FEVERISHLY
EVOLVING ANTIGENS
CASE STUDY
IN
MOLECULAR EVOLUTION NO. 4
Written by Harold B. White 8/93, Most
recently revised 10/00
C-667 BIOCHEMICAL EVOLUTION, SPRING
2013
Page 3
Warfare
at the Molecular Level
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Because
human survival depends on disease resistance, it is natural to have an
anthropocentric perspective on evolutionary changes in gene frequencies
and
neglect that pathogens also evolve (2). With modern techniques of
immunology,
biochemistry, and molecular biology, epidemiologists can monitor both
the
distribution of disease resistance genes and the evolution of virulence
genes
in infectious organisms. The picture
is ominous.
Most pathogenic bacteria have become resistant to one or more
antibiotics and
some appear to be resistant to all major antibiotics. Plasmids,
containing
multiple resistance genes, move from one bacterial species to another
in a
natural form of lateral gene transfer that creates transgenic
pathogens. We
promote this process by including antibiotics in animal feed. If
bacterial
evolution seems fast compared to human evolution, viral evolution is
even
faster.
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Among
human pathogens, influenza virus is remarkable. Its proteins evolve
about one million times faster than typical human proteins (4), a rate
that makes the influenza virus a model for evolutionary studies (5 -
8). The spherical virus (6) is surrounded by a lipid bilayer in which
two types of viral-encoded proteins, hemagglutinin
(H) and neuraminidase (N), project as is shown in the figure at the
left. Within the virus are eight separate RNA molecules, each of which
encodes an mRNA for a different protein. Checkout the influenza sequence data base. |
Influenza
viruses evolve in two ways. Antigenic drift is the accumulation of
acceptable
amino acid replacements primarily in the H and N surface antigens that
is
driven in part by immune surveillance (9 -11). These proteins play an
important
role in the infection and pathogenicity of various influenza strains
(12) that
have killed millions of people during periodic pandemics (5). Antigenic
shift
occurs when two different strains coinfect a cell and the resulting
progeny
virus contains a random combination of genes from each strain (6, 13).
The
sudden antigenic shift to a new strain usually occurs by recombination
between
a human and an avian or mammalian influenza virus (14, 15).
Because
the three-dimensional structures of the H (16-18) and N (4, 19)
antigens have
been determined, it is possible to assess the role of human antibodies
in viral
protein evolution. By determining the nucleotide sequences of genes
obtained
from influenza A viruses isolated and preserved over the past fifty
years, the
molecular evolution of influenza virus has been reconstructed in some
detail
(20, 21). This virus evolves so rapidly that a fifty-year-old influenza
virus
is analogous to a 50-million-year-old fossil!
Assignment: Discuss all
of the questions below
in your groups. As a group, construct a Concept
Map
on the "Evolution of Influenza Viruses" that incorporates the issues
and concepts highlighted by the questions below. This is the one of two
assignments this semester for which a group grade will be given. The assignment is due Wednesday, April 10
at the beginning of class. Remember that a neat, well organized map
will be
more effective at communicating your understanding.
1. Familiarize yourself with
the structure and epidemiology of influenza virus (6, 8) and its
surface
proteins (4, 16-19). How does the evolutionary response of the pathogen
play
into the approach to treatment (22, 23)? Is there any point in trying
to
produce an influenza vaccine useful for more than a couple of years?
2.
The survival
strategy of the human influenza virus is to evolve rapidly (24), but in
order
to do so it must have a very high mutation rate. If the virus
replicates within
human cells, how can it have a vastly different mutation rate than the
human
genomic DNA?
3.
Several authors
have claimed that the rate of evolution of human influenza virus H
antigen is
due simply to the high mutation rate and not to natural selection (25,
26).
Their basic argument is that the rate of evolution of the first and
second
codon positions was not very different from the third. Why would that
imply
little, if any, selection?
4.
Fitch and
coworkers (21) and others (27) attribute a majority of the nucleotide
substitutions in the hemagglutinin gene to positive selection due to
the immune
system and provide tests to support their hypothesis over the
neutrality
hypothesis described above (25, 26). From the point of view of
hypothesis
testing, do these tests disprove the neutral evolution hypothesis in
this case?
Can one predict the evolutionary changes that might occur in future
influenza
outbreaks (35)?
5. HIV evolves at a rate
similar to influenza virus. Rather than move from host to host, HIV
evolves
within a single host over a decade, producing several lineages (28, 29)
and
eventually swamping the host immune system before AIDS develops.
Infection of
new hosts occurs sporadically. Compendia of articles on AIDS can be
found in
refs. 30 and 31. Compared to the phylogeny of influenza virus isolates
based on
nucleotide sequence analysis, what would a phylogeny of contemporary
HIV
isolates look like? What implications does the natural history and
evolution of
HIV have for therapy (32)? When and where did the AIDS epidemic start
(33, 34)?
References
1.
Zinsser, H. (1933) Rats, Lice and History, Little,
Brown and Co., Boston.
2.
Burnet, M. and White, D. O. (1972) Natural History of
Infectious Disease,
4th edition, Cambridge University Press, Cambridge, U.K.
Note:
Refs. 1
and 2 are classics and are highly recommended reading for anyone
aspiring to be
a physician. In particular they show the importance of an evolutionary
perspective on disease.
3.
Anderson, R. M. and May, R. M. (1992)
Understanding the AIDS epidemic. Scientific
American 266 (5), 58-66.
4.
Colman, P. M., Varghese, J. N. and Laver,
W. G. (1983) Structure of the catalytic and antigenic sites in
influenza virus
neuraminidase. Nature 303, 41-44.
5. Krug,
R. M. (editor) (1989) The Influenza Viruses, Plenum,
New York.
