Researchers have shown how an antiviral protein produced by the immune system, dubbed tetherin, tames HIV and other viruses by literally putting them on a leash, to prevent their escape from infected cells. The insights reported in the October 30th issue of the journal Cell, a Cell Press publication, allowed the research team to design a completely artificial protein — one that did not resemble native tetherin in its sequence at all — that could nonetheless put a similar stop to the virus.

“Tetherin is essentially a rod with anchors at either end that are critical for its function,” says Paul Bieniasz of Howard Hughes Medical Institute and the Aaron Diamond AIDS Research Center at The Rockefeller University. Either one of those anchors gets incorporated into the envelope surrounding HIV or other viruses as they bud through the plasma membrane of an infected cell. “One anchor gets into the virus and the other in the cell membrane to inevitably form a tether.

“We showed we could design a completely different protein with the same configuration - a rod with lipid anchors at either end - and it worked very well,” he continued. The finding helped to confirm that tetherin is capable of acting all on its own, he added.

They also explain tetherin’s broad specificity to protect against many viruses. “It is just targeting lipids,” Bieniasz said. “It’s not about viral proteins.” That’s conceptually important, he continued, because there is no specific interaction between tetherin and any viral protein, which makes it a more difficult problem for viruses to evolve resistance. Rather than tweaking an existing protein-coding gene, “the virus has to make the more difficult adjustment of acquiring a new gene antagonist [of tetherin].”

Unfortunately, many viruses have managed to do just that. In the case of HIV, a protein called Vpu counteracts tetherin. They now show it does so by sequestering the host protein, which prevents its incorporation into the virus. The new insight into tetherin’s and Vpu’s modes of action, however, may lead to the development of Vpu blockers that could free up the innate host defense and inhibit HIV’s spread, Bieniasz suggests.

Bieniasz said there is some possibility that tetherin exists in different forms that might explain differences among people in the progression of HIV or other viral infections. However, the only common variation they’ve seen in the tetherin gene so far does not appear to affect its function. The tetherin sequence does vary quite a lot from one species to the next, he added, as is often the case due to strong selection when host defense genes meet viral inhibitors.

To place the findings in context, Bieniasz says it is worth noting that tetherin is encoded by just one of more than 900 genes that get switched “on” in response to interferon, a cell signaling protein of the immune system.

“There are hundreds of interferon-induced genes,” he said. “The functions are known for only a very small number - less than a dozen. There are potentially a large number of antiviral mechanisms we still know nothing about.”

Going forward, his team intends to look more closely at many of those others, and Bieniasz suspects more surprising mechanisms will be in store.

The researchers include David Perez-Caballero, The Rockefeller University, New York, NY; Trinity Zang, The Rockefeller University, New York, NY, Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, NY; Alaleh Ebrahimi, The Rockefeller University, New York, NY; Matthew W. McNatt, The Rockefeller University, New York, NY; Devon A. Gregory, University of Missouri School of Medicine, Columbia, MO; Marc C. Johnson, University of Missouri School of Medicine, Columbia, MO; and Paul D. Bieniasz, The Rockefeller University, New York, NY, Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, NY.

Source: Cathleen Genova

Cell Press

Researchers in New York City are reporting their work uncovering a new epidemic of hepatitis C virus (HCV) infection among men-who-have-sex-with-men (MSM) who have HIV infection. These authors have previously reported unusually rapid fibrosis progression due to new HCV in MSM who have HIV infection and now expand on their findings, demonstrating that sexual transmission rather than injection drug use is the route of infection. Treatment is highly successful if started early in the course of infection, however, they report ominous news about liver disease progression. “This epidemic represents a new clinical syndrome for HCV infection that turns much of our knowledge on its ear: a new risk group becoming infected through a previously rare route of transmission resulting in unprecedented progression of liver fibrosis,” said Daniel Fierer, MD, principal investigator on this study.

