Scientists Identify Two Genes that ‘Shut Down’ HIV-1 Viru

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An international group of researchers has identified genes that disable HIV-1, suggesting a promising new strategy for battling the virus that causes AIDS.

HIV-1 virion. Image credit: US National Institute of Health.

In their two studies, the scientists found that host cell membrane proteins called SERINC5 and SERINC3 greatly reduce the virulence of HIV-1 by blocking the ability of the virus to infect new cells.

HIV-1 Nef, a protein important for the development of AIDS, counteracts the SERINCs. New drugs that target Nef would permit the SERINC proteins to inactivate the virus.

“It’s amazing, the magnitude of the effect that these proteins have on infectivity. The SERINC proteins reduce the infectivity of HIV-1 virions by more than 100-fold,” said Prof. Jeremy Luban from the University of Massachusetts Medical School.

“The ability of HIV to inhibit these SERINC proteins has a profound impact on its capacity to infect other cells,” said Prof. Heinrich Gottlinger, also from the University of Massachusetts Medical School.

“Disrupting this mechanism could be a very powerful strategy for treating HIV and similar viruses that express the Nef protein.”

The two studies used completely different, yet complementary, methodologies to unravel the complex interaction between the HIV-1 protein Nef and the cell surface membrane proteins SERINC5 and SERINC3, both of which are expressed in the immune system’s T cells.

The researchers performed parallel sequencing on 31 human cell lines that differed in terms of the magnitude of dependence on Nef for HIV-1 replication.

They also approached the problem biochemically. Conducting proteomic analysis of purified virions, they were able to identify host cell proteins that Nef regulated.

“It has been known for more than 20 years that Nef is needed to make HIV-1 such a deadly virus. Our new studies may finally give us an important glimpse into how Nef might do this,” Prof. Luban said.

The HIV-1 virus consists of only nine genes. To replicate its genome, the virus requires a host cell.

Once the virus has infected a cell it takes over certain native cellular processes so that it can replicate.

Ultimately, the infected host cell produces new virions carrying the HIV-1 genome. These virions, in turn, search for new cells to infect, continuing the cycle of infection.

Nef, one of nine primary proteins expressed by HIV, induces numerous changes in the host cell that increase the virus’s ability to infect new cells.

One of its jobs is to sequester SERINC3 and SERINC5 so that these cellular proteins do not reach the surface of the cell and cannot be incorporated into newly formed virions.

In the absence of Nef, virions incorporate the SERINC3 and SERINC5 proteins into the viral envelope as they leave the host cell, rendering them unable to infect new target cells.

“These virions are able to latch onto potential host cells, but the HIV-1 genome can’t pass through the viral envelope when SERINC3 and SERINC5 are present. Somehow these proteins are blocking the release of the virus’s genome, essentially keeping the virus from spreading,” Prof. Gottlinger said.

The scientists said that the anti-retroviral effect of SERINC seems to extend across all retroviruses and may turn out to be universal.

The findings, published online yesterday in the journal Nature, could have implications for treating all enveloped viruses.