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Immunology

Another avenue of HIV trickery reveals opportunity

Emory and University of Rochester researchers have discovered an extra way by which HIV adapts to survive in a hiding spot in the human immune system. The results are published in the Journal of Biological Chemistry.

A team led by Baek Kim from the University of Rochester and Raymond Schinazi from Emory found that when HIV faces a shortage of the building blocks it usually uses to replicate, the virus adapts by using different building blocks. The discovery may offer scientists a new way to try to stop the virus.

One of HIV’s favorite hiding spots is an immune cell called a macrophage, whose job is to chew up and destroy foreign invaders and cellular debris. One can think of macrophages as worker bees: they don’t reproduce because they’re focused on getting stuff done.

Raymond Schinazi, PhD, DSc, is director of the Laboratory of Biochemical Pharmacology at Emory's Center for AIDS Research

Normally, HIV uses “dNTPs” (building blocks of DNA), but dNTPs are found at very low levels in macrophages because they’ve stopped dividing and making new DNA. Current drugs generally target dNTPs, and aim at the infection in a different type of cells: T cells.

Macrophages do have high levels of RNA building blocks (“rNTPs”). The team found that HIV uses primarily rNTPs instead of dNTPs to replicate inside macrophages. When the team blocked the ability of the virus to interact with rNTPs, its ability to replicate in macrophages was cut by more than 90 percent.

“The first cells that HIV infects in the genital tract are non-dividing target cell types such as macrophages,” Kim says. “Current drugs were developed to be effective only when the infection has already moved beyond these cells. Perhaps we can use this information to help create a microbicide to stop the virus or limit its activity much earlier.”

Compounds that interfere with the use of rNTPs already exist and have been tested as anti-cancer drugs.

“We are now developing new anti-HIV drugs jointly based on this novel approach that are essentially non-toxic and can be used to treat and prevent HIV infections,” Schinazi says.

Baek Kim, PhD

The first authors of the paper are graduate students Edward Kennedy from Rochester and Christina Gavegnano from Emory. Other authors include graduate students Laura Nguyen, Rebecca Slate and Amanda Lucas from Rochester, and postdoc Emilie Fromentin from Emory.

The research was funded by the National Institute of Allergy and Infectious Disease and the Department of Veterans Affairs.

University of Rochester press release

Posted on by Quinn Eastman in Immunology 1 Comment

H1N1 2009 virus may point way to universal flu vaccine

Emory MedicalHorizon

Scientists at Emory and the University of Chicago have discovered that the 2009 H1N1 flu virus provides excellent antibody protection. This may be a milestone discovery in the search for a universal flu vaccine.

Researchers took blood samples from patients infected with the 2009 H1N1 strain and developed antibodies in cell culture. Some of the antibodies were broadly protective and could provide protection from the H1N1 viruses that circulated over the past 10 years in addition to the 1918 pandemic flu virus and even avian influenza or bird flu (H5N1).

The antibodies protected mice from a lethal viral dose, even 60 hours post-infection.

The research is published online in the Journal of Experimental Medicine.

Some of the antibodies stuck to the “stalk” region, or hemagglutinin (H in H1N1) protein part of the virus. Because this part of the virus doesn’t change as much as other regions, scientists have proposed to make it the basis for a vaccine that could provide broader protection. The antibodies could guide researchers in designing a vaccine that gives people long-lasting protection against a wide spectrum of flu viruses.

The paper’s first author, Emory School of Medicine’s Jens Wrammert, PhD, says “Our data shows that infection with the 2009 pandemic influenza strain could induce broadly protective antibodies that are very rarely seen after seasonal flu infections or flu shots. These findings show that these types of antibodies can be induced in humans, if the immune system has the right stimulation, and suggest that a pan-influenza vaccine might be feasible.”

Rafi Ahmed, PhD, director of the Emory Vaccine Center, and a Georgia Research Alliance Eminent Scholar, is co-senior author of the publication, along with Patrick Wilson at University of Chicago.

Multimedia

Video

  • See YouTube for video commentary by Dr. Ahmed
  • For access to raw video for media purposes, contact Kathi Baker, kobaker@emory.edu, 404-727-9371 Office, 404-686-5500 Pager (ID 14455), 404-227-1871 Mobile.

