SERINC5: a blood cell guardian against HIV
HIV-1 is a virus that currently affects 36 million people worldwide. While the trend of the epidemic has slowed down in recent years thanks to a drug cocktail capable of efficiently inhibiting virus replication, neither a preventive vaccine nor an eradication therapy exist. New targets are therefore needed to develop therapeutic strategies complementary to the existing ones, in order to eradicate the infection.
HIV carries proteins that the virus needs to infect new cells within infected individuals (click here to read more about how HIV replicates within cells). One of these proteins, called Nef, was found to be particularly important for the development of the syndrome linked to this virus, AIDS. This was demonstrated by rare cases of patients infected with HIV lacking the Nef protein. These patients remained healthy for a long time despite carrying the virus in their blood. This observation raised interest on the mechanism of action of Nef, and several research groups investigated its activity at the cellular and molecular levels. We now know that Nef is a multifunctional protein that carries out several activities for the virus' particles. Among these activities, however, one has remained enigmatic: the importance of Nef for maximizing the ability of HIV to infect new cells.
The aim of our research was to understand how the Nef protein enhances HIV infectivity. We first observed that the importance of Nef for the infectivity of HIV depends on the cell type in which the virus is generated. In fact, while Nef does not appear to improve the infectivity of HIV generated in cells from some tissue types, it is required by viruses produced in most blood-derived cell types. Such cell type-dependency suggested the existence of a factor in the cell which generates the virus, capable of inhibiting HIV and being neutralized by Nef. This factor must then be present in most blood-derived cells but absent in other cell types. To identify this key-regulator we screened for genes able to generate a certain factor only in blood-derived cell types but not in the cell lines where Nef is not required to produce infectious viruses. The investigation took advantage of a technique called massive parallel sequencing, capable of retrieving the sequence of all genes that are actively generating factors in a specific cell. The analysis identified SERINC5 as the only gene whose level of activity could accurately predict the effect of Nef on the infectious power of the virus. All subsequent experiments demonstrated that SERINC5 acts as a powerful inhibitor of HIV infectivity and, consistently, that this inhibitory effect is counteracted by Nef.
The SERINC5 gene encodes for a protein inserted into the cell membrane and localized at the surface of the cell. HIV, like many other viruses, is surrounded by a membrane that the virus derives from the cell where it is generated. Our experiments have shown that when SERINC5 is present on the cell surface, it is incorporated into the membrane of the emerging virus particles. Then, with a mechanism yet to be understood, SERINC5 inhibits the infectivity of the newly produced virus by interfering with its ability to penetrate into a new cell. However, HIV developed a mechanism to overcome such inhibition. In fact, Nef protects the virus by removing the SERINC5 protein from the host cell surface, allowing the virus to emerge from the cell with a membrane that does not carry the cellular inhibitor.
SERINC5 belongs to a family of five genes encoding similar membrane proteins, with functions that remain largely unknown. In addition to SERINC5, SERINC3 was also similarly found to act against HIV, suggesting a prevalent anti-retroviral role for this group of proteins.
Our research has further unveiled that other retroviruses, which infect different animals (for example mice and horses), are also inhibited by SERINC5 and, like HIV, these viruses have evolved factors capable of overcoming its inhibiting activity. SERINC5, therefore, is an endogenous and ancient defense system against retroviruses that retroviral pathogens have been able to bypass. We can use this discovery in two ways. We can either generate a SERINC5-like molecule which acts in a similar way but is not counteracted by Nef, or we can develop a drug to prevent Nef from recognizing SERINC5, therefore unleashing its full antiviral activity. Further research will hold the answer.
Rosa A, Chande A, Ziglio S, De Sanctis V, Bertorelli R, Goh S, McCauley S, Nowosielska A, Antonarakis S, Luban J, Santoni F, Pizzato M.HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. Nature. 2015;526(7572):212-217. doi:10.1038/nature15399.
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