This phenomenon has been shown in test tube laboratory experiments, but now researchers at the University of North Carolina School of Medicine have demonstrated that the same phenomenon occurs in a humanized mouse model, suggesting a promising new target for tackling the virus, which has killed nearly 30 million people worldwide since it first appeared three decades ago.

A family of human proteins called APOBEC3 effectively restrict the growth of HIV and other viruses, but this action is fully counteracted by the viral infectivity factor gene (vif) in HIV. In the study, researchers intravenously infected humanized mice with HIV. They found that the most commonly transmitted strains of HIV are completely neutralized by APOBEC3 proteins when vif is removed from the virus.

“Without the vif gene, HIV can be completely destroyed by the body's own immune system,” said J. Victor Garcia, PhD, professor of medicine at the UNC School of Medicine and senior author on the study. “These results suggest a new target for developing drugs fully capable of killing the virus.”

Garcia and his colleagues pioneered the humanized mouse model used for these studies. The aptly named “BLT” mouse is created by introducing human bone marrow, liver and thymus tissues into animals without an immune system of their own. The mice have a fully functioning human immune system and can be infected with HIV in the same manner as humans. In previous research, Garcia and his team have effectively prevented intravenous, rectal, vaginal and oral transmission of HIV in the mice with pre-exposure prophylaxis (PrEP).

For the current study, Garcia and his colleagues also infected BLT mice with another, highly harmful strain of the virus. The results show that this strain of HIV does continue to replicate, even without vif, but at a much slower rate and without harming the human immune system. Further, the researchers found that virus replication in this case was limited to one tissue—the thymus—in the entire body.

“These findings demonstrate a fundamental weakness in HIV,” said John F. Krisko, PhD, lead author on the study.  “If this weakness can be exploited, it might eventually lead to a cure for HIV/AIDS,” Krisko said.

The study appears March 28 in the online journal PloS Pathogens.

In addition to Garcia and Krisko, other study authors are Francisco Martinez-Torres, PhD, and John L. Foster, PhD, all of the Center for AIDS Research at the University of North Carolina School of Medicine.

Inaugurated this year, ID Week is the first-ever combined meeting of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America , the HIV Medicine Association, and the Pediatric Infectious Diseases Society. ID Week aims to be the annual scientific meeting for infectious diseases professionals, featuring the latest science and bench-to-bedside approaches in prevention, diagnosis, treatment, and epidemiology of infectious diseases, including HIV, across the lifespan.

The SHEA Lectureship award is given annually to recognize the career contributions of a senior investigator in healthcare epidemiology and infection prevention and control.

Certified in infectious control, Rutala is an advisor to the Centers for Disease Control and Prevention, the Food and Drug Administration, the U.S. Environmental Protection Agency, and the Federal Trade Commission. He has more than 500 publications in the fields of infectious diseases, infection control, disinfection, sterilization and medical waste.

Rutala will deliver his SHEA lecture at the Friday Morning Infectious Diseases Conference on Nov. 16 at 8:30 a.m. in 1131 Bioinformatics.

Senior clinical staff at UNC Project are now part of the clinical training teams responsible for nearly 100 third-year medical students attending their clinical rotations.  UNC Project clinicians will teach in the areas of medicine, pediatrics, surgery, and pathology.

This added responsibility will result in joint faculty appointments at the Malawi College of Medicine for eight in-country UNC Project clinicians, including Mina Hosseinipour, MD, MPH Satish Gopal, MD, MPH, Cecelia Kanyama, MD, and Agnes Moses, MD, in medicine; Amy Sims, MD, and Portia Kamthunzi, MD, in pediatrics; Jonathan Samuel, MD, in surgery; and George Liomba, MD, in pathology.

“This partnership will increase the College of Medicine’s capacity for clinical training,” said Irving Hoffman, PA, MPH, professor of medicine at UNC and US-based director of UNC Project-Malawi. “More importantly, though, it will lead to improved clinical care for the people of Malawi.”

