Spanish researchers have discovered a new mutation that confers protection against HIV infection. The genetic alteration is located in the TNPO3 gene (which encodes the transportin 3 protein in humans). This is the second genetic mutation described that protects against the virus. The first, revealed two decades ago, was found in the CCR5 virus entry receptor.
The study conducted by researchers at the Carlos III Health Institute (ISCIII) in Spain was published in the latest issue of Plos Pathogens.
Transportin 3 is a cellular protein that is responsible for the transport of proteins between the cytosol (part of the cell cytoplasm without the organelles) and the cell nucleus, which has been the target of the scientific community for some time now.
More than 10 years ago, in 2008, a series of scientific publications showed that this protein is essential for HIV infection. In later years, experts from the Vall d´Hebrón hospitals in Barcelona and La Fe de Valencia described that patients with a rare muscular disease (Limb-girdle muscular dystrophy type 1F, LGMD1F) which affects a single family in Spain and Italy, were carriers of a mutation in the gene of transportin 3.
The researchers proposed from this finding the hypothesis that, due to this mutation, the affected patients would be resistant to HIV infection. José Alcamí, head of the AIDS Immunopathology Unit at the National Center for Microbiology, points out that this hypothesis has now been confirmed and that this study describes the mechanism that blocks HIV infection.
Multitude of functions
Transportin 3 acts at several levels in the HIV cycle: cytosolic transport of the capsid, transport to the nucleus and integration of the virus genome into cellular DNA. The results obtained suggest that transport to the nucleus and integration are significantly altered in patients with this new mutation.
“Viruses carry necessary genetic information, but not enough to complete their replicative cycle; they need cell proteins, which adapt to the cell pathways that allow them to multiply,” explains Alcamí.
Among the proteins to which they adapt are those that regulate intracellular transport, so HIV has become accustomed to using transportin 3 to achieve its ultimate goal “which is the integration into our genes,” continues the researcher, who concludes : “We can consider it a ‘stowaway’ of the transport line 3.”
According to the researchers, this discovery allows us to understand the infection process and how HIV reaches the cell nucleus. It also explain why the mutation in transportin 3 causes muscle disease in patients, since among the proteins it carries there are factors that regulate the expression and processing of muscle proteins.
Common border between HIV and rare diseases
“We are faced with an exceptional situation, on a common border between rare diseases and infectious diseases,” Alcamí continues: “Mutant transportin 3 is involved in two diseases: it causes hereditary muscular dystrophy and protects against HIV infection. If we can understand the underlying mechanisms, we could design pharmacological and gene therapy strategies to, on the one hand, block HIV infection in lymphocytes, and on the other, cancel the action of the mutant transportin at the muscular level and thus improve the symptoms of the illness.”
The research is part of an international consortium in which La Fe Hospital in Valencia also participates, with Juan Jesús Vilchez as principal investigator; Rubén Artero, from the University of Valencia, and the Zeger Dbyser group, from the University of Leuven in Belgium. The project has been funded thanks to the ISCIII Strategic Health Action, the Merck Health Foundation and a crowfunding launched by the Conquistando Escalones patient association and the Precipita platform.