2023-06-22 11:00:04
For decades, chemists and biologists have tried to understand why only one form of HIV is sexually transmitted while its other forms seem to be blocked by seminal fluid. An international team of scientists finally lifts the veil on this enigma of more than 40 years by demonstrating the role of two small molecules: spermine and spermidine.
In contact with the target cells of HIV, the polyamines (spermine and spermidine, in yellow) bind to the CXCR4 coreceptors (in blue on the cell). This inhibits infection by viruses (A virus is a biological entity that requires a host cell, which it uses…) X4 (in blue) and only R5 (red) viruses infect target cells and disseminate in the ‘body.
© Jean-Philippe Herbeuval
The human immunodeficiency virus (HIV-1) targets 3 types of immune system cells: T lymphocytes, monocytes and macrophages. Its entry into these cells involves the binding of the viral envelope glycoprotein gp120 to the CD4 receptor expressed on the cell surface. This binding leads to a change in conformation (In chemistry, the conformation of a molecule is the spatial arrangement of the atoms that compose it….) of the glycoprotein which allows the virus to bind to two other membrane coreceptors expressed by the host cell: CXCR4 or CCR5 receptors. We then speak respectively of strains of HIV with tropism (Tropism comes from the Greek which means “to give a direction”.) X4 (HIV-X4) or R5 (HIV-R5). These two steps, binding to the main receptor and then to the coreceptor, are essential for the infection of the target cells.
Sperm is the main vector for the sexual transmission of HIV-1 and both virus subtypes (X4 and R5) are indeed found in the liquid fraction (The liquid phase is a state of matter. In this form, the matter is…) sperm, called seminal fluid. This liquid is composed of proteins, lipids, metabolites and very large quantities of small positively charged molecules: polyamines, mainly spermine and spermidine. Surprisingly, despite the concomitant presence of X4 and R5 viruses in seminal fluid, only HIV-R5 viruses are sexually transmitted. This is all the more surprising since the CXCR4 receptor is more widely expressed on the surface of HIV target cells than the CCR5 receptor. There is therefore an anti HIV-X4 “barrier” which has still not been discovered.
To identify the factors likely to limit the sexual transmission of HIV-X4, a European group of chemists and biologists, led by a team from the Chemistry and Biochemistry Laboratory (Biochemistry is the scientific discipline that studies the chemical reactions that take place… ) pharmacological and toxicological studies (CNRS/Université Paris (Paris is a French city, capital of France and the capital of the region…)), have generated a library of compounds derived from seminal fluid. They then assessed the anti-HIV effects of each fraction on HIV target cells. Of these, four flanking fractions blocked infection by HIV-X4 but not by HIV-R5. Analysis of these fractions revealed that they all contained polyamines, mainly spermine and spermidine. The study showed that spermine binds to the CXCR4 co-receptor, which has the effect of selectively blocking the infection of T lymphocytes and macrophages by HIV-X4. The spermine and spermidine contained in the seminal fluid therefore seem to be at the origin of the unsolved enigma for more than 40 years of the sexual transmission of viruses.
Reference
Spermine and spermidine bind CXCR4 and inhibit CXCR4- but not CCR5-tropic HIV-1 infection.
Mirja Harms, Nikaïa Smith, Mingyu Han, Rüdiger Groß, Pascal von Maltitz, Yasser B. Ruiz-Blanco, Yasser Almeida-Hernández, Armando Rodriguez-Alfonso, Dominique Cathelin, Birgit Caspar, Bouceba Tahar, Sophie Sayettat, Nassima Bekaddour, Kanika Vanshylla , Franziska Kleipass, Sebastian Wiese, Ludger Ständker, Florian Klein, Bernard Lagane, Arnaud Boonen, Dominique Schols, Serge Benichou, Elsa Sanchez-Garcia, Jean-Philippe Herbeuval & Jan Münch.
Science Advances 2023
DOI: 10.1126/sciadv.adf8251.
1687740906
#40year #riddle #HIV #finally #solved
