From an etymological point of view, the word virus comes from the Latin virus, meaning certain types of poisons or infectious substances present in nature. Biologically speaking, these organisms are considered to be non-living because they do not comply with three fundamental premises: being able to replicate themselves, have a life cycle and carry out metabolic processes to obtain energy and different molecules.
The first point, the replication, is vital for virus infectivity. For this reason, once the virus enters a cell, it has to control different cellular machineries, taking them all to itself and using them to its advantage.
CONICET researchers and other colleagues in France, US and Portugal described for the first time the role of Rab27a in the replication process of the Human Immunodeficiency Virus (HIV). The scientists found that it takes the endosomal pathway regulated by Rab27a forcing it to carry the necessary molecules to the plasma membrane for the production of new viral particles.
Rab27a is one of the proteins involved in the ordinary control of intracellular traffic of endosomes towards the cellular membrane. Through the manipulation of this pathway, the HIV promotes the arrival of various molecules that turn out to be essential for it.
Matías Ostrowski, CONICET assistant researcher at the Institute for Biomedical Research on Retroviruses and AIDS (INBIRS, CONICET-UBA) and coordinator of the study, explains that this is the first time the role of Rab27a is described in the virus replication process. “The aim of this study was to understand how the virus takes and uses the cellular machine. Rab27a plays key roles in the cell and the virus uses it to form a platform for its assembly.”
In CD4 T lymphocytes, the main target cells of HIV, the viral particles are assembled in specific parts of the cell membrane where there is high concentration of PI (4,5) P2 phospholipid, which binds the Pr55Gag protein responsible for the production of new virions. In the study, the authors proved that the enrichment of PI (4,5) P2 is achieved because Rab27a moves a key enzyme for its synthesis.
In order to assess if the lack of Rab27a decreased viral production, the researchers contacted some colleagues in France who work with patients with Griscelli syncrome, a rare disease in which a genetic defect precludes the synthesis of this protein. The scientists obtained CD4 + T lymphocytes from patient samples and infected those cells with HIV so as to test their replication. The results showed that the process was greatly diminished when it was compared with rates of infected cells of healthy patients.
“Having a patient with a defect in Rab27a síntesis allowed us to validate the results we had and was fundamental for our study”, Pehuén Pereyra Gerber, CONICET doctoral fellow at INBIRS and first author of the paper together with doctor Mercedes Cabrini.
Nevertheless, the authors are cautious about the assessment of potential therapeutic applications of this finding. “This was a basic science study to know what cellular pathway the virus uses to replicate”, Ostrowsky explains and adds: “Although we do not exclude it in the long term, so far we cannot argue that our findings represent a new therapeutic possibility.”
In the future, the authors seek to know and characterize the rest of the molecules that are involved in this cellular pathway that takes HIV so as to improve the knowledge of the mechanisms it uses. A better understanding of the molecules and cellular processes exploited by HIV in order to achieve its assembly is vital to think about the possibility of controlling this stage of the replicative cycle of the virus.
By Ana Belluscio.
About the research:
Pehuén Pereyra Gerber.Doctoral fellow. INBIRS.
Mercedes Cabrini. INBIRS.
Carolina Jancic. Associate researcher. IMEX.
Luciana Paoletti. Assistant researcher. IBR.
Claudia Banchio. Independent researcher. IBR.
Catalina von Bilderling. Postdoctoral fellow. IFIBA.
Lorena Sigaut. Assistant researcher. FCEyN, UBA.
Lía I. Pietrasanta. Independent researcher. FCEyN, UBA.
Gabriel Duette. Doctoral fellow. INBIRS.
Eric O. Freed. National Cancer Institute, EE.UU.
Genevieve de Saint Basile. Institut National de la Santé et de la Recherche Médicale and Université Paris Descartes-Sorbonne Paris Cité, France.
Catarina Ferreira Moita. Instituto Gulbenkian de Ciência, Brazil.
Luis Ferreira Moita. . Instituto Gulbenkian de Ciência, Brazil.
Sebastian Amigorena. Institut Curie, France.
Philippe Benaroch. Institut Curie, France.
Jorge Geffner. Principal researcher. INBIRS.
Matías Ostrowski. Assistant researcher. INBIRS.