Assistant Professor of Microbiology and Immunobiology,
Harvard Medical School
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 TRIM5alpha 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 TRIM5 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 TRIM5alpha 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.
Newman, R.M., Hall, L., Kirmaier, A., Pozzi, L., Pery, E., Farzan, M., O’Neil, S., Johnson, W.E.
2008. Evolution of a TRIM5-CypA Splice Isoform in Old World Monkeys. PLoS Pathogens. In Press.
Lee, A.S., Gutierrez-Arcelus, M., Perry, G.H., Vallender,
E.J., Johnson, W.E., Miller, G.M., Korbel, J.O., Lee, C. 2008. Analysis of copy number
variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease
studies. Human Molecular Genetics. In Press.
Johnson, W.E. Endogenous Retroviruses. In The Encyclopedia of Virology (in press).
W.E. Assisted Suicide for Retroviruses. 2007. Nature Biotechnology 25:643-644.
Newman, R.N., Johnson, W.E. A Brief History of TRIM5alpha. 2007. AIDS Reviews 9:114-125.
Sato, S. and Johnson, W.E. Antibody-mediated Neutralization and Simian Immunodeficiency Virus Models of HIV/AIDS. 2007. Current HIV Research 5:594-607.
Johnson, W.E. Host Genetic Variation and Susceptibility
to Primate Lentiviruses. 2007. Future HIV Medicine 1(4):399-413.
Newman, R.M., Hall, L., Connole, M., Chen, G-L., Sato, S., Yuste, E., Diehl, W., Hunter, E., Kaur, A., Miller, G., Johnson, W.E. 2006. Balancing Selection and the Evolution of Functional Polymorphism in Old World Monkey TRIM5alpha. Proceedings of the National Academy of Sciences 103:19134-19139.
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.
Johnson, W.E., Lifson, J.D., Lang, S.M., Johnson, R.P. and Desrosiers,
R.C.2003. The importance of B-cell responses for immunological control of
variant strains of simian immunodeficiency virus. Journal of Virology 77:375-381.
Johnson, W.E., Sanford, H., Schwall, L., Burton, D.R., Parren, P.W.H.I., Robinson, J.E., and Desrosiers, R.C. 2003. Assorted mutations in the envelope gene of simian immunodeficiency virus lead to loss of neutralization resistance against antibodies representing a broad spectrum of specificities. Journal of Virology 77: 9993-10003.