Retroviruses exhibit a wealth of evolutionary phenomena, including the ability of replicating populations to undergo rapid genetic change in response to varying selective pressure;the ability to vary in the use of host cell receptors;and the ability to become integrated in the genome of their host species and passed down through the generations as endogenous proviruses. In the prior project period, we have engaged all these aspects of retrovirus evolution: We have studied the evolution of env genes by analyzing unusual mutants that extend the host range of ALV beyond chicken, to quail, dog, and even human cells. We have analyzed the evolutionary pathway as well as the novel biochemical mechanism involved. We have extensively analyzed the coevolution of retroviruses and their hosts, both in humans and in mice. We have probed the role of an important antiviral host factor (AP0BEC3G) in the evolution of both endogenous MLV and exogenous HIV. We have developed sophisticated mathematical models for the evolution of replicating virus populations, describing the effects of mutation, selection, drift, linkage, and recombination on the accumulation (or loss) of deleterious mutations, and begun development of an in vitro model system to apply these models to the real world. Future work will continue these studies, with the following aims. 1. How do retroviral envelope genes evolve from receptor independence to use new receptors and to alter other important properties? 2. What are the functional and pathogenic properties of human endogenous retroviruses, particularly HERV-K? Are any of these elements still active and capable of replication and integration at new sites in the human genome? 3. How do important forces of mutation, selection, recombination, and drift combine to direct retrovirus evolution?
The evolution of retroviruses has important consequences for public health. Retroviruses like HIV and HTLV have evolved to use humans as hosts, with devastating consequences. Furthermore, evolution of viruses within a given host can have important consequences, such as use of different receptors, increased virulence, or resistance to drugs. Understanding of how this evolution has occurred in our past and how it occurs in simple models will leave us better prepared to deal with such events as they happen.
|Wildschutte, Julia Halo; Williams, Zachary H; Montesion, Meagan et al. (2016) Discovery of unfixed endogenous retrovirus insertions in diverse human populations. Proc Natl Acad Sci U S A 113:E2326-34|
|Witkin, Keren L; Hanlon, Sean E; Strasburger, Jennifer A et al. (2015) RNA editing, epitranscriptomics, and processing in cancer progression. Cancer Biol Ther 16:21-7|
|Coffin, John M (2015) The discovery of HTLV-1, the first pathogenic human retrovirus. Proc Natl Acad Sci U S A 112:15525-9|
|Bhardwaj, Neeru; Montesion, Meagan; Roy, Farrah et al. (2015) Differential expression of HERV-K (HML-2) proviruses in cells and virions of the teratocarcinoma cell line Tera-1. Viruses 7:939-68|
|Batorsky, Rebecca; Sergeev, Rinat A; Rouzine, Igor M (2014) The route of HIV escape from immune response targeting multiple sites is determined by the cost-benefit tradeoff of escape mutations. PLoS Comput Biol 10:e1003878|
|Maldarelli, F; Wu, X; Su, L et al. (2014) HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345:179-83|
|Cillo, Anthony R; Vagratian, David; Bedison, Margaret A et al. (2014) Improved single-copy assays for quantification of persistent HIV-1 viremia in patients on suppressive antiretroviral therapy. J Clin Microbiol 52:3944-51|
|Bhardwaj, Neeru; Maldarelli, Frank; Mellors, John et al. (2014) HIV-1 infection leads to increased transcription of human endogenous retrovirus HERV-K (HML-2) proviruses in vivo but not to increased virion production. J Virol 88:11108-20|
|Wildschutte, Julia H; Ram, Daniel; Subramanian, Ravi et al. (2014) The distribution of insertionally polymorphic endogenous retroviruses in breast cancer patients and cancer-free controls. Retrovirology 11:62|
|De Ravin, Suk See; Gray, John T; Throm, Robert E et al. (2014) False-positive HIV PCR test following ex vivo lentiviral gene transfer treatment of X-linked severe combined immunodeficiency vector. Mol Ther 22:244-245|
Showing the most recent 10 out of 41 publications