Media contact: Lisa Chensvold, 919-843-5719 or lisa_chensvold@med.unc.edu

A partnership between UNC, Johns Hopkins, Morehouse, and Tulane, the UJMT Fogarty Global Health Fellowship Program provides newly appointed junior faculty, postdoctorates, and predoctoral candidates from the United States and low-and middle-income countries with an 11-month mentored clinical research training program. The program will enhance the career trajectory of the participants, strengthen the global health research programs at U.S. and foreign institutions, and will bolster networking among program alumni and senior scientist mentors. The UNC-led consortium is one of five academic consortia to receive funding under this new program.

Read the rest of this story. . .

She is a clinical leader in the cervical dysplasia clinic and has completely revamped the operation of the clinic to reflect recent advances in viral detection and immunization. She has also set up an infrastructure that allows for research as part of clinical care.

“Lisa is in the top decile of junior faculty clinicians in Obstetrics and Gynecology and Public Health that I have worked with during my time at UNC,” said John Thorp, MD, Director, Women’s Primary Healthcare.

“She combines the attributes that one would link to Dr. Woods, in that she is an excellent clinician and is embarking upon a research career with great potential centered in her clinical activities.”

The Woods Award was established through the generosity of the late James Watson Woods, MD, a cardiologist and professor in the School of Medicine from 1953 to 1983.  Dr. Rahangdale will receive a total of $3,000 to be used at her discretion for the support of her scholarly endeavors.

Dr. Rahangdale plans to use the funds to conduct a focused research project to test topical treatments for moderate dysplasia of the cervix.  This approach may provide effective treatment of dysplasia and also improve the child-bearing potential of the affected women.

September 21, 2012 –The Collaboratory of AIDS Researchers for Eradication, or CARE, a multi-institutional research team led by David Margolis, MD, professor of medicine at the UNC School of Medicine, has been awarded a $2 million supplemental grant from the National Institutes of Health to conduct expanded analysis of resting CD4+ T-cells of people infected with HIV.  CD4+ T-cells are special cells that the virus uses to replicate.

With the new funding, Margolis and others in the collaboratory will study the effect of a variety of interventions on these resting CD4+ T-cells.

CARE researchers are studying latent, or “hidden,” HIV infection in patients who are controlling the virus with anti-AIDS drugs. Flushing out and clearing this hidden virus is critical to finding a cure for AIDS.

In July 2012, Margolis and other researchers at UNC published novel research showing that a drug used to treat certain types of lymphoma was able to dislodge hidden virus in patients receiving treatment for HIV.

This latest NIH funding supplements a previous $32 million, five-year award to CARE to develop strategies to cure AIDS.

CARE is a group of over 20 research scientists who believe that HIV can be eradicated by working together as a collaboratory, combining our scientific expertise, our efforts and our shared vision of a world free from HIV.  For more information and to get involved go to http://www.delaneycare.org/.

Media contact: Lisa Chensvold, 919-843-5719, lisa_chensvold@med.unc.edu

Cohen is an infectious disease specialist whose research is focused on the transmission and prevention of transmission of HIV. He is study chair of the HIV Prevention Trials Network 052 study, a landmark clinical trial which is considered a cornerstone of the global HIV prevention strategy and has influenced changes policy at the national and international levels.

The R. E. Dyer Lecture was established in 1950 in honor of former NIH director Dr. Rolla E. Dyer, a noted authority on infectious diseases. The Dyer lectureship is an honor conferred on an internationally renowned researcher who has contributed substantially to medical as well as biological knowledge of infectious diseases.

The lecture will be recorded and posted online on the NIH website.

The academy promotes excellence in teaching and supports the work and career paths of excellent teachers. It also functions as a forum for education leadership and advice for the leaders of the medical school.

