The dangerous effects of genital herpes infections, the routes of HIV infection and the possible vaccine against this dangerous virus – these were the subjects of the work of researchers from Poland, Sweden, France and Italy presented at the Paris immunological symposium.
Genital herpes, HSV-2, is, contrary to appearances, a common disease. Sexually transmitted, it occurs in 10-60 percent. population (in developing countries even among 80%). It is a viral infection – HSV-2, passing through the mucous membranes, colonizes the sacral ganglia and causes relapses. HSV-2 also increases the risk of infection with other sexually transmitted diseases, particularly HIV. Infection of a child with HSV-2 during labor can lead to meningitis and changes in the central nervous system.
During the Paris conference The Underestimated Role of Eptithelium In Inflammation held in mid-April, organized by the Pasteur Institute and the GREMI research panel, the results of a joint study by Dr. Małgorzata Krzyżowska from the Military Institute of Hygiene and Epidemiology in Warsaw and prof. Francesci Chiodi from the Karolinska Institutet in Stockholm about the action of this virus.
The researchers focused on the most important problem – the integrity of the mucosa epithelium. This is the way, during genital herpes infection, the virus enters the body and, at the same time, the mucous membranes are the body’s first line of defense against infection. Unfortunately, the conclusions from the analyzes of cell samples and experiments in the mouse model were not comforting.
In the course of research experiments, it turned out that HSV-2 can freely multiply in the mucosa of female genital organs, influencing the mechanisms of inflammation development. These studies allow for the development of a new type of treatment for herpes through a microbicide – a local drug in the form of a cream or gel that would kill the amount of HSV-2 and weaken its ability to penetrate epithelial cells to such an extent that it cannot cause infection.
Significant discoveries were also presented in Paris by the French research team from the Institut Conchin, led by Prof. Morgane Bomsel. This institute has been dealing with HIV for 20 years, hence the discoveries of the last year, presented at the conference, are among the most important concerning this virus.
The team concluded that the male urethra is a very good environment for HIV-1. The urethra in men is an excellent habitat and site of transmission for viral and bacterial pathogens, as has been found in previous experiments, but it has not yet been proven that HIV can enter the body through this route. Meanwhile, scientists from Institut Cochin obtained various sizes of tissue samples, both genital and epithelial tissue from the ureters and urethra, taken from people undergoing elective sex reassignment surgery. Then, keeping them in tissue culture, they treated them with HIV-1 for 1 hour. The same was done with separately cultured epithelial cells of the urinary tract. As it turned out, the first to be infected were macrophages with CD4 antigen and CCR5 co-receptor, residing in the urethra; T lymphocytes existing in this area were infrequently infected. Infections rarely occurred in the distal part of the male urinary tract, eg in the area of the scaphoid fossa of the urethra. Prof. Morgane Bomsel and prof. Lucia Lopalco from the Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele in Italy therefore concluded that there was a possibility of inhibiting HIV infection by developing a CCR5 blocking vaccine.
CCR5 is the basic chemokine coreceptor, which also determines the entry of HIV into the cell. After binding to the CD4 and CCR5 antigen, the viral envelope fuses with the cell membrane, allowing it to enter the cell. Reverse transcription of the viral RNA then takes place, causing the production of double-stranded DNA, integrated into the host genome, by the enzyme integrase. The cell then produces viral mRNA and structural proteins. Inside it, new viruses are assembled by cutting a large protein molecule with a protease enzyme. This creates new virus particles and leaves the cell. This is how HIV-1 infections occurred in the epithelium of the male urethra, as identified by researchers at the Cochin Institute.
Prof. Bomsel and Prof. Lopalco stated in their research that CCR5 is the only molecular coreceptor that allows HIV to enter the cell. It occurs in the genital epithelium and the gastrointestinal tract and plays a role not only in the infection of the immune system cells, but also in the transmission of the virus to the intact epithelial cells through endosomes. In the case of people with CCR5 deficiency or producing CCR5 antibodies that reduce the amount of this coreceptor in the tissue, most tests carried out on cells, despite the presence of HIV, showed no evidence of HIV infection. This proves that infections first take place in the epithelial tissue and the immune system, mediated by CCR5.
Anti-CCR5 antibodies protect against viral infection by blocking its receptors and preventing its envelope from fusing with the cell membrane. Besides, only this type of antibody, according to the researchers, would permanently reduce the concentration of CCR5 and thus completely block the HIV transmission mechanism. Interestingly, such counteracts naturally occur in the body – they were found in breast milk, saliva and mucus, secreted during sexual arousal in men and women. The secretion of these antibodies does not disappear in HIV-infected individuals. Researchers believe that the presence of these antibodies in infected people plays an important role in stopping the virus from spreading throughout the body. They have already been proven to function as a kind of passive immune mechanism in animal models.
Serum anti-CCR5 antibodies have now been successfully produced and it is possible to transpose them into genital secretions so that they mimic natural anti-CCR5 antibodies and act when there is a threat of infection. This is very important because introducing artificial antibodies to the body’s natural receptors and coreceptors may result in immunological intolerance and endanger the patient’s life. Meanwhile, the introduction of anti-CCR5 antibodies will give a long-lasting and strong immune response, which may contribute to the long-term elimination of the HIV threat, and a vaccine of this type itself should not have side effects.
However, despite the research of scientists from the Cochin Institut and prof. Lopalco will probably have to wait a long time for a vaccine based on anti-CCR5 antibodies – it will take at least a few years to construct an immune mechanism with a long-lasting effect, although work is probably already underway.
text: Marek Mejjsner
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