UMass Medical researchers uncover promising clue to battling HIV

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Two independent research teams at the University of Massachusetts Medical School have worked out a key step in HIV-1 infection — and their findings point to a possible way to fight the virus.

Further, new treatments for other infections caused by similar enveloped viruses could be speeded by the discovery.

Through different means, the two teams at the Worcester institution unraveled part of the mechanism of retroviral infection in host cells. The details could lead to the development of drugs targeting one of the few proteins the HIV-1 virus makes from its own DNA: called Nef. Drugs would aim to take that protein down.

Nef, the researchers showed, disables two cell membrane proteins -- SERINC5 and SERINC3 — that otherwise protect the host by somehow impeding the virus’s ability to replicate and spread to other cells.

The two labs’ papers will be published in the Oct. 8 issue of Nature, and are available now online. The study by the team of Jeremy Luban, M.D., on which scientists at two universities in Europe collaborated, is available here. The study by Heinrich Gottlinger, professor of molecular, cell and cancer biology at UMass Medical School, is available here.

“It’s amazing, the magnitude of the effect that these proteins have on infectivity,” Luban said in a statement Wednesday from the medical school. He is the David J. Freelander professor in AIDS Research and a professor of molecular medicine at the school. “The SERINC proteins reduce the infectivity of HIV-1 virions by more than 100-fold.”

HIV-1 is the predominant strain of the AIDS-causing human immunodeficiency virus.

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

According to the statement from the medical school, the two studies used completely different, yet complementary, methods to probe the complex interaction between Nef and the cell surface membrane proteins SERINC5 and SERINC3, both of which are expressed in the immune system’s T cells.

Dr. Luban — working with former members of his lab Massimo Pizzato, now of the University of Trento in Italy, and Federico Santoni of the University of Geneva in Switzerland — "performed massively parallel sequencing on 31 human cell lines that differed in terms of the magnitude of dependence on Nef for HIV-1 replication," the school said.

Gottlinger approached the problem biochemically. Analyzing proteins in purified virions, his lab was able to identify host cell proteins regulated by Nef.

The statement from the medical school explains: “Viruses are relatively simple agents that lack the machinery needed to reproduce on their own. The HIV-1 virus, for example, consists of only nine genes. To replicate its genome, HIV-1 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.”

A virion is a complete, infective form of a virus outside a host cell.

When host proteins SERINC5 and SERINC3 have been allowed to do their jobs — that is, when the virus’s Nef protein cannot counteract them — they enter the viral envelope as the virion leaves the host cell, and render the virion a dud, unable to keep infecting cells. The school said further research will aim to determine just what SERINC5 and SERINC3 do to block the virus from replicating. In some way they seem to lock the viral genome inside the envelope, preventing the genetic material from entering new host cells.

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

And, how to stop it.