Hobbs, one of 27 new members of the UNC-CH School of Medicine Academy of Educators, joins 199 faculty members committed to the promotion and support of excellence in teaching.  She brings over 30 years of experience in the classroom and laboratory and has received prior recognition for her teaching, most recently as recipient of the Freshman Basic Science Teaching Award in 2010.

In the United States, about one out of every five people infected with HIV do not know that they are infected. In addition, patients are often diagnosed at advanced stages. In North Carolina, about half of HIV-infected patients who come to the infectious disease clinic at UNC Hospitals are diagnosed with AIDS within a year of their HIV diagnosis.

Recent research out of UNC has demonstrated that proper treatment for HIV with antiretroviral therapy renders people virtually non-contagious, making early diagnosis all the more critical. As a result, the U. S. Centers for Disease Control and Prevention and other government bodies now recommend that all adolescents and adults routinely be screened for HIV. Previously, HIV screening was recommended for people with certain risk factors, such as men who have sex with men, sex workers, injection drug users and heterosexuals with multiple partners.

June 27 is National HIV Testing Day!
Know your status. Get tested.

“Despite the new recommendations, we have learned from local and national surveys that expanded HIV testing is not being widely implemented,” said White, who also co-directs HIV services for the North Carolina Department of Corrections. With this award, White will administer the first statewide survey of HIV screening practices among primary care physicians.

Based on the results, she will develop an intervention to increase routine HIV screening in North Carolina. “The goal is to get people diagnosed early and on treatment,” she said. “Widespread HIV testing is the first step to reducing the spread of HIV in our state.”

“This award recognizes Dr. White as a highly promising investigator,” said White’s mentor, Carol Golin, MD, associate professor of medicine at UNC. “With the results of her statewide survey, she and others can design interventions for improving access to HIV screening and care and hopefully reduce ethnic-racial disparities in HIV outcomes.”

The southeastern United States continues to have the largest number of people living with HIV. Although North Carolina has seen an 18 percent decline in the number of new diagnoses, “there has been a shift of the epidemic to young men of color who do not come in for routine HIV screening,” said Peter Leone, MD, MPH, medical director of the North Carolina HIV/STD Prevention and Control Branch and UNC professor of medicine. “Dr. White's research will provide critical information to help us understand why more people aren’t getting tested.”

CHAPEL HILL, NC – The findings of a new study in monkeys may help clarify why some people infected with HIV are better able to control the virus. They also may pinpoint a target for treatment during early HIV infection aimed at increasing the supply of certain immune cells in the gut, which the study shows could be an important factor in limiting HIV growth in cells throughout the body.

The study was led by researchers at the University of California, San Francisco (UCSF) and included Kristina Abel, PhD, an assistant professor in the department of microbiology & immunology at UNC, at the time of the study a faculty member at the University of California, Davis (UCD).  “The research involved a rhesus macaque model of HIV, monkeys who were infected with simian immunodeficiency virus, SIV” Abel said. “The course of SIV infection in these monkeys is quite similar to that of HIV in humans.”  

Both HIV and SIV infections cause severe CD4 T cell loss in the gut during early infection. As a result, the intestinal mucosal barrier, which is like the body’s second skin or front line of defense against pathogens, is compromised. The “leaky gut” causes bacteria that are normally located in the gut (the normal flora) to migrate out and activate the immune system throughout the body with disastrous health consequences.  “The immune activation contributes to higher replication of the virus. And so the question is, why do some patients progress from infection to AIDS faster than others?” Abel asks.

This new study looked at the balance between certain immune cell populations that might influence disease outcome.  The study shows the presence of a subtype of CD4-positive immune cells called Th17 (T helper 17) cells in the gut “could influence disease outcome.”

A report of the research appeared in the May 30, 2012 on-line issue of Science Translational Medicine.
Th17 cells are commonly found at mucosal surfaces and activate epithelial or outer layer barrier cells to secrete antimicrobial molecules, thus blocking disease-causing bacteria from entering.  Abel points out that they also stimulate the production of “tight junction” proteins that keep all the cells that make up the intestinal barrier in close contact, “so that bacteria of the normal flora or their products cannot leak out.”

