Transportin-3: HIV Immunity Due to an Extremely Rare Genetic Mutation

An extremely rare genetic mutation, responsible for the onset of a muscular disease affecting a group of about 100 people worldwide, creates a natural immunity against the virus that causes AIDS.

The discovery was made by Spanish scientists, who hope that the research will be able to obtain new anti-HIV drugs.

A first mutation was already known to scientists: the one that was discovered after being transmitted to the famous “Berlin patient”, Timothy Brown, cured of HIV by a stem cell transplant containing a rare mutation of the CCR5 gene, which confers a natural immunity against this virus.

The new mutation targets another gene (Transportin-3 or TNPO3) and is much rarer: it was discovered several years ago in a family in Spain, whose members were affected by an ultra-rare muscular disease – Limb-girdle muscular dystrophy (LGMD).

Model of the potential roles of the CA-dependent nuclear transport factors during HIV-1 infection. NUP358, NUP153, and CPSF6 at the nuclear pore most likely act on PIC-associated CA to aid HIV-1 infection. TNPO3 is required to localize CPSF6 to the nucleus; premature cytoplasmic CPSF6 binding to CA prevents nuclear import. TNPO3 may affect integration by interacting with IN within the nucleus. CypA modulates CA uncoating, altering dependencies on NUP358, NUP153, and TNPO3. Perturbation of this pathway by CA mutation or TNPO3, NUP153, or NUP358 knockdown results in altered integration site selection away from gene-dense regions of chromatin.

Doctors noted that a number of researchers studying HIV were interested in separate studies on the same gene, as it plays a certain role in transporting the virus inside cells.

They got in contact with the geneticists in Madrid, who did a lab test and infected the blood taken from the members of the same Spanish family with the virus that causes AIDS.

The experiment gave them a big surprise: the lymphocytes of the patients suffering from that ultra-rare muscular disease were naturally resistant to HIV. The virus couldn’t penetrate inside them.

“This helps us to understand the transport of the virus in cells much better,” explained Jose Alcami, a virologist at the Carlos III Institute of Health in Madrid, who conducts this study. The results were published in the American journal – PLOS Pathogens.

HIV is a well-known virus, the Spanish researcher added, “but there are still many things we know less about. For example, we do not know why 5% of infected patients do not develop AIDS. There are mechanisms of resistance to the infection that we understand very little about.” he said.

The road is still very long before doctors can exploit this gap and produce a new drug. But the discovery of this natural resistance confirms that the TNPO3 gene may be considered another interesting research target, which deserves to be considered in stopping the spread of HIV.

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