[Music] You must eat this life didn't publish many many times, but I use it to to remind you that the beginning of the epidemic, Damian, 1950s, 1960s, but the acceleration of the epidemic indeed in the 1970s and 1980s when

jet air travel became common, and Simpson [Music] They are also seasonal epidemics and increase transmission non-endemic areas, always the curves are almost always occur in joint arrangement in the countries above the equator, the other states. This was the three epidemics

[Music] because we need to deal with the dynamics of the mosquito, the attendants are cycling, there are seasonal that are often Poquelin nature, they don't always spread throughout the entire country, and they vary in severity [Music] The very end, it's very ugly. So the what

what is probable that the temple do we think we know the answer to this for 50 years, but it's much more complex. There are many times and I heard of unity in certain importance, I hear the urban growth we've seen has had a tremendous impact on academic

human behavior that then relates to standards in areas where you have hermetically sealed colleges that are air-conditioned and that television [Music] [Music] [Applause] Then changing virus in this course, all these [Applause]

for 50 years, we focused on her immunity and mutant emphasis as the major factors relating to academic transmission and to disease severity, Asian population [Music] Another relation to severe [Music] Being accumulated evidence that the variation in virus fitness, so what I want to do is use some of my

Study these are 40 studies that I worked on over the years and a lot of collaborators in the work. These are the references at the end of this talk so you can see the collaborators, archived, there are too many to list but basically these are for these more case studies, each

have two epidemiologic data suggesting that there was something unusual about the viruses. So what I'm going to do, though, I'm not going to talk about Indonesia here as I don't have these genome sequences fully, and finally, we're getting close to very well complete

begin with the earliest Monday that South, the South Pacific, our report islands, they were pretty much isolated for 25 years so they have genetics of human population rather homogeneous and all of the time and in 1971 the American genotype, what I call a French Connection

was introduced in convenient from the West, French West, and it caused a massive epidemic of severe, almost simultaneously, severe epidemic in D and D key shortly thereafter in [Music]. We were three years, we watched for Tom, didn't pick up, never did from January

1994 a couple of months later. So we, so that was a puzzle, something was dented about this polywire and again, though we didn't have the tools to do that [Music], survivors or not but the point is is there was a linear change in that water

arrested cannulation dispensed more severe, more bed, exactly 10, you listed and a lot of the fires beside recycled silently in the could be the population without detective, as we look with this there was one change in the CRM and a changing to the

amino acid change of the two A's and for the only changes in so we hypothesized that those three amino acid changes actually change the phenotype of this virus and made it more endemic. So next case study, Sri Lankans had a history of dengue for many things

in here it was confirmed accidentally in the early 1960s. Logical, but they didn't have any capability to do BIOS isolation, computer was non-existent. We didn't know [Music] [Music] so he didn't get any viruses in the latter part, there was one in 1982 maybe

secondary dengue infection in 1989, an epidemic, an unprecedented one, and they didn't have the facility guys like the virus when they attacked them open, send them to me at that time. And I have turned out to do all four sewer pipes were circulating, their dominant

survivors. Danger by three, and over the next few years, there were cases of dengue hemorrhagic fever, then a series of epidemics in the earth that were associated with, and during this time also, the dengue virus begins throughout the. The interesting thing is looking at the

the genetic tree before the we have isalus from 1989 to 2000 here in the air. So what happened with this system, it each year actually changed again. No evidence of any user conspires this, this is strictly as any change within the viruses of a circuit, a circuit

everything, it is so in this case again, I have taken the viruses and not really like the enemies of this sooner than the briefer forgot about. So I had these viruses that I could pull out the creature that were decisions, while the virus would just like the girl in here today

and so again Sri Lanka [Music] [Music] dude and in 1981 days or was introduced that maybe one day before again 1984 to recoup from enacted from Cuba the same virus that was positive human academic and [Music]

[Music] in 1997 frequency [Applause] but the point is interesting the sequence of the events you're not sure yet exactly what all that all means but clearly associated with this so this just shows it in a different way different academic beginning in 1986

year 1994 1998 with it shows the virus is down here and the achievement data doesn't like Ken Annette and her group of University of Hawaii to the genetic history of dengue forums for people if you look here this is plain one this is the virus that was

instituted because the 1982 epidemic DENV-1 was not dating other people there was a claim change sometime that occurred and in this country another then another clay change from this to this and this mistake the virus actually more like vomited it went underground it there was for

expansion for over ten years no epidemic that they were still there and we were able to isolate hey Danny why don't they change in with another epidemic of thing before - fever they say creamer this is the virus that was associated with knowing them and

then another change with [Music] [Music] and the epidemic that we associated with the is that there were changes in the [Music] essentially this this is the interferon you can see the hiring of their on in the PR1 versus at the are too

every one of these initiatives, these are human livers of neither monocyte and the race between genomic RNA and subgenomic RNA is shown here all of the PR2 parts entire genomic [Music] [Music] the initiative de virus in humans and

resulting in hierarchy underscores the complex physiology [Music] so in conclusion, epidemiologic sequences and molecular biology data from three dengue serotypes 2, 3 & 4 are isolated from epidemics in three countries. The three geographic regions show a close

correlation between small genetic changes in viruses and a phenotypic expression in humans. The phenotypic changes included clinical severity and by reading the levels and humans virus replication in the spirit and cell culture in division of interferon expression Cathedral and changes in epidemic potential and the

data suggests that dengue virus evolution by drift and positive selection results in the emergence of new viral images of the same genotype that play an important role in the epidemiology of epidemics of disease in humans. And we all know the epidemic

potential disease severity and pathogenesis of dengue are determined by a complex interaction of viral cultures and environmental factors. So I would hope that we some of these infections earn immunity [Music] [Music] at the end of the day, increased probability of genetic change, positive

selections and convergence of virus or greater epidemic potential and it's those epidemic viruses that are most frequently associated with severe disease and that also increased disease. So this is a different automatically so this is this recent paper here by Piero [Music]

shows the same thing there's another paper here all the rest of these are our papers but this one here by the *Vanasara indica* lock also shows that similar change to the TV to Nicaragua so

The Role of Viral Evolution in the Epidemiology of Dengue Viruses

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