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Genomics

A new network for the viruses

Project will study the genetics of four organisms with high incidences in São Paulo

FAPESP has just finished creating Rede de Diversidade Genética de Vírus, the VGDN (in English the Viral Genetic Diversity Network), a consequence of FAPESP’s Genome Program. The VGDN is going to be leaning towards this class of micro organism which houses the smallest agents which cause the infectious processes known to us. Though they have only a small genome, their study is fundamental for understanding the diversity among their strains and their mutations. The network has as its objective over the next four years, the genetic variations of four viruses: the HIV-1, the type of Aids most common in Brazil; the HCV, the agent responsible for hepatitis C; the Hantavirus, which provokes an as yet mysterious lung syndrome; and the VRS (sinusitis respiratory virus), responsible for infections in the respiratory tract, mostly in children.

Budgeted at US$ 8 million, the program will create a State network of 17 laboratories, with the intention of radiographing the mutations and genetic varieties of the viruses from samples of these pathological agents collected from the principle regions of the State of São Paulo. “With the VGDN, we shall have the conditions to carry out a series of studies: to identify the dominant types of viruses in the State, to carry out studies on the genealogy of these organisms, to establish transmission links and even to know who passed the virus to whom and who got it from whom.” said José Cássio de Moraes, director of the Center of Epidemiological Vigilance (CVE), from the Health Secretary of the State, given the responsibility of coordinating the epidemiological part of the project.

As well as being organisms with unstable genetic structures, the four viruses of the new project have characteristics in common, a fact that influenced their choice as the objects of the study by the VGDN. All of them cause sicknesses with a high rate of mortality, and for which there is no vaccine. With the exception of the syndrome caused by Hantavirus, an illness still considered to be rare, the other maladies present high indices of occurrence in State.

When the work of the mapping of these four viruses is completed, the VGDN will turn itself into a permanent network and will probably be incorporated into the Secretary of Health of the State, which will use it to radiograph the genetic varieties of other micro organisms. The edict with the rules for the laboratories interested in inscribing into the project is already available on the Internet on the homepage of FAPESP (www.fapesp.br). The coordination of the Genome Virus is the responsibility of a committee with members from the participating project institutions, bringing together specialists in virology, epidemiology and bioinformatics: Paolo Zanotto, Marcos Dimas Gubitoso, Edison Luiz Durigon, Eduardo Massad, João Renato Rebelo Pinho, José Cassis de Moraes, Ester Cerdeira Sabino and Leda Jamal.

Three large centers will group together the research developed by the network and will have the function of coordinating the work of the sequencing and analysis of the genetic material of one or more of the viruses. The Foundation Pro-Blood Hemocenter São Paulo and the Center of Reference and Training into DST/Aids of the Secretary of Health of the State will be responsible for the coordination of the work with HIV-1.

The Institute of Biomedical Sciences of the University of São Paulo (ICB- USP) will be the center of reference for the VRS, as well as administering all the part of bioinformatics. The Adolfo Lutz Institute will have the tariff of supervising the analysis of the data on the two viruses, HCV and Hantavírus. The project will also be able to count on the support of two other units of USP: the Institute of Mathematics which will look after the computational support and the Faculty of Medicine which will occupy a part of the medical information program.

Importance
Why is it important to study the genetic diversity of the viruses most common in São Paulo? Wouldn’t it be enough to analyze the data produced in the exterior about these micro organisms and adapt it to the reality of the State or of the country? No, it wouldn’t be enough. As they are organisms with unstable DNA, composed of mutant and recombined genes (the union of two or more genes which results in a new and different gene) the strains of the HIV-1, HCV, VRS and Hantavirus in the majority of the cases in São Paulo could be very different from those found outside.

The case of the agent responsible for Aids clearly demonstrates to illustrate the importance of understanding in detail the genetic outline of a virus, in a given location. There are two major types of Aids virus in the world, the HIV-1, dominant in Europe and in the Americas, and the HIV-2, present above all in West Africa. Each one of these types of virus presents different behavior with respect to a series of parameters such as the speed of the progress of the infection and responding to treatment. To complicate things even more, the HIV-1 has shown itself in the form of more or less nine sub-types designated by the letters A, B, C, D, E, F, G, H and I.

