Virology
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Welkin Johnson, Ph.D.

Assistant Professor in Microbiology and Molecular Genetics

NEPRC
One Pine Hill Drive
Southborough, MA 01772
Tel: 508-624-8041
Fax: 508-786-3317
e-mail: wjohnson@hms.harvard.edu
2 postdoctoral fellows

  

The genomes of all metazoan species, from insects to elephants, are riddled with the proviral remnants of ancient retroviral epidemics. These DNA “fossils” are a testament to the great adaptability of the retroviridae and serve as proof that the lineages of all living species have been subject to retroviral onslaughts for tens of millions of years. Although we are generally

not aware of it, when we study infection and replication of retroviruses in the lab we are really studying relationships that have been fine-tuned by millions of years of co-evolution of retroviruses and their animal hosts.

Among other things, we are interested in using these viral “fossil” sequences to reconstruct both retroviral and host evolution. We are also interested in the host side of this conflict, which we address by studying genes that influence susceptibility to infection and cross-species transmission of retroviruses. One recently described host factor affecting retroviral replication is the TRIM5a?protein. We have found that the TRIM5 locus of old-world monkeys is highly polymorphic, suggesting that this locus is evolving under the influence of balancing selection (selection that maintains equilibrium between two or more alleles). A classic example of balancing selection is provided by the major histocompatibility complex (MHC) locus. Polymorphic sites in MHC proteins define the binding pockets that recognize target epitopes. By analogy, we hypothesize that polymorphic sites in primate TRIM5a homologues represent residues that determine specificity for different retroviruses. Thus, while comparative genomics helps us reconstruct the evolution of the TRIM5 locus, it also provides us with working hypotheses for hands-on molecular dissection of TRIM5a function. Our approach, which combines phylogenetics and molecular virology, can also serve as a template for future investigation of other host genes that affect viral replication and disease progression.

We also study replication and pathogenesis of the lentiviruses, which include HIV-1 and its siblings, the simian immunodeficiency viruses (SIV), and it distant cousins, the various non-primate lentiviruses.We are particularly interested in understanding how these viruses accomplish the feat of continuous, long term replication in hosts that are, at least initially, fully competent to mount virus-specific immune responses. Our focus at this time is on understanding the antibody-resistant phenotype displayed by clinical isolates of HIV-1, bringing to bear on the problem techniques of molecular and cellular biology, recombinant antibody technology, surface plasmon resonance (SPR) and phage-display. The hope is to identify the adaptations that permit these viruses to replicate in spite of vigorous antiviral immune responses, and to apply this knowledge to the rational design of vaccine immunogens or viral entry inhibitors.

 

References:

  1. Newman et al. 2006. Balancing selection and the evolution of functional polymorphism in Old World monkey TRIM5alpha. Proceedings of the National Academy of Sciences 103(50) 19134-19139.
  2. Johnson, W.E. and Coffin, J.M.1999. Constructing Primate Phylogenies from Endogenous Retrovirus Sequences. Proceedings of the National Academy of Sciences 96(18):10254-60. Describes novel properties of ancient viral sequences, such as those found in the human genome, and how these are useful for reconstructing evolutionary history.
  3. Johnson, W. E., Desrosiers, R. C. 2002. Viral persistance: HIV's strategies of immune system evasion. Annual Review of Medicine 53: 499-518. An overview of immune evasion strategies used by the immunodeficiency viruses, with an emphasis on comparisons between HIV and SIV.
  4. Yuste, E., Sanford, H.B., Carmody, J., Bixby, J., Little, S., Zwick, M., Greenough, T., Burton, D.R., Richman, D.D., Desrosiers, R.C., Johnson, W.E. 2006. Simian Immunodeficiency Virus Engrafted with HIV-1 Specific Epitopes: Replication, Neutralization, and Survey of HIV-1-Positive Plasma. Journal of Virology 80:3030-3041. An example of using comparative virology as an experimental approach- in this case SIV strains engrafted with HIV-1-specific epitope structures were used to better understand resistance to antibody-mediated neutralization.