CVVR

Researchers Uncover Earliest Events Following HIV Infection, Before Virus Is Detectable

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Findings Could Lead to New HIV Prevention Strategies

BOSTON – New research in monkeys exposed to SIV, the animal equivalent of HIV, reveals what happens in the very earliest stages of infection, before virus is even detectable in the blood, which is a critical but difficult period to study in humans. The findings, published online today in the journal Cell, have important implications for vaccine development and other strategies to prevent infection.

“The events during the first few days after exposure to the virus and prior to the initial detection of virus in the blood are critical in determining the course of infection, but this period is essentially impossible to study in humans,” said lead author Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School. “Our study is the most comprehensive evaluation of acute HIV/SIV infection to date.”

The study was initiated as part of the National Institutes of Health–funded Consortium for AIDS Vaccine Research and involved multiple collaborating laboratories, including those headed by Rafick-Pierre Sekaly, PhD, of Case Western Reserve University and Jeffrey Lifson, MD, of the Frederick National Laboratory for Cancer Research.

When Barouch and his colleagues exposed 44 rhesus monkeys to SIV and conducted analyses of the animals on days 0, 1, 3, 7 and 10 following exposure, they found that SIV could disseminate rapidly through the body, with viral RNA (SIV’s genetic material) present in at least one tissue outside the reproductive tract in most monkeys analyzed 24 hours after exposure.

“In addition to rapid viral dissemination, the virus triggered a local inflammatory response that appears to suppress antiviral innate and adaptive immunity, thus potentially augmenting its own replication,” explained Barouch. “These data provide important insights into the earliest events of infection.”

The inflammatory response occurred in virus-infected tissues soon after exposure to SIV, and increasing amounts of viral RNA correlated with rising amounts of a host protein called NLRX1, which inhibits antiviral immune responses. In addition, the TGF-beta cell-signaling pathway, which suppresses adaptive immune responses, was triggered and correlated with lower levels of antiviral T immune cell responses, as well as higher levels of SIV replication. The researchers observed elevated expression of genes in the TGF-beta pathway in tissues that contained viral RNA as early as day 1 after exposure to the virus.

The findings suggest that there may be a very narrow window of opportunity to contain or eliminate the virus. HIV prevention strategies should take these factors into account. “We believe that these insights into early HIV/SIV infection will be critical for the development of interventions to block infection, such as vaccines, antibodies, microbicides and drugs,” Barouch said. “The next step in this line of research is to evaluate how various interventions may impact these early events.”

Study coauthors include BIDMC investigators Jinyan Liu, Kaitlin Smith, Erica Borducchi, Crystal Cabral, Lauren Peter, Amanda Brinkman, Mayuri Shetty and Hualin Li. Other team members include Khader Ghneim, William J. Bosche, Yuan Li, Brian Berkemeier, Michael Hull, Sanghamitra Bhattacharyya, Mark Cameron, Courtney Gittens, Chantelle Baker, Wendeline Wagner, Mark G. Lewis, Arnaud Colantonio, Hyung-Joo Kang, Wenjun Li, Jeffrey D. Lifson, Michael Piatak, Jr., and Rafick-Pierre Sekaly.

This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health (AI060354, AI078526, AI084794, AI095985, AI096040, AI100645 and HHSN261200800001E), and by the Ragon Institute of MGH, MIT and Harvard.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding.

BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

CVVR

CVVR Volunteer Registry is Now Live!

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The Center for Virology and Vaccine Research launched a Volunteer Registry for adults interested in clinical trial participation on December 21st, 2015. The new CVVR Clinical Trials Unit established the Volunteer Registry in anticipation of CVVR clinical trials beginning this year at Beth Israel Deaconess Medical Center. These clinical trials will connect the CVVR lab bench where the research vaccines were developed to the research volunteer’s bedside where the vaccines will be administered, all under the roof of BIDMC. Research volunteers are essential to clinical trials. The Volunteer Registry brings together researchers and volunteers with the common goal of helping others live healthier lives. The purpose of the Volunteer Registry is to collect and maintain information that people voluntarily supply so they may be contacted by the CVVR Clinical Trials Unit about participating in future studies. To find out more information about the Volunteer Registry follow this link: http://cvvr.hms.harvard.edu/registry or to join the Volunteer Registry please call the Clinical Trials Unit at (617)-735-4610 or follow this link:   https://redcap.bidmc.harvard.edu/redcap/surveys/?s=MKTMD7NKLH.

CVVR

amfAR Gives $2 Million to CVVR Researchers to Study HIV Eradication

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amfAR, The Foundation for AIDS Research, announced on July 21st that a CVVR research team has been awarded $2 million to pursue a range of strategies aimed at curing HIV. The team of researchers will be led by Dan Barouch, M.D., Ph.D., and will investigate the ability of combinations of antibodies to specifically kill latently infected cells in the lab, in monkeys, and then in people. The researchers will test two promising antibodies alone and together, in combination with a newly described drug that can “shock” the virus out of latently infected cells and possibly enhance the ability of the antibodies to locate the infected cells.

See full press release from amfAR here 

CVVR

Does NK Memory Exist? The Reeves Lab Shows It Does

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Keith Reeves and colleagues at CVVR published in Nature Immunology this month that robust, durable, antigen-specific natural killer (NK) cell memory can be induced in primates after both infection and vaccination. This data upsets the long held maxim that NK cells are nonspecific parts of the innate immune system, and raises the possibility that NK cells might be harnessed in the development of vaccines for HIV and other pathogens.

Article at Nature Immunology

CVVR

The Bad Side of CD4 T Cells

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CVVR in the News:

“Vaccine-Induced CD4 T Cells Lead to Adverse Effect in a Mouse Model of Infection” – Science Daily, Jan 15, 2015

“A study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that a vaccine that elicits only CD4 T cells against a mouse model of a chronic viral infection results in an overwhelming — and lethal — inflammatory response. Reported in the January 16, 2015 issue of the journal Science, the new findings provide a cautionary tale for the development of vaccines aimed at eliciting robust CD4 T cell immunity against chronic infections, including HIV.” See full article >

CVVR

New Vaccine Shows Protection in Monkeys

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Dan Barouch and colleagues reported in the journal Science on July 17th that an adenovirus-based HIV vaccine demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIV challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. Clinical trials of these vaccine candidates are ongoing, in collaboration with Johnson and Johnson, the U.S. Military HIV Research Program, the International AIDS Vaccine Institute, and the U.S. National Institutes of Health.