This oft repeated truism captures our philosophy that understanding evolutionary pathways is an important component of understanding complex biological phenomena. HIV-1 evolution is reflected in sequence diversity within the viral population. Defining sequence diversity can provide the genetic underpinning for exploring HIV-1 biology and pathogenesis.
We use viral diversity to 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, resulting in genetic compartmentalization in the CNS and genital tract. Compartmentalization is associated with neurological symptoms when virus is independently replicating in the CNS, and may reflect distinct populations that can be transmitted when there is compartmentalization in the genital tract, potentially affecting vaccine design. Progression to immunodeficiency allows evolution of the virus to infect new cell types, and this may result in further pathogenic potential. Dynamic changes in the sequences in the latent pool may provide information important for eradication. Our goal is to understand the genetic basis for each of these aspects of viral evolution/host selection and the impact on phenotype.
Next generation sequencing offers the opportunity to view viral populations in dramatically new ways. However, this technology is limited by the need for PCR to amplify viral sequences before sequencing, introducing the problem of sequence resampling, and by high error rates of the sequencing technology. We have developed Primer ID as a way to overcome these problems and are applying this technology to the study of viral populations to examine the role of pre-existing drug resistance mutations as well as more general features of population structure.
We are also developing tools to screen for new viral inhibitors that could block processing at the viral Gag protein matrix/capsid junction. Failure to cleave Gag at this site has a strong dominant negative effect on virion infectivity, even at low levels of uncleaved protein, making this the most sensitive target in the entire viral life cycle.
This website is designed to introduce you to our work and to the people in the lab. We will also try to keep it updated with upcoming presentations by lab members at scientific meetings. We will use the links section to make information and datasets readily available. Please feel free to contact us about training opportunities, reagents, protocols, or anything else not readily available through this website.