The HIV-2, for its part, has more or less five sub-types, also nominated by the letters (A, B, C, D and E). As if this wasn’t enough, there are rare varieties of the virus which contain pieces of HIV-1 and of HIV-2 in their genetic structure. For apparently being the most common variety encountered throughout the world, the HIV-1 of sub-type B is used in many agreements of the treatment of the disease and in tests of vaccines as the main virus of Aids. And there is the danger. In the end, there are no detailed information showing that it is really dominant in all the areas of the State of São Paulo and in Brazil.

“We’ve got to understand our viruses. If we don’t do this, one day there could appear a laboratory wanting, for example, to sell an Aids based on a determined variety of HIV. What would we do then if we didn’t have at our finger tips the details about the types of virus that we have here ? In a situation such as this, without information about the viral diversity in our country, we could end up buying a vaccine which would not serve for our sick patients.” affirmed Dr. Paolo Zanotto, professor at ICB-USP and the coordinator of bioinformatics of VGDN. In the same way as HIV-1, the other three viruses which are the objectives of the project also present various known sub-types (the HCV has at least six identified varieties) without counting on the ignored strains.

Autonomy
As well as generating data which will result in research in the area of virology, to have an effective and permanent network of laboratories capable of tracing and monitoring the genetic profile of the viruses, will also augment the capacity for action by the State. When it will be functioning at full speed, the VGDN will confer international autonomy and agility to the State to be able to carry out analysis at critical moments. In the middle of an epidemic, for example, it could provide a radiography almost in real time of the strain of the virus which is causing the outbreak. Today there are few centers capable of carrying out this type of tariff such as the Adolfo Lutz Institute. However, there is missing a more comprehensive network which can coordinate, group together, and when necessary, concentrate efforts to realize common objectives.

A network such as the VGDN would have been very useful to the Paulista population in 1997. During that year there was a measles epidemic which intrigued the Brazilian infectologists and became world news. Inexplicably, as well as children, a large number of adults, some vaccinated, also developed the sickness. At the time, public officials of the CDC (Center of Disease Control) in Atlanta, United States, gathered samples of the virus which circulated around here. As it was not a priority of the CDC, which occupies itself fundamentally with health problems in North America, the results of these analysis were only available some time afterwards when the epidemic had already been put under control.

The data served to enrich the studies on the disease, without a doubt, but didn’t help in the least to deter the advance of the outbreak. “Officially, we were only informed by the CDC about the type of measles virus of the epidemic in 2000.” affirmed José Cássio. Perhaps, with a more rapid diagnosis of the type of virus which was causing the epidemic, the doctors might have managed to detain it in a shorter time and with a lesser cost in terms of people infected and deaths provoked by the disease.

Small DNA
Compared with the genetic material of other species, the DNA of a virus is very small. It has a few thousand, sometimes dozens or hundreds of thousands of pairs of bases, the chemical groupings which form the basis of life. In the four types of virus to be studied, the number of pairs of bases is not greater than fifteen thousand. That is to say, for the effect of comparison, the genome of each of these pathological agents is, at the least, 180 times smaller than all of the genetic code of the bacteria Xylella fastidiosa which causes the yellowing of oranges (2.7 million pairs of bases), the first organism sequenced through the FAPESP Genome Project.

If confronted with the size of the human DNA, 3 billion pairs of bases, the genetic material of the viruses takes on airs even more negligible: it has 200,000 times less in the chemical groupings than that of the genetic code of Homo Sapiens. Since it is very small, the genetic material of the viruses, in theory, should not offer any great difficulty to being totally sequenced. In the exterior, various samples of HIV-1, HCV, Hantavirus and VRS have had their DNA mapped in an integrated manner.

As was already said, the challenge of the project is not to simply produce complete genomes of the viruses – but to sequence and analyze a large quantity of samples of these pathological agents coming from all of the State, with the objective of obtaining a general panorama of the genetic diversity of the virus and of establishing which strains are strongest. With this intention, each one of the 17 participating laboratories of the program should generate 4,350,000 pairs of bases of HCV, 4,180,350 of HIV-1, 1,200,000 de VRS and 180,000 of Hantavirus. On average, each nucleotide (pair of bases) should be sequenced five times.

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