In an analysis of 21 HCV-infected patients matched with uninfected controls, unprotected receptive anal and oral sex were significantly associated with new HCV infection. Neither current nor prior injection drug use was associated with HCV infection. In addition, treatment with pegylated interferon and ribavirin, initiated within 6 months of diagnosis, was completed in 16 patients with genotype 1 HCV infection; 12 (75%) achieved sustained viral response (SVR), compared to the 15-30% SVR rate expected with chronic genotype 1 HCV infection. Of significant concern, however, 30 patients underwent liver biopsy during the early infection period and 23 (77%) already had moderate fibrosis, making early curative treatment even more important to prevent further progression of liver fibrosis.

Because of these findings, study authors recommend routine screening for acute HCV for all MSM patients with HIV, using a simple and inexpensive algorithm of ALT measurement every 3 months and HCV antibody measurement every 6 to 12 months. “Changing the perception and behavior of physicians and patients is difficult,” said Dr. Fierer, “One of the main barriers to early detection is the lack of recognition by physicians and patients alike that HIV-infected MSM are at risk for HCV infection. This lack of perception of the problem results in lack of screening of HIV-infected MSM and therefore lack of timely diagnosis and treatment.”

Dr. Fierer thinks the next steps in battling this epidemic are educating HIV providers about the existence of this world-wide epidemic, educating patients at risk that unprotected sex among HIV-infected men is a significant risk for HCV infection, and changing the official recommendations by the US national authorities such as the CDC, HIVMA, etc, as has already been done in Europe and more recently at the state level in New York.

Abstract title:

Characterization of an epidemic of sexually-transmitted acute hepatitis C infection in HIV-infected men in New York City

About the AASLD

AASLD is the leading medical society focused solely on advancing the science and practice of hepatology and represents more than 3,300 practitioners, researchers, and allied health professionals worldwide. Founded by physicians in 1950, AASLD has upheld the standards of the profession and fostered research that generates treatment options for the millions of patients with liver diseases.

Source: American Association for the Study of Liver Diseases

The National Institutes of Health has awarded $75 million to Charles Drew University of Medicine and Science and three other historically black institutions to establish a medical research consortium to combat health disparities in minority and underserved populations.

The award by the National Center for Research Resources (NCRR), part of NIH, will support clinical and translational research focusing on cardiovascular disease, diabetes, chronic kidney disease, HIV/AIDS and other conditions.

“We are going to create a clinical and translational research center by building partnerships among institutions and communities,” said Dr. Eric G. Bing, Charles Drew University’s Endowed Professor of Global Health & HIV, who will direct the NIH grant-funded program: Accelerating Excellence in Translational Science (AXIS).

“Our goal is to develop innovative solutions that transform the health of underserved communities,” he added.

Under the terms of the award, Charles Drew University in Los Angeles, Meharry Medical College in Nashville and Morehouse School of Medicine in Atlanta will each receive about $4 million a year for up to five years. Xavier University in Louisiana will receive $2 million a year for five years to establish a cancer research center.

Charles Drew, Meharry and Morehouse will each be funded through Research Centers in Minority Institutions, an NCRR program designed to enhance research capacity and infrastructure in minority institutions.

“The three inaugural RCTR institutions already have an exemplary record of transforming basic research into positive outcomes at the doctor’s office and in the community,” said Dr. Barbara Alving, director of NCRR. “The increased efficiency and partnerships that come out of the RCTR program will accelerate this progress to improve the health of minority communities.”

Xavier University, which suffered heavy damage as a result of Hurricane Katrina in2005, will be added to the pool of RCMI institutions with funds from the fourth award.

RCMI Awardees:

Charles Drew University
$20.9 million
Accelerating Excellence in Translational Science
Principal Investigator: Keith C. Norris, M.D.

Meharry Medical College
$21.4 million
Meharry Clinical and Translational Research Center
Principal Investigators: Ayman Al-Hendy, M.D., Ph.D. and James E.K. Hildreth, M.D., Ph.D.

Morehouse School of Medicine
$22.2 million
RCMI Infrastructure for Clinical and Translational Research
Principal Investigator: Eve J. Higginbotham, M.D.

Xavier University of Louisiana
$10.1 million
Xavier’s RCMI Cancer Research Program
Principal Investigator: Gene D’Amour, Ph.D.Contact:

Source: John L. Mitchell

Charles Drew University of Medicine and Science