Audio

Posted on by Jennifer Johnson in Immunology 2 Comments

Reassuring news on viral immunity + HIV vaccine

A recent paper in Journal of Immunology suggests that a platform for an HIV vaccine developed by Yerkes National Primate Research Center scientists won’t run into the same problems as another HIV vaccine. Postdoc Sunil Kannanganat is the first author of the JI paper, with Emory Vaccine Center researcher Rama Amara as senior author.

Harriet Robinson, MD and Rama Rao Amara, PhD

Many HIV vaccines have been built by putting genes from HIV into the backbone of another virus. Some have used a modified cold virus (adenovirus 5). The vaccine developed at Yerkes uses modified vaccinia Ankara (MVA), a relative of smallpox and chicken pox.

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Posted on by Quinn Eastman in Immunology Leave a comment

Scientists still searching for HIV’s lethal ways

Guido Silvestri, MD

It’s a knotty, complex question, and one that’s nearly 30 years old: how does HIV cause AIDS? That is, how does the virus slowly destroy the immune system?

Emory immunologist and Georgia Research Alliance Eminent Scholar Guido Silvestri, MD, and his colleagues are using a method called comparative AIDS research to try and answer that question. In other words, the scientists compare humans infected with HIV who develop AIDS and nonhuman primates from Africa who are infected with SIV, or simian immunodeficiency virus.

Silvestri is chief of the Division of Microbiology and Immunology at Yerkes National Primate Research Center.

Although SIV is very similar to HIV in terms of genetic and molecular structure, once infected with this virus, the Old World Monkey, the sooty mangabey, does not get sick.

“It’s a major mystery in AIDS research because these animals have virus replication that remains active in their body as long as they’re alive,” says Silvestri. “So, it’s not just the infection and the virus replicating that kills people. There’s something more that happens.”

Silvestri describes this research in Emory University’s Sound Science.

Posted on by Robin Tricoles in Immunology Leave a comment

Secrets of the elite: Effective immune control of HIV

A small minority of individuals infected with HIV — about one in 300 – are naturally able to suppress viral replication with their immune systems, and can keep HIV levels extremely low for years. Doctors have named these individuals “elite controllers.”

“These individuals have naturally achieved the outcome sought by HIV vaccine researchers worldwide.  Studying them will ultimately inform the design of a more effective HIV vaccine,” says Vincent Marconi, a physician-scientist at Grady Health System’s Infectious Disease Clinic on Ponce de Leon and an associate professor in the Emory School of Medicine.

Vincent Marconi, MD

Marconi is a co-author (along with investigators at over 200 institutions) on a genomics study of elite controllers published Thursday in Science Express. Led by Bruce Walker at Massachusetts General Hospital and Paul de Bakker at the Broad Institute and Brigham and Women’s Hospital in Boston, the team of researchers scanned through the genomes of close to 1,000 elite controllers and 2,600 people with progressive HIV infection. They identified several sites linked with immune control of HIV, all in a region encoding HLA proteins.

HLA proteins play key roles in activating T cell immunity, and are also necessary for the development of T cells. They grab onto segments of proteins, called peptides, inside the cell and carry them to the cell membrane. In the right context, certain viral peptides can mark infected cells for destruction by “killer” T cells.

Previously, MGH/MIT researchers theorized that people with certain forms of their HLA genes develop T cells with a restricted repertoire, yet broader activity. Their T cells would be more likely to still recognize HIV when the virus mutates. A drawback is that these individuals may have a higher risk for developing autoimmune diseases. The theory is described in more detail in this Nature News article.

Marconi is continuing his part of this research into what makes elite controllers’ immune systems special, which he began at the Department of Defense Infectious Disease Clinical Research Program, in collaboration with Eric Hunter, co-director of Emory’s Center for AIDS Research, and research associate Ling Yue at Emory Vaccine Center. The research is supported by the Center for AIDS Research and the National Institute of Allergy and Infectious Diseases.

Posted on by Quinn Eastman in Immunology Leave a comment

Adjuvants: once immunologists’ “dirty little secret”

Two presentations on Emory research at last week’s AIDS Vaccine 2010 conference concerned adjuvants. These are substances that act as amplifiers, stimulating the immune system while keeping its focus on the specific components of a vaccine.