The researchers wondered if there are more Th17 cells in the gut, would infection with the AIDS virus still have that early massive effect on gut permeability?  And if you could keep the intestinal barrier intact during early infection with HIV, would it have an impact on the severity of disease progression, on having less severe disease in the long run?

Results of the study suggest that the answers may be yes. Rhesus macaques with higher numbers of Th17 cells in blood and intestinal tissue before they are infected with SIV subsequently have lower SIV viral loads. “It appears they’re more able to control the infection,” Abel said.

The study also found that among animals given a drug that increases regulatory T cells and thereby suppresses Th17 cell development, disease progression occurred more rapidly, and they had higher levels of SIV virus six months after infection.

“The main message of the study is that the frequencies of certain immune cell populations in the normal, still uninfected individual are important in subsequent disease progression and outcome,” Abel said. “The paper also suggests that treatment aimed at increasing Th17 cells may improve the control of HIV growth by promoting an environment in which T cells having more anti-viral capabilities are produced.”

The study’s principal investigator was Dennis J. Hartigan-O’Connor, MD, PhD, from UCSF (now at UCD). Other investigators are Koen K.A. Rompay, from UCD; Bitoo Kanwar, from UCSF; and study senior author Joseph M. McCune, MD, PhD, from UCSF.

Support for the research came from the National Institutes of Health, the Bill and Melinda Gates Foundation, the California National Primate Research Center, the National Center for Research Resources, and the Harvey V. Berneking Living Trust.

Media contact: Les Lang (919) 966-9366, llang@med.unc.edu

CHAPEL HILL – More than 15 percent of new HIV infections occur in children. Without treatment, only 65 percent of HIV-infected children will live until their first birthday, and fewer than half will make it to the age of two. Although breastfeeding is attributed to a significant number of these infections, most breastfed infants are not infected with HIV, despite prolonged and repeated exposure.

HIV researchers have been left with a conundrum: does breast milk transmit the virus or protect against it?

New research from the University of North Carolina School of Medicine explores this paradox in a humanized mouse model, demonstrating that breast milk has a strong virus killing effect and protects against oral transmission of HIV.

“This study provides significant insight into the amazing ability of breast milk to destroy HIV and prevent its transmission,” said J. Victor Garcia, PhD, senior author on the study and professor of medicine in the UNC Center for Infectious Diseases and the UNC Center for AIDS Research. “It also provides new leads for the isolation of natural products that could be used to combat the virus."

Garcia and colleagues pioneered the humanized “BLT” mouse model, which is created by introducing human bone marrow, liver and thymus tissues into animals without an immune system of their own. Humanized BLT mice have a fully functioning human immune system and can be infected with HIV in the same manner as humans.

In the study, the researchers first determined that the oral cavity and upper digestive tract of BLT mice have the same cells that affect oral transmission of HIV in humans and then successfully transmitted the virus to the mice through these pathways. When the mice were given virus in whole breast milk from HIV-negative women, however, the virus could not be transmitted.

“These results are highly significant because they show that breast milk can completely block oral transmission of both forms of HIV that are found in the breast milk of HIV-infected mothers: virus particles and virus-infected cells,” said Angela Wahl, PhD, a post-doctoral researcher in Garcia’s lab and lead author on the paper. “This refutes the ‘Trojan horse’ hypothesis which says that HIV in cells is more stubborn against the body’s own innate defenses than HIV in virus particles."

Finally, the researchers studied the effectiveness of pre-exposure prophylaxis (PrEP) with antiretroviral medication for oral transmission of HIV. Garcia and his team have previously shown that PrEP is effective against intravenous, vaginal and rectal transmission of HIV in humanized BLT mice. In this study, they gave the mice antiretroviral drugs for seven days (3 days before and 4 days after exposing them to the virus) and found 100 percent protection against virus transmission.

