface proteins (receptors) to gain entry to different types of cells? Our initial experiments imply a complex series of adaptive evolutionary events, starting with mutants that do not require any receptor for infection. We are testing this hypothesis, and using the mutant viruses we generate to study the virus-cell interaction in more detail.
- What are the roles of human endogenous proviruses (HERVs) in evolution and disease? Because of their ability to become part of the genetic material of their host, retroviruses that infect the germ line can become established and passed down through the millennia as endogenous proviruses. These elements then provide a true fossil record of the association of the virus and its host, tracing back many millions of years. We have used this fossil record to understand both the types of retroviruses that existed in the very distant past, the impact that these viruses have had on primate evolution, and the insight that they can provide into the processes of human evolution. In some animal species, such viruses are important causes of cancer. We are attempting to determine whether this is also true in humans, particularly in the case of breast cancer. We are also attempting to determine whether any of these elements are still active as infectious agents, or can be restored to infectivity by manipulating their genomes.
- How do viruses like HIV evolve during the course of infection? Mutations that lead to escape from the immune response as well as from antiviral drugs accumulate during the course of the multiple replication cycles that characterize HIV infection. We are continuing to develop mathematical models that describe the roles of important evolutionary factors (mutation, selection, drift, recombination) in the accumulation of mutations in virus populations, and are developing simple model experimental systems to test these models in the real world of viruses. All together, we expect these studies to provide important new insights into the way these remarkable viruses have evolved to infect and cause disease, and how they continue to do so.