Olomouc Immunologists and U.S. Colleagues Seek HIV Vaccine and Way to Treat Kidneys
Milan Raška
Docent Milan Raška from the Department of Immunology at the Faculty of Medicine of Palacký University has been exploring ways how to prevent HIV infection for several years. Together with Prof. Jiří Městecký and his team at the University of Alabama in Birmingham, they have been developing an efficient vaccine. Raška has also been successful in the description of the causes and functioning of IgA nephropathy, an autoimmune kidney disease.
A vaccine against HIV has been searched for by scientists since 1983, when the virus was first described. Research has been conducted by dozens of institutes from all over the world, and Palacký University joined into the research in 2005. A vaccine preparation has not been developed yet, however. One of the reasons is that glycoproteins on the surface of the HIV envelope change rapidly.
‘We have been mostly trying to find out to what extent it is possible to prepare and modify structures which are present on the HIV envelope and could become the target of immune response of the vaccinated person so that the protection works against variants of the virus. We cannot take an HIV viral coat glycoprotein, use it for vaccination and expect that the person will not be infected by other HIV variants. Therefore, we look for structures which could be similar to a certain extent for all the virus variants,’ said Raška, outlining the research.
The important role of sugars
As the research findings suggest, one of the universal structures of HIV are sugars. They are present in glycoproteins (glyco- meaning sugar) on the surface of the virus, and the immune system might have an effect on them in order to prevent the infection from spreading. Sugars are connected to the protein backbone of the glycoprotein during its formation inside a cell attacked by the virus. The importance of the sugars contained in the glycoprotein on the surface of HIV as possibly effective targets for defensive antibodies has been observed in some individuals, who did not fall ill despite being infected by HIV. Their antibodies, binding on the sugars in the HIV envelope proteins, prevented the virus form entering their cells. Unlike the protein backbone of the HIV envelope glycoprotein, its sugars are much less variable.
The sugars in HIV envelope proteins thus have become the centre of attention for Olomouc scientists, who are observing their structure during the formation of the HIV envelope protein in various cells. This information can help them fulfil one of their research goals, which is the development of a DNA vaccine against HIV. Its application will ensure that the immune response will not be activated by the administration of the protein, but directly by adding the HIV gene which codes the protein. When the gene enters the nucleus of a cell, the cell starts to produce the protein on its own. However, as it is a foreign element, it stimulates the reaction of the immune system. Another advantage of a DNA vaccine is that it allows getting around the intricate and expensive preparation of the protein for vaccination.
Doctors suggested how to develop the vaccine
The main outcome has been the confirmation of the fact that sugars on the HIV envelope protein vary fundamentally with regard to whether the protein is formed in various tissue cultures, or in the cell infected by HIV.
‘This finding is essential in terms of the practical development of the vaccine. We have shown that the biotechnological process of its production is important in the preparation of the vaccine. It has not been discovered how to make such a vaccine yet. We are showing the way, however, how it should be produced. The focus on the sugar complements in the HIV envelope protein is one of the ways,’ added Raška. According to him, the key factor is also the concordance between the virus and the protein used in the vaccine. This is why the Olomouc team is collaborating with the Alabama centre, which has a large amount of viruses at its disposal and is capable of reproducing, characterising, and modifying them genetically in various ways. Olomouc researchers together with their U.S. partner have now decided to compare the sugars on a larger number of viruses and asses their reactivity with a broad range of antibodies obtained from individuals infected with HIV.
A new way of treating an autoimmune kidney disease?
Even more concrete results have been achieved in the study of the causes of an autoimmune kidney disease—IgA nephropathy, one of the most common autoimmune diseases of this organ. Olomouc researchers are collaborating with the laboratory of Prof. Městecký and his colleague Jan Novák in this direction as well.
‘The IgA antibody occurs in the kidneys of patients with IgA nephropathy in the form of immune complexes. Immune complexes are formed there as other antibodies bind specifically to IgA. The autoimmune diseases are in essence a response of the immune system to proteins, DNA, or other structures which are normally present in the body. In this case, it is the antibody—the immunoglobulin IgA, which is different from other immunoglobulins in the attached sugars,’ said Raška.
His team tries to find out why the sugars on IgA in the bodies of such patients differ from those in the bodies of healthy people. A further goal is to determine how to prevent such immune complexes from forming.
‘Using bacteria, we can produce a short version of IgA without sugars. We have also produced enzymes allowing us to attach sugars to this IgA according to our needs. So we have the whole cascade, by means of which the shortened IgA protein can be arranged suitably so that it becomes very similar to the IgA immunoglobulin of the patients. We presume that the patients’ antibodies will bind both the pathological IgA and our shortened IgA. This will disrupt the balance of the pathological immune complexes and result in the suppression of the inflammation process in kidneys,’ explained Raška, adding that their procedure is being tested at present.
IgA nephropathy is not a disease common in the population, with 5 cases in 100,000 inhabitants. In some races, however, microscopic examination of kidney tissue may display features characteristic for IgA nephropathy in up to 15 % of the population. As it is with many other autoimmune diseases, no specific treatment has yet been found. Drugs against high blood pressure have been used in the meantime. The procedure in which Olomouc scientists are participating could result in a brand new therapy. The current findings, as summarised by Raška and his colleagues, were published in the prestigious journal Annual Review of Pathology: Mechanisms of Disease, and Raška was awarded for his achievement with the Faculty of Medicine and Dentistry’s Dean’s Prize this year.