These latest findings provide important leads to alternative treatments that could be used to prevent transmission.

“No child should ever be infected with HIV because it is breastfed. Breastfeeding provides critical nutrition and protection from other infections, especially where clean water for infant formula is scarce,” Garcia said. “Understanding how HIV is transmitted to infants and children despite the protective effects of milk will help us close this important door to the spread of AIDS.”

The study appears in the June 14, 2012 issue of the online journal PLoS Pathogens.

The research was supported by funds from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the UNC Center for AIDS Research.

Media contact: Lisa Chensvold, (919) 843-5719, lisa_chensvold@med.unc.edu

A team of researchers led by the University of North Carolina at Chapel Hill School of Medicine has demonstrated that latency develops soon after infection and slows when antiretroviral therapy is given.

The results were published today online in the early edition of Proceedings of the National Academy of Sciences.

The team studied 27 patients with acute HIV infection (AHI). AHI occurs soon after exposure, when virus is found in blood plasma but antibodies are not yet detectible. All but one of the patients studied had been infected in the last 45 days. The study team developed a mathematical model to predict how often latent cells were infected based on when ART was started. They found that early treatment reduced the production of latently infected cells.

In addition, the researchers found that there are two types of latently infected cells, one short-lived, but another extremely durable, what the authors refer to as a “deep” latent infection. “We found that latent infection decayed in some patients, but that all had a few deeply latent infected cells,” said David Margolis, MD, professor of medicine, microbiology and immunology, and epidemiology at UNC and senior author on the study. “These are the cells that we must eliminate to cure infection.”

The team made other hopeful observations. “The immune response of some patients appear to play a role in limiting the size of the latent reservoir,” said Nancie Archin, PhD, the study’s lead author and a research scientist at the medical school. “Efforts to improve the immune response to prevent HIV infection may also teach us to eradicate it.”

The research was conducted through the Center for HIV/AIDS Vaccine Immunology and as part of a UNC-led consortium, the Collaboratory of AIDS Researchers for Eradication (CARE), funded by the National Institute of Allergy and Infectious Diseases. The consortium is administered by the North Carolina Translational and Clinical Sciences (NC TraCS) Institute at UNC, one of 60 medical research institutions in the US working to improve biomedical research through the NIH Clinical and Translational Science Awards (CTSA) program.

Other UNC authors on the paper include Nancie Archin, PhD, Joann Kuruc, MSN, Abigail Liberty, Myron Cohen, MD, Cynthia L. Gay, MD, and Joseph Eron, MD, all of the medical school.

Funding for this research was provided by the Center for HIV/AIDS Vaccine Immunology, the National Institutes of Health, and the James B. Pendleton Charitable Trust.

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Media contact: Lisa Chensvold, (919) 843-5719 or lisa_chensvold@med.unc.edu

Two UNC scientists have received $2.35 million to combine the power of technologies developed in each of their laboratories to answer this question.

Lishan Su, PhD, is a professor of microbiology and immunology and a member of UNC Lineberger Comprehensive Cancer Center and the UNC Center for Infectious Diseases.  His team has developed a laboratory model of hepatitis C that more faithfully replicates the course of the disease in humans, both in terms of inflammation, immune response and other factors.

Stanley M. Lemon, MD, is a professor of medicine and microbiology and immunology and a member of UNC Lineberger Comprehensive Cancer Center, the Center for Translational Immunology, and the UNC Center for Infectious Diseases.  His laboratory’s recombinant DNA virus technology will help the team understand how genetic changes in hepatitis C virus may affect disease progression, including liver cancer.

The researchers are both principal investigators on the five-year grant from the National Cancer Institute, a member institute of the National Institutes of Health.

