Retroviral Evolution Section (RES)
The Retroviral Evolution Section (RES) was established in 2012 with the mission to conduct groundbreaking research to better understand fundamental features of HIV transmission, persistence, and evolution that allow this deadly pathogen to continue to evade eradication strategies. The RES harnesses molecular biology approaches to generate, manipulate, and employ novel viral systems to take full advantage of the unique benefits afforded by nonhuman primate (NHP) models to test specific hypotheses in vivo. My lab seeks to identify and address key areas of AIDS research that are high-impact and high-risk or are time and resource intensive, factors that make these goals particularly challenging in an academic research setting. As part of the Frederick National Laboratory, I take great pride in performing highly collaborative research with my colleagues in the ACVP as well as other intramural and extramural investigators. I work closely within the program both with the principal investigators and cores to leverage limited resources, maximize output, and minimize the number of animals necessary to address my research questions. The RES actively pursues opportunities to share model viruses, reagents, and expertise with the broader research community and fully embraces the ACVP’s long-standing tradition of collaborative science.
My research interests are focused on three main projects:
PROJECT I: Retroviral Transmission and Early Viral Dynamics
Built upon the striking observation that most mucosal HIV infections result from the successful transmission of only a single transmitted/founder virus, one highly prioritized area of my research has been to understand the process of mucosal transmission. My current scientific objective is to fundamentally address the viral/host mechanics and dynamics that occur between initial virus exposure and detectable plasma viremia weeks later (i.e. the “black-box” of transmission). I developed new approaches to assess both vaginal and rectal transmission. Our overall research goal is to facilitate the development of new interventions by providing key insights into the processes involved in initiating a new infection. Furthermore, I plan to expand our previous work to assess viral requirements essential for successful transmission such as replicative capacity, interferon sensitivity, and other biologically relevant phenotypes
PROJECT II: Reservoir Establishment and Persistence
A primary obstacle to curing HIV infection with current antiretroviral therapies is the establishment of long-lived viral reservoirs. These cells or anatomic sites retain replication competent virus that persists for years despite suppressive antiretroviral treatment and can initiate recrudescent viremia upon treatment interruption. Our scientific objective is to inform the development of novel therapeutic strategies for an effective HIV cure by exploiting the unique advantages of NHP models.
Expanding on our original concept of a molecularly tagged virus, we recently developed a barcoded virus system that allows for the sequence-based differentiation of over 10,000 isogenic and phenotypically equivalent viral genomes differing only by a randomized 34-base insert. We have used this barcoded virus to track and quantify individual viral variants during the establishment of viral reservoirs and to subsequently identify the number and dynamics of rebounding viral lineages once suppressive therapy was removed. We also defined the rate of reactivation from latency that led to systemic rebound in early cART treated animals. Our overall research goal is to provide unique insights into the complex nature of reservoir formation and rebound that will inform intervention strategies that seek to eliminate the viral reservoir or allow for a functional cure of HIV.
PROJECT III: Retroviral Dynamics of Evolution
My research interests also include the basic biological functions of lentiviruses: viral escape, viral fitness, replicative capacity, compartmentalization, and recombination. Our objective is to understand the dynamics involved in driving the generation of viral mutations, phenotypic consequences of these mutations, and the resultant process of fitness selection. While we know a great deal about viral dynamics at a population level, our knowledge is limited for many viral processes at the individual viral lineage level. I seek to more fully clarify the properties required for a virus population to make all changes necessary to survive in a new host. To address this fundamental idea, we have developed key reagents and harnessed the molecularly barcoded virus in a manner that allows for unprecedented insights into viral dynamics. With these tools, we now have the capability to assess how viruses adapt at the population level, but also discover how adaptation occurs within individual, genetically defined viral lineages. Overall, our research goal is to use specialized virus models and NHPs to identify potential viral weaknesses that can be exploited through thoughtful interventions.
Retroviral Evolution Section Staff
Brandon Keele, Ph.D.
- O'Brien, Sean
- Djikeng, Sybelle
- Immonen, Taina
- Thorpe, Abigail
- Reid, Carolyn M.
- Macairan, Agatha