INFLUENZA EPIDEMIOLOGY AND EVOLUTION
See internal "NOTE" concerning YOUR participation on Wednesday and Friday.
Because viruses can reproduce so rapidly and produce such large numbers of progeny, the effects of natural selection can produce evolutionary change in viruses over a shorter time scale than seen for complex organisms. In general, RNA genome viruses can undergo evolutionary change quicker than DNA genome viruses. This is because most viral DNA polymerases have a proofreading activity but viral RNA polymerases do not. Thus, a random nucleotide mistake made by the viral genome replicating enzyme would almost always be immediately repaired in dsDNA but not in RNA. So, there will be much more inherent variation at the nucleotide sequence level in a replicating population of an RNA virus than for an otherwise similar DNA virus. Because essentially all RNA viruses have a genome in the range 10-20Kb, it's possible to make a general statement that "In RNA viruses, roughly one nucleotide per genome is incorrectly reproduced in each replication." (Quote from review article by Bonhoeffer and Sniegowski, Nature, Nov. 28, 2002, page 367.)
For Influenza and HIV, viral evolutionary change is actually an important aspect of the replicative success of the virus in human populations. In both cases, the evolutionary change is largely the result of inherent variation and then better replication of those variants that somehow partially evade the effects of the body's immune response.
1. What are the properties of Influenza virus relevant
to its ability to undergo noticeable evolutionary change?
There are several properties that "come together" in influenza that make evolutionary change particularly noticeable and important
for this virus. The main factors are:
(1) The viral RNA polymerase that replicates the viral RNA genome does not have
a proofreading capability.
(2) The virus genome is in 8 pieces.
(3) Various strains of Influenza
A virus can productively infect multiple mammalian and avian spieces. (This is not generally the case for strains of Influenza B virus.)
(4) The main immune response to influenza infection
is the synthesis of antibodies that recognize portions of the HA glycoprotein
that do not have to have a specific conserved structure for HA function. As
shown in the handout figure (taken from the orginal 1981 article in Nature reporting the 3-D X-ray crystallography structure of HA), the major antibody-interacting domains of HA are
distinct from the main functional domains.
2. What are the mechanisms of the processes of "antigenic
drift" and "antigenic shift" by which influenza virus undergoes
evolutionary change?
Antigenic drift is a result of the gradual accumulation of mutational
changes in the genome. Some of these changes will be neutral and some will be
favored ("disfavored" changes will not accumulate in the population).
From the beginning to end of a winter "flu season", or from one winter
to the next, a given strain of influenza virus may change by a percent or so
at the nucleotide sequence level. (One percent of 12 Kb is 120
nucleotides.) Thus, there is a gradual change at the amino acid
sequence level in some parts of some of the viral proteins. Over a decade or
so, a given "strain" of influenza virus can change quite significantly
in, for example, the region of HA to which antibodies bind. So, your memory B cells (and memory T cells) from a case of flu you
had just a few years ago may not be able to protect you from getting the flu
from "the same strain" now.
Antigenic shift is a sudden major change in antigenic type. This can result from a mixed infection (in a single
cell) with two influenza type A strains, producing a new strain with some genome
pieces from each original strain. Strains of influenza A are defined mainly by their HA and
NA structures, since these two virion surface glycoproteins are the major targets
of antibody binding. So, if we imagine an "H1N1" strain and a "H2N2"
strain infecting the same cell in the same organism (human or non-human), we
could expect that it might be possible that one of the new virions produced
from this infected cell might have the "H1" HA-coding RNA piece and
the "N2" NA-coding RNA piece. If this new mixed-genome virion is indeed
infectious, it could be the beginning of a "new strain" of influenza
A virus, "type H1N2". (This kind of recombination
to produce a new strain is not necessarily limited to the HA and NA genome segments;
thus, we could imagine that there may be various possible viable combinations
that could result from an infection with two strains.)
3. What were the major influenza pandemics
of the past 50 years or so?