“Chronic hepatitis C infection is now the leading cause of hepatocellular carcinoma (HCC) in the U.S., but how it causes liver cancer is not well understood because of the lack of a small animal model for hepatitis C.  This multi-PI project will allow us to further refine a recently developed mouse model that develops a human immune response to HCV and human liver diseases when infected with HCV.  The project will combine the expertise of the Su group in human immunology and humanized mouse models with that of the Lemon group in HCV viral genetics and liver cancer to elucidate mechanisms of HCV-induced liver cancer,” said Dr. Su.

“A number of studies have documented that inflammation plays a role in liver cancer.  But there is evidence that there is more to the story of virus-cell interaction in the development of cancer.  We believe that the virus is interacting specifically with host cell tumor suppressor pathways to promote cancer and we want to understand what drives this progression from infection to cancer in order to figure out how to stop it,” said Dr. Lemon.

According to the Centers for Disease Control and Prevention, hepatitis C is the most common chronic blood borne infection in the United States, affecting approximately 3.2 million people.  The disease accounts for the deaths of more Americans each year than HIV/AIDS.   Liver cancer is the third leading cause of death from cancer worldwide and the ninth leading cause of cancer deaths in the United States.  Chronic hepatitis virus infections account for more than two-thirds of these cases.

Contact: Ellen de Graffenreid, 919-962-3405, ellen_degraffenreid@med.unc.edu

April 26, 2012 – In early results of a large-scale randomized study published in 2010 and led by researchers from the University of North Carolina at Chapel Hill, giving daily antiretroviral drugs (ART) to HIV-infected moms or their breastfeeding babies for 28 weeks proved safe and effective for preventing mother-to-child HIV transmission through breast milk.

Now it appears that early weaning – stopping breastfeeding before six months – is of little, if any, protective value against HIV transmission nor is it safe for infant survival.

The findings came from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) trial that was conducted in Lilongwe, Malawi, between April 21, 2004 and January 28, 2010. The study involved more than 2,300 HIV-infected breastfeeding mothers and their newborn babies. BAN investigators were from theU.S. Centers for Disease Control and Prevention (CDC), UNC-Chapel Hill, and UNC Project-Malawi in Lilongwe, Malawi.

In 2010, BAN investigators reported early results demonstrating a 74 percent reduction in HIV transmission to the breastfeeding babies if they were taking a single daily dose of the antiviral medication nevirapine for 28 weeks. In light of this and other emerging evidence, the World Health Organization in 2010 recommended that antiretroviral drugs be given to either HIV-infected mothers or infants throughout breastfeeding. 

A report of the latest and long-term (48 week) BAN outcomes appears in the online edition of The Lancet on April 26, 2012. Here, the researchers focused specifically on the safety and effects of weaning and stopping of maternal or infant ART at 28 weeks after birth. The study’s first author is Denise J. Jamieson, MD, MPH from the CDC.  Senior author and principal investigator of BAN is Charles van der Horst, MD, a professor in the UNC School of Medicine, Division of infectious diseases.

Jamieson and her BAN colleagues found the overall risk of HIV transmission was significantly greater at 48 weeks (7 percent) in the control group of infants (breastfeeding only) than in the maternal ART group (4 percent) and the infant ART group (4 percent). However, about a third of the infants became HIV infected after most mothers said they had stopped nursing their babies at 28 weeks after giving birth. 

“Our 48-week follow-up of women in Malawi has shown that either infant or maternal prophylaxis [with ART] effectively reduces postnatal HIV transmission and that this protective effect persists until after breastfeeding cessation,” states Dr. Jamieson. “However, transmission does occur after mothers report that they have weaned their infants.”

The report also noted that infant illnesses (diarrhea, malaria and TB), growth problems, and deaths significantly increased after early weaning.  “Breastfeeding is essential for babies in Malawi. There should be no early weaning and anti-HIV medications given to the mother or infant should be continued throughout the breastfeeding period,” Dr. van der Horst said.

Support for the research came from the CDC, National Institute of Allergy and Infectious Diseases, the UNC Center for AIDS Research, the NIH Fogarty AIDS International Training & Research Programs, and the American Recovery and Reinvestment Act.