Charlie Janeway (1943-2003)

Immunologist Charlie Janeway once described adjuvants as immunology’s “dirty little secret,” because for a long time scientists did not know how they worked. Some adjuvants can sound irritating and nasty, such as alum and oil emulsion. Alum is the only vaccine adjuvant now licensed for human clinical use in the US. Over the last few years, scientists have learned that adjuvants rev up what is now known as the “innate immune system,” so that the body knows that the vaccine is something foreign and dangerous.

Rama Rao Amara, a vaccine researcher at Emory Vaccine Center and Yerkes National Primate Research Center, and Harriet Robinson, former head of microbiology and immunology at Yerkes and now chief scientific officer at the firm GeoVax, both described extra ingredients for the DNA/MVA vaccine that Robinson designed while at Yerkes in collaboration with NIH researchers.

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Posted on by Quinn Eastman in Immunology Leave a comment

What if HIV was just another virus

Imagine that HIV was a “normal” virus. An infection begins and the body responds, without getting trapped in a cycle where CD4+ T cells are consumed and the immune system is crippled.

SIV can infect sooty mangabeys but it doesn't cripple their immune systems.

The attractiveness of this idea explains some of why scientists are interested in sooty mangabeys and other non-human primates. HIV’s relative SIV can infect them, but they usually don’t develop immunodeficiency.

At last week’s AIDS Vaccine 2010 conference, Cynthia Derdeyn reported her laboratory’s recent results investigating sooty mangabeys, which don’t develop high levels of neutralizing antibodies against SIV when infected. Derdeyn’s group at Emory Vaccine Center and Yerkes National Primate Research Center studies how HIV and SIV evade the immune system.

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Posted on by Quinn Eastman in Immunology Leave a comment

Re-energizing AIDS vaccine research

Emory President James Wagner welcomed participants Wednesday to the AIDS Vaccine 2010 conference in Atlanta, hosted by the Global HIV Vaccine Enterprise and locally hosted by the Emory Center for AIDS Research.

“Only occasionally are there scientific challenges that unite people powerfully towards a common goal,” Wagner said. “We are proud for the role we’ve been able to play in the pursuit of vaccine research. I am particularly pleased that so many students and young investigators have been able to participate in this conference.”

John Mascola from the Vaccine Research Center at the NIH gave the day’s first scientific talk, describing the discovery of broadly cross-reactive neutralizing antibodies to HIV and the ability to isolate those antibodies. This is the kind of recent discoveries that has re-energized the HIV vaccine research community.

Bette Korber of the Los Alamos National Laboratory noted that HIV mutations that escape immune response in some infected people are frequently susceptible in others. New “mosaic vaccines” can expand the breadth and depth of these immune responses, she said. She also described the effort underway in her laboratory to re-examine results of an earlier vaccine trial, VAX004, in light of new analytic strategies.

Giuseppe Pantaleo of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland expressed the need to implement adaptive clinical trial study design. This theme — the need to examine clinical trial results early and often, and then adapt, rather than waiting for all results at the very end of a years-long trial — has been echoed often at the conference.

At a midday press briefing, Peter Kwong of the NIH Vaccine Research Center discussed his research with broadly neutralizing antibodies, one of which attacks the initial site of vital attachment to CD4 T cells.

Hendrik Streek from Harvard’s Ragon Institute described how vaccines induce antibody and CD4 response and contraction. Even though CD4 cells are the ones attacked during HIV infection, Streek believes CD4 responses may be a missing link to effective vaccine development

Alan Bernstein, executive director of the Global HIV Vaccine Enterprise, led a discussion of the new Enterprise Scientific Strategic Plan. Less than two out of five people who need treatment for HIV are receiving it, said Bernstein, which underscores the importance of an effective vaccine.

The new plan arrives at a time of great momentum and excitement in the field. A year of important advances has included discoveries about broadly neutralizing antibodies, new technologies, and a vaccine that demonstrated an immune response. The plan emphasizes novel clinical trials design, a strong commitment and engagement by many partners, and expanded diversity of funding by many stakeholders.

