Biochemistry and Biophysics
Area of interest
The HIV-1 pandemic represents one of the greatest challenges of our time. The immunodeficiency that is the result of an infection results in opportunistic infections and viral-induced malignancies. Infection with HIV-1 results in sustained viral replication and a large population size which results in rapid rates of evolution. Viral diversity is an important source of information, to a large extent reflective of the changing selective environment in which the virus is replicating. We use patterns of viral diversity as the starting point to explore virus-host interactions. Sequence diversity is used to provide genetic evidence for specific changes in the viral genome that are then tested for their effect on the viral phenotype in the context of the changing host environment.
We apply this approach to look examine issues related to HIV-1 pathogenesis in several settings. Transmission of HIV-1 involves a severe bottleneck that may include specific selective pressures. The virus becomes disseminated in the host and this can result in the establishment of distinct populations in the host, resulting in genetic compartmentalization in the CNS and genital tract. This compartmentalization is associated with neurological symptoms when virus is independently replicating in the CNS. Progression to immunodeficiency includes evolution of the virus to be able to infect new cell types, and this may result in further pathogenic potential.
In collaborative efforts we are exploring the importance of RNA secondary structure based on the new structure of the entire HIV-1 genome (Weeks lab), and we are developing tools to screen for new viral inhibitors that could block processing at the viral Gag protein matrix/capsid junction. We have previously shown that failure to cleave Gag at this site has a strong dominant negative effect on virion infectivity, even at low levels of uncleaved protein.