[Review by R. G. Webster in Nature 344,
208 (1990)]
6.
Kaplan, M. M. and Webster, R. G. (1977)
The epidemiology of influenza. Scientific
American 237 (6), 88-106.
7.
Palese, P. (1980) Genetic variation of
human influenza viruses. TIBS, March
1980, pp. iii-v.
8.
Stuart-Harris, C. (1981) The epidemiology
and prevention of influenza. American
Scientist 69, 166-172.
9. Young,
J. F., Desselberger, U. and Palese,
P. (1979) Evolution of human influenza A viruses in nature: Sequential
mutations in the genomes of new H1N1 isolates. Cell 18, 73-83.
10.
Webster, R. G., Laver, W. G., Air, G. M.
and Schild, G. C. (1982) Molecular mechanisms of variation in influenza
viruses. Nature 296, 115-121.
11.
Laver, W. G., Air, G. M. and Webster, R.
G. (1981) The mechanism of antigenic drift in influenza virus. J. Mol. Biol. 145, 339-361.
12. Rott,
R. (1982) Determinants of influenza
virus pathogeneity. Hoppe-Seyler's Z.
Physiol. Chem. 363, 1273-1282.
13.
Young, J. F. and Palese, P. (1979)
Evolution of human influenza A viruses in nature: Recombination
contributes to
genetic variation in H1N1 strains. Proc.
Natl. Acad. Sci. USA 76,
6547-6551.
14. Ward,
C. W. and Copheide, T. A. (1981)
Evolution of the Hong Kong influenza A subtype. Biochem. J.
195,
337-340.
15. Hall,
S. S. (1983) The flu. Science 83, November, 56-63.
16.
Wilson, I. A., Skehel, J. J. and Wiley,
D. C. (1981) Structure of the haemagglutinin membrane glycoprotein of
influenza
virus at 3 Å resolution. Nature 289,
366-373.
17.
Wiley, D. C., Wilson, I. A. and Skehel,
J. J. (1981) Structural identification of the antibody-binding sites of
Hong
Kong influenza haemagglutinin and their involvement in antigenic
variation. Nature 289,
373-378.
18.
Bullough, P. A., Hughson, F. M., Skehel,
J. J. & Wiley, D. C. (1994) Structure of influenza hemagglutinin at
the pH
of membrane fusion. Nature 371, 37-43.
(See also the commentary
on page 19 of the same issue.)
19.
Varghese, J. N., Laver, W. G. and Colman,
P. M. (1983) Structure of the influenza virus glycoprotein antigen
neuraminidase at 2.9 Å resolution. Nature
303, 35-40.
20.
Buonagurio, D., Nakada, S., Parvin, J.
D., Krystal, M., Palese, P. and Fitch, W. M. (1986) Evolution of human
influenza A viruses over 50 years: Rapid, uniform rate of change in the
NS
gene. Science 282, 980-982.
21.
Fitch, W. M., Leiter, J.M.E., Li, X., and
Palese, P. (1991) Positive Darwinian evolution in human influenza A
viruses. Proc. Natl. Acad. Sci. USA 88,
4270-4274.
22.
Amábile-Cuevas, C. F., Cárdenas-García,
M. and Ludgar, M. (1995) Antibiotic resistance. American
Scientist 83,
320-329.
23.
Evolution of antibiotic resistance is
discussed in several articles in Science
257, 1050-1082 (1994).
24.
Clarke, D. K., Duarte, E. A., Elena, S.
F., Moya, A., Domingo, E. & Holland, J. (1994) The red queen reigns
in the
kingdom of RNA viruses. Proc. Natl. Acad.
Sci. USA. 91, 4821-4824.
25.
Saitou, N. and Nei, M. (1986)
Polymorphism and evolution of influenza A virus genes. Mol.
Biol. Evol. 3,
57-74.
26.
Sugita, S., Yoshioka, Y., Iamura, S.,
Kanague, Y., Oguchi, K., Gojobori, T., Nerome, K. and Oya, A. (1991)
Molecular
evolution of hemagglutinin gene of H1N1 swine and human influenza A
viruses. J. Mol. Evol. 32, 16-23.
27. Ina,
Y. & Gojobori, T. (1994)
Statistical analysis of nucleotide sequences of the hemagglutinin gene
of human
influenza A viruses. Proc. Natl. Acad.
Sci. USA. 91, 8388-8392.
28.
Holmes, E. C., Zhang, L. Q., Simmonds,
P., Ludlam, C. A., and Leigh Brown, A. J. (1992) Convergent and
divergent
sequence evolution in the surface envelope glycoprotein of human
immunodeficiency virus type 1 within a single infected patient. Proc. Natl. Acad. Sci. USA 89, 4835-4839.
29.
Ewald, P. W. (1994) Evolution of Infectious Disease.
Oxford University Press.
30. What
science knows about AIDS. Scientific American (October
1988).
31. AIDS:
10 years later. FASEB Journal (July 1991).
32.
Coffin, J. M. (1995) HIV population
dynamics in vivo: Implications for genetic variation, pathogenesis, and
therapy. Science 267, 483-489.
33.
Korber, B. et al. (2000) Timing the
ancestor of the HIV-1 pandemic strains Science 288, 1789 - 1796. See also the
commentary by D. M. Hillis on page 1757-8 of the same issue.
34. Hahn
B. H., Shaw, G. M., DeCock, K.
M., and Sharp, P. M. (2000) AIDS as a zoonosis: Scientific and public
health
implications. Science 287, 607 - 614.
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Created 3
October 2000. Last updated 31 March 2013 by Hal White
Copyright
2013, Harold B. White,
Department of Chemistry and Biochemistry, University of Delaware,
Newark, DE
19716