A simplified history of influenza in the 20'th century is
provided in this diagram from the late 1990's,
showing the antigenic shifts that resulted in several pandemics. (The information about the 1890 and 1900 pandemics must be considered to be speculative, because influenza virus was first isolated in the 1930's.)
Throughout the 1930's, 40's, and early 50's, H1N1 was the only Influenza A strain in circulation in people. In 1957, the "Asian flu" pandemic was due to an antigenic shift to H2N2 (with the almost total disappearance of H1N1). Eleven years later, in 1968, the "Hong Kong flu" pandemic was due to an antigenic shift to H3N2 (with the almost total disappearance of H2N2). Molecular analyses have shown that both the 1957 and 1968 pandemic viruses were a result of the reassortment of a human strain with an avian strain. The "Russian flu" of 1977 was due to a re-emergence of H1N1, but with the continued major presence of H3N2 in the population. H1N1 and H3N2 have remained in circulation, while undergoing continuous antigenic drift, for nearly 30 years now.
NOTE: On Wednesday and Friday, March 14 & 16, you (plural) will cover the links listed below. Each student in the class will have 8 minutes to cover one link. The latest time to sign up for yours is the end of class on Monday. You may request a specific article/link ahead of time by email to me no later than Sunday at 5 PM.
4. To what extent do we understand the nature of the deadliest influenza pandemic, that of 1918?
Attempts to understand the deadliest of the 20'th century pandemics, the 1918 "Spanish flu", were stimulated several years ago by the discovery of preserved tissue from a few victims. Fragments of viral RNA were isolated from these human tissues, allowing sequence analysis of this influenza A strain from nearly a century ago. Read the following four summary articles from the past year and a half.
Heather Wilson will cover Kaiser, Virology: Resurrected Influenza Virus Yields Secrets of Deadly 1918 Pandemic, a News of the Week article. (Science, October 2005).
Daniell Rowles will cover Taubenberger et al., Molecular virology: Was the 1918 pandemic caused by a bird flu? Was the 1918 flu avian in origin? (Reply). (Nature, April 2006).
Alanna Nattis will cover Loo and Gale, Influenza: Fatal immunity and the 1918 virus, a News and Views article. (Nature, January 2007).
Alyssa Nielubowicz will cover Enserink, Virology: From Two Mutations, an Important Clue About the Spanish Flu, a News of the Week article. (Science, February 2007).
5. What is the current status of influenza in the US?
H1N1 and H3N2 strains of Influenza
A have remained in circulation throughout the 1990's and 2000's.
Along with a strain of Influenza B, these are the viral strains responsible
for almost all of the cases of influenza that occur. These strains have been
undergoing antigenic drift for the past several decades.
Ashley BeBarba will cover Koelle et al., "Epochal Evolution Shapes the Phylodynamics of Interpandemic Influenza A (H3N2) in Humans" (Science, December 2006).
Michael DeVito will cover the CDC's latest update on this winter's flu season in the U.S.
6. What is the late 1990's-early 2000's history of avian influenza in Asia?
Near the end of the 1990's, the first documented infection of humans by an avian H5N1 influenza strain occurred. This strain was shown to be highly pathogenic in humans but not easily transmitted from person to person. In 2004, the first reports of likely (but still inefficient) human to human transmission were documented.
Brittany Grier will cover Li et al., "Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia". (Nature, July 8, 2004).
Christa Buckheit will cover Montco, "The Threat of an Avian Influenza Pandemic." (New England Journal of Medicine, January 25, 2005).
7. What are some late 2006-early 2007 updates on the spread of H5N1 influenza?
Jamie Wohlhagen will cover Webster and Govorkova, "H5N1 Influenza - Continuing Evolution and Spread". (New England Journal of Medicine, November 23, 2006).
Amy Johnston and Aalok Shah will cover update articles on the U.S. Dept. of Health and Human Services' pandemic flu website.