Jose Esparza, senior advisor on HIV vaccines to the Bill & Melinda Gates Foundation, emphasized the need to rapidly capitalize on new science, and said HIV vaccines are one of the foundation’s top priorities. High risk, high reward projects will be funded through the Gates Grand Challenges Explorations grants.

Posted on by Holly Korschun in Immunology Leave a comment

Strengthening community engagement in HIV vaccine research

Paula Frew, PhD

The scientific part of the AIDS Vaccine 2010 meeting began Tuesday evening with an exciting summary of issues facing the field from NIAID director Tony Fauci. But before that, participants in this year’s conference got a chance to warm up with several “satellite sessions.”

One of them, “Effective Community Engagement in HIV Vaccine Research Among Communities and Researchers,” was organized by Paula Frew, PhD, director of health communications and applied community research at Emory’s Hope Clinic.

Two prominent themes emerged from this session. The first was that community members should be involved in clinical trials at every step of the process: from design and recruitment to dissemination of results.

“In the past, scientists often came to the community late in the process, after a protocol for a study was already approved, and said: “Will you support what we’ve already decided?” said Steve Wakefield of HIV Vaccine Trials Network. “This doesn’t work.”

The Joint United Nations Programme on HIV/AIDS and AVAC presented proposed guidelines for “good participatory practice,” analogous to good clinical practices.

Another theme that emerged from the satellite session was the search for more flexible “adaptive” clinical trial formats. Glenda Gray from South Africa’s University of the Witwatersrand emphasized that adaptive trials could be faster and avoid enrollment of large numbers of patients unnecessarily.

Posted on by Quinn Eastman in Immunology Leave a comment

AIDS Vaccine 2010 conference brings global research focus to Atlanta

This week’s AIDS Vaccine 2010 conference, Sept. 28-Oct. 1, is underway at Atlanta’s Omni Hotel. Under the auspices of the Global HIV Vaccine Enterprise, the international meeting is hosted by the Emory Center for AIDS Research (CFAR).

Over 1,100 scientists, advocates, funders, and policy makers are attending 500 sessions about scientific discoveries and future directions for developing an effective HIV/AIDS vaccine. This goal is considered critical in fighting the ongoing epidemic, which newly infects 50,000 people each week around the world.

Emory HIV/AIDS researchers are playing a significant role in the meeting. The four co-chairs are Eric Hunter, PhD, co-director of the Emory CFAR; James Curran, MD, MPH, dean of Emory’s Rollins School of Public Health and co-director of the CFAR; Carlos del Rio, MD, chair of the Hubert Department of Global Health and co-chair of the CFAR; and Harriet Robinson, PhD, formerly of Yerkes Primate Center and Emory Vaccine Center and now at GeoVax, Inc.

Hunter led the opening press conference and opening session on Tuesday afternoon.

A fellowship program hosted 21 journalists from media outlets around the world.

Alan Bernstein, executive director of the Global HIV Vaccine Enterprise, emphasized the need to build a bridge between basic science and clinical research. On Wednesday, Bernstein will talk about the Enterprise’s new strategic plan for an HIV vaccine.

Dazon Dixon Diallo, director of the African-American women’s organization Sisterlove, noted that the South has been particularly hard hit by the AIDS epidemic, with over half the HIV cases in the United States. The human rights dimensions of the disease are enormous, she said, and engagement with community partners is essential in fighting HIV. Researchers need to solve the problem with the help of people who know the most about it.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases of the NIH, said that even though the road to an HIV vaccine has been a rocky one over the past 23 years, the limited success reported last year with the RV144 trial was the first signal that it is possible for a vaccine to block HIV acquisition, a finding that has re-energized the vaccine community.

Future directions for HIV vaccine research, said Fauci, will include research that builds on insights from the success of RV144, multiple clinical trials conducted as scientific tools and not just all-or-nothing aims for vaccine licensing, more research into the early events of HIV infection that could provide targets for vaccines, and new structure-based vaccines using newly discovered neutralizing antibodies.

“I don’t think there is any question we are going to get there,” said Fauci. “The light at the end of the tunnel is the science we are now implementing.”

Press conferences are streamed live and available for playback at the conference website:

For more information on Emory’s role in the conference and Emory HIV/AIDS research, including video, see the website.

Posted on by Holly Korschun in Immunology Leave a comment