Retroviruses exhibit a wealth of evolutionary phenomena, including the ability 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 studied all these aspects of retrovirus evolution: We have looked at the mechanism of evolution of env genes by analyzing an unusual mutant that extends the host range of ALV beyond chicken, to quail, dog, and even human cells. We have isolated and studied an unusual mouse endogenous provirus that appears to occupy a special phylogenetic location between mouse and non mouse species. We have extensively analyzed the coevolution of humans and their endogenous proviruses, particulary the relatively recently inserted HERV-K family. 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. Future work will address the following aims. 1. How do retroviral envelope genes evolve to use new receptors and to alter other important properties? We will use our extended host range mutants to test specific hypotheses for this process. 2. What are the functional and pathogenic properties of human endogenous retroviruses, particularly HERV-K? Can we isolate infectious virus? Is their expression or reintegration associated with malignancy? 3. How do important the forces of mutation, selection, recombination, and drift combine to direct retrovirus evolution? We will combine mathematical and in vitro modelling of virus replication to test specific evolutionary models. Relevance: In addition to its inestimable value as a tool of basic discovery, retrovirus evolution has important consequences for public health. In recent history, several retroviruses 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 both 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA089441-10
Application #
7780021
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2001-02-05
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
10
Fiscal Year
2010
Total Cost
$666,343
Indirect Cost
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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
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
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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
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 22:244-5
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
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

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