Proteins Found to Inhibit HIV Reproduction

Research may offer powerful new tool in the treatment of HIV.

Two studies from the University of Massachusetts Medical School, the University of Trento in Italy, and the University of Geneva in Switzerland, illustrated a promising new anti-retroviral strategy that combats HIV-1.

The studies proved that the host cell membrane proteins SERINC5 and SERINC3 reduce the virulence of HIV-1 by blocking the ability of the virus to infect new cells.

As a reaction, HIV-1 encodes a protein called Nef that counteracts the SERINCs; however, newer targeted therapies can eliminate Nef from the equation, allowing the SERINCs to inactivate the virus.

“It’s amazing, the magnitude of the effect that these proteins have on infectivity,” said Jeremy Luban, MD, the David J. Freelander Professor in AIDS Research and professor of molecular medicine at UMass Medical School. “The SERINC proteins reduce the infectivity of HIV-1 virions by more than 100-fold.”

In order to unravel the complex interaction between the HIV-1 protein Nef and the cell surface membrane proteins SERINC5 and SERINC3, Luban and his team of scientists performed massively parallel sequencing on 31 human cell lines that differed in terms of magnitude of dependence on Nef for HIV-1 replication.

“The ability of HIV to inhibit these SERINC proteins has a profound impact on its capacity to infect other cells,” said Heinrich Gottlinger, professor of molecular, cell and cancer biology at UMass Medical School. "Disrupting this mechanism could be a very powerful strategy for treating HIV and similar viruses that express the Nef protein.”

Dr. Gottlinger approached the problem biochemically, conducting proteomic analysis of purified virions in order to properly 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,” Luban said. “Our new studies may finally give us an important glimpse into how Nef might do this.”

Viruses do not have the capacity to reproduce on their own. The HIV-1 virus consists of only nine genes and to replicate its genome, it must belong to a host cell.

When the virus enters a cell, it overtakes certain cellular processes that enable it to reproduce. Ultimately, the infected host cell produces new virions carrying the HIV-1 genome. The virions then search for new host cells, continuing the cycle of infection.

Nef is one of the 9 primary proteins expressed by HIV and induces numerous changes in the host cell that allow the virus to infect new cells more easily.

According to Luban, Gottlinger, and colleagues, one of Nef’s primary functions is to sequester SERINC3 and SERINC5 so that the cellular proteins do not reach the surface of the cell and cannot be incorporated into newly formed virions.

When there is no Nef to perform this action, virions incorporate 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,” Dr. Gottlinger said.

Getting the SERINC proteins alone was a difficult task for Gottlinger.

“The SERINC proteins are hard to detect under standard experimental conditions because they tend to aggregate at any temperature above 37 C,” he said. “To get around this problem, we had to devise a way to run the experiment below a set temperature so the protein would remain soluble.”

Both groups additionally ran the same experiments using the murine leukemia virus protein known as glycoGag, which is known to be a good substitute for Nef. The findings indicate that SERINC proteins most likely inhibit the infectivity of all retroviruses, even those distantly related to HIV-1.

“The anti-retroviral effect of SERINC therefore seems to extend across all retroviruses and may turn out to be universal,” Luban said. “Our findings could have implications for treating all enveloped viruses.”

Further research must be done to determine precisely how the SERINC proteins are blocking the virions from downloading its genome into new host cells.

“One possibility is that SERINC is physically keeping the virus’s genome from passing through the viral envelope and the cellular membrane into the new host cell,” Luban explained. “There’s still much that we don’t know about this process and how SERINC works.”