September 30, 2015

UMMS scientists identify genes that shut down HIV-1

Heinrich Gottlinger, MD, PhD

Discoveries in Luban, Gottlinger labs point to new strategies for disabling viruses

(September 30, 2015)  A pair of studies in the journal Nature, one by Jeremy Luban, MD, and colleagues in Italy and Switzerland, and the other by Heinrich Gottlinger, MD, PhD, and colleagues; have identified genes that disable HIV-1, suggesting a promising new strategy for battling the virus that causes AIDS.

The studies, published online Sept. 30, show that the host cell membrane proteins SERINC5 and SERINC3 greatly reduce the virulence of HIV-1 by blocking the ability of the virus to infect new cells. HIV-1 encodes a protein called Nef that counteracts the SERINCs. New drugs that target the HIV-1 protein Nef would permit the SERINC proteins to inactivate the virus. The papers will appear in the Oct. 8 Nature print edition.

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

Jeremy Luban, MD

Dr. Gottlinger, professor of molecular, cell & cancer biology and principal investigator of one of the studies, 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.”

The studies, each done independently, used 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. Luban, working with former members of his lab Massimo Pizzato, PhD, 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. Independently, Gottlinger approached the problem biochemically. Conducting proteomic analysis of purified virions, he was able to identify host cell proteins that Nef regulated.

journal reference (Nature/ Gottlinger) >>