NIAID Scientists develops a novel treatment for HIV infection

With more than 70 million people reportedly infected with the HIV virus, Scientists at the NIAID Laboratory of Viral Diseases have developed a novel treatment for HIV infection.

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HIV-infected T cell. Scanning electron micrograph of an HIV-infected T cell. Credit: NIAID

The scientists developed nucleic acids that encode novel chimeric antigen receptor (CAR) proteins that can be used to specifically kill HIV-infected cells within HIV-infected individuals.

When the CARs are expressed on host T cells (CAR T cells), they can be used to specifically kill HIV-infected cells within HIV-infected individuals. This technology can also be used to protect uninfected cells within HIV-infected individuals by rendering them resistant to infection by HIV.

There is a growing body of in vitro and in vivo data that provides support for the continued development of NIAID’s CAR T-cells as a treatment, and potential cure, for HIV infection

According to the World Health Organization (WHO), more than 70 million have been infected with the HIV virus and about 35 million people have died of HIV.

Since the beginning of the epidemic, more than 70 million people have been infected with the HIV virus and about 35 million people have died of HIV. Globally, 36.7 million [30.8–42.9 million] people were living with HIV at the end of 2016. An estimated 0.8% [0.7-0.9%] of adults aged 15–49 years worldwide are living with HIV, although the burden of the epidemic continues to vary considerably between countries and regions. Sub-Saharan Africa remains most severely affected, with nearly 1 in every 25 adults (4.2%) living with HIV and accounting for nearly two-thirds of the people living with HIV worldwide. – WHO

NIAID scientists say the potential commercial applications include therapy for HIV infection and research on antiretroviral infection while it will also enhance potency for HIV inhibition and does not render transduced CD8T cells susceptible to HIV infection.

NIAID dedicated to helping eliminate tuberculosis

NIH Statement on World Tuberculosis Day 2018

Statement of Christine F. Sizemore, Ph.D., Richard Hafner, M.D., and Anthony S. Fauci, M.D.

In the 130 years since the discovery of Mycobacterium tuberculosis (Mtb) — the bacterium that causes tuberculosis (TB) — at least 1 billion people have died from TB. That death toll is greater than the combined number of deaths from malaria, smallpox, HIV/AIDS, cholera, plague and influenza. Today, in commemoration of World TB Day, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), renews and reinvigorates its commitment to the research needed to end this ancient scourge.

 

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Tuberculosis (TB) remains the world’s leading cause of death alongside HIV

Mtb is transmitted through the air and primarily affects the lungs.  TB is the leading killer among infectious diseases and among the top 10 causes of death worldwide.  The World Health Organization (WHO) estimates that in 2016, TB claimed the lives of 1.7 million people, including 250,000 children, and 10.4 million people were newly infected with Mtb. TB is the primary cause of death for individuals co-infected with HIV. According to the WHO, more than 2 billion people globally are “latently” infected with TB, meaning they carry the bacteria but are currently without symptoms, which would include cough, fever, weight loss and night sweats. People with latent TB infection cannot actively transmit TB bacteria to another person. Up to 13 million people in the United States are estimated to have latent TB infection, according to the U.S. Centers for Disease Control and Prevention. Overall, people with latent TB infection have a 5 to 15 percent lifetime risk of developing active TB disease. This risk increases for people with compromised immune systems, such as those living with HIV, people receiving immunosuppressive therapy (such as individuals being treated for cancer), as well as diabetics, smokers and the malnourished.                                                                                                                                                                              WHO’s End TB Strategy envisions an end to TB by 2035. To accomplish this, incremental improvements in understanding the disease and in the tools used to identify, treat, and prevent it will not be sufficient. Rather, accelerated efforts and transformative advances are needed. Recent engagement includes NIAID participation in the first “WHO Global Ministerial Conference on Ending TB in the Sustainable Development Era: A Multisectoral Response” in Moscow. At this November 2017 meeting, the urgent need for a more intensive biomedical research approach to controlling and ultimately eliminating TB was clearly articulated. Specifically, we need a more intensive interdisciplinary systems biology approach (using cutting-edge methods, large data sets, and modeling to understand complex biological systems) to improve our understanding of how Mtb infection causes disease. Additionally, we must work toward improved diagnostics that can detect Mtb in a variety of clinical specimens in addition to sputum. Also, rapid, accurate, and inexpensive “point-of-care” tests to distinguish between drug-sensitive and drug-resistant Mtb must be developed. NIAID investments in research contributed substantially to the WHO-endorsed GeneXpert MTB/rifampicin resistance diagnostic currently in use, and the Institute continues to support the development of next-generation TB diagnostics.

 

Today’s treatment regimens for TB require too many drugs, often with toxic side effects, that must be taken for six months or longer. With the increasing incidence of multidrug resistant TB (MDR-TB), these regimens often become very lengthy (up to 20 months), more complex, costly, and more prone to failure. Extensively drug-resistant TB (XDR-TB) is even more difficult to treat, and for some patients, no effective treatment regimens exist. Despite the urgent need for new and improved TB treatments, there is a paucity of new drugs in the clinical development pipeline. To address this deficit, NIAID-supported investigators have engaged in cross-disciplinary, international collaborations designed to spur basic science and early-stage TB drug discovery. Additionally, NIAID has used its HIV/AIDS clinical trials networks to enhance TB clinical research by conducting key studies of potential TB treatment strategies. For example, a NIAID-led study found that a one-month antibiotic regimen to prevent active TB disease in people with latent TB infection was as safe and effective as the standard 9-month course in people living with HIV.  Additionally, the NIAID-funded HIV/AIDS clinical trials networks have conducted studies of improved regimens for MDR-TB therapeutics geared to treat both HIV-infected and uninfected adults and children.

A broadly effective preventive TB vaccine could avert millions of new Mtb infections; however, critical knowledge gaps have made developing such a vaccine a difficult challenge. The current Bacille Calmette-Guerin (BCG) vaccine, developed in 1921, offers protection against disseminated TB disease and death in children, but this protection does not reliably extend into adulthood.  A recent study suggests that revaccination with the vaccine could potentially prevent Mtb infections in high-risk adolescents. To reliably protect against the transmissible pulmonary form of the disease in adults, a new, more effective intervention strategy is needed. NIAID supports basic, preclinical and clinical research to find and develop new, innovative vaccines to prevent TB infection and disease.

The WHO estimates that 53 million lives were saved between 2000 and 2016 through improved TB diagnosis and treatment. Through an intensified research agenda, a sustained commitment to supporting and conducting TB research, and a renewed effort to work with other agencies and organizations, NIAID is dedicated to helping eliminate this disease and improving and saving the lives of people with TB. In September 2018, the United Nations General Assembly will conduct a high-level meeting on TB—representing an important step forward by governments and other partners from around the world in the fight against TB. On this World TB Day, we stand with global leaders in response to the bold call of action to make history and end TB.

Anthony S. Fauci, M.D., is Director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health in Bethesda, Maryland. Richard Hafner, M.D., is chief of the TB Clinical Research Branch in NIAID’s Division of AIDS; Christine F. Sizemore, Ph.D., is chief of the Tuberculosis and other Mycobacterial Diseases Section in the NIAID Division of Microbiology and Infectious Diseases.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses.


About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH and partners launch HIV vaccine efficacy study

The National Institutes of Health and partners have launched a large clinical trial to assess whether an experimental HIV vaccine regimen is safe and able to prevent HIV infection.

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Scanning electromicrograph of an HIV-infected T cell.NIAID

The new Phase 2b proof-of-concept study, called Imbokodo, aims to enroll 2,600 HIV-negative women in sub-Saharan Africa. Of 1.8 million new HIV infections worldwide in 2016, 43 percent occurred in eastern and southern Africa, with women and girls disproportionately affected.

“Imbokodo,” the Zulu word for rock, is part of a well-known proverb in South Africa that refers to the strength of women and their importance in the community. The study is sponsored by Janssen Vaccines & Prevention, B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with co-funding from two primary partners, the Bill & Melinda Gates Foundation (BMGF) and NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

The vaccine regimen being tested in Imbokodo is based on “mosaic” immunogens — vaccine components designed to induce immune responses against a wide variety of global HIV strains. This regimen differs from the one being tested in the Phase 2b/3 HVTN 702 study, an ongoing HIV vaccine efficacy trial sponsored by NIAID that launched late last year in South Africa with major co-funding from NIAID and BMGF. HVTN 702 is evaluating a newer version of the vaccine regimen tested in the RV144 Thai trial — the only candidate HIV vaccine regimen ever shown to provide some protection against the virus.

“Together with the implementation of existing HIV prevention and treatment strategies, the development and delivery of a preventive HIV vaccine that is safe and at least moderately effective would help bring about a durable end to the HIV/AIDS pandemic,” said NIAID Director Anthony S. Fauci, M.D. “We are committed to pursuing multiple vaccine development strategies to achieve this goal.”

The first Imbokodo participants have received vaccinations at clinical research sites in South Africa. Regulatory approvals are being sought to conduct the study at additional sites in Malawi, Mozambique, Zambia and Zimbabwe. With the start of Imbokodo, two HIV vaccine efficacy trials now are taking place in sub-Saharan Africa. Results from HVTN 702, which is enrolling HIV-negative men and women in South Africa, are expected in late 2020. Results from Imbokodo are expected in 2021.

“Both Imbokodo and HVTN 702 have resulted from years of scientific testing and clinical development, and they represent science’s current best efforts to develop a vaccine to prevent HIV infection,” said Kathy Mngadi, M.B.Ch.B., M.Phil., senior scientist at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) and Imbokodo co-chair. “We are grateful to the people of southern Africa who volunteer for these trials, and the communities in which the trials are conducted to help develop what could be a true game-changer for the HIV/AIDS pandemic.”

The NIAID-funded HIV Vaccine Trials Network (HVTN), headquartered at Fred Hutchinson Cancer Research Center in Seattle, is implementing Imbokodo. The South African Medical Research Council (SAMRC) is helping implement the study in South Africa. Additional partners providing support include the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research, the U.S. Army Medical Materiel Development Activity, and the Ragon Institute of MGH, MIT and Harvard.

NIAID provided funding for preclinical and early phase clinical development of the mosaic-based vaccine, which was initially developed by the laboratory of Dan H. Barouch, M.D., Ph.D., at Beth Israel Deaconess Medical Center, together with Janssen and other partners. The mosaic immunogens incorporated in the vaccine were designed by the Los Alamos National Laboratory.

In preclinical studies, regimens with mosaic-based vaccines protected monkeys against infection with an HIV-like virus. Findings from two early-stage human clinical trials suggest that these vaccines are well-tolerated and can generate anti-HIV immune responses in healthy adult volunteers. Based on results from an early-stage clinical trial called APPROACH, reported in July 2017, as well as findings from a second early-stage trial called TRAVERSE, researchers selected a lead candidate regimen for further evaluation.

Data from TRAVERSE confirmed the decision to move forward with the larger trial to evaluate whether the experimental regimen can prevent HIV infection. The ongoing TRAVERSE study is comparing two regimens containing vaccines that use a strain of common-cold virus engineered so that it does not cause illness (adenovirus serotype 26, or Ad26) to deliver either three (trivalent) or four (quadrivalent) mosaic antigens among 198 healthy, HIV-negative adult volunteers in the United States and Rwanda. Interim data indicate that both are well-tolerated and can elicit anti-HIV immune responses. Imbokodo is evaluating the quadrivalent vaccine.

All Imbokodo participants will receive vaccinations at four timepoints over one year. They will be randomly assigned to receive either the experimental vaccine regimen or placebo. The experimental regimen includes four doses of the quadrivalent mosaic vaccine. The final two doses will be given together with doses of an HIV protein, clade C gp140, and an aluminum phosphate adjuvant to boost immune responses. Participants will be followed for at least two years.

For more information about Imbokodo, also known as HVTN 705/HPX2008, please see ClinicalTrials.gov using identifier NCT03060629.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

Combination HIV prevention reduces new infections by 42 percent in Ugandan district

A study published today in the New England Journal of Medicine provides real-world evidence that implementing a combination of proven HIV prevention measures across communities can substantially reduce new HIV infections in a population.

 

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A research assistant draws blood for HIV testing from a participant in the Rakai Community Cohort Study.Rakai Health Sciences Program

Investigators found that HIV incidence dropped by 42 percent among nearly 18,000 people in Rakai District, Uganda, during a seven-year period in which the rates of HIV treatment and voluntary medical male circumcision increased significantly.

 

The HIV prevention strategy whose impact was observed in the study is based on earlier findings by the National Institutes of Health and others demonstrating the protective effect of voluntary medical male circumcisionfor HIV-uninfected men and of HIV-suppressing antiretroviral therapy (ART) for halting sexual transmission of the virus to uninfected partners. The strategy is also based on studies showing that changes in sexual behavior, such as having only one sexual partner, can help prevent HIV infection.

“Before this study, we knew that these HIV prevention measures worked at an individual level, yet it was not clear that they would substantially reduce HIV incidence in a population — or even if it would be possible to get large numbers of people to adopt them,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “This new analysis demonstrates that scaling up combination HIV prevention is possible and can turn the tide of the epidemic.”

NIAID co-funded the research, and NIAID investigators oversaw all laboratory operations. The President’s Emergency Plan for AIDS Relief (PEPFAR) funded the provision of combination HIV prevention, including ART and circumcision services, during the period observed in the study.

The newly reported research involved nearly 34,000 people ages 15 to 49 years residing in 30 communities that participate in the Rakai Community Cohort Study (RCCS) conducted by the Rakai Health Sciences Program in Uganda. With funding from NIH and others, this program promoted HIV testing, ART and voluntary medical male circumcision to study participants. Every one or two years from April 1999 until September 2016, participants were tested for HIV and surveyed about their sexual behavior, use of HIV treatment, and male circumcision status. The authors of the new paper analyzed these survey data under the leadership of M. Kate Grabowski, Ph.D., an assistant professor of pathology at the Johns Hopkins University School of Medicine in Baltimore and of epidemiology at the Johns Hopkins University Bloomberg School of Public Health, and an epidemiologist with the Rakai Health Sciences Program.

The investigators found that the proportion of study participants living with HIV who reported taking ART climbed from zero in 2003 to 69 percent in 2016. The proportion of male study participants who were voluntarily circumcised grew from 15 percent in 1999 to 59 percent in 2016. While levels of condom use with casual partners and the proportion of people reporting multiple sexual partners remained largely unchanged, the proportion of adolescents ages 15 to 19 who reported never having sex rose from 30 percent in 1999 to 55 percent in 2016.

As an apparent consequence of these increases, particularly in ART use and voluntary male circumcision, the annual number of new HIV infections in the cohort fell from 1.17 per 100 person-years in 2009 to 0.66 per 100 person-years in 2016, a 42 percent decrease. Person-years are the sum of the number of years that each cohort member participated in the study. The researchers calculated the annual number of new HIV infections using data from nearly 18,000 of the almost 34,000 total participants.

In addition, the proportion of cohort members living with HIV whose treatment suppressed the virus increased from 42 percent in 2009 to 75 percent in 2016, showing the feasibility of meeting the goal of the UNAIDS 90-90-90 initiative(link is external) to achieve 73 percent viral suppression.

“These findings are extremely encouraging and suggest that with sustained commitment to increase the number of people who use combination HIV prevention, it may be possible to achieve epidemic control and eventual elimination of HIV,” said David Serwadda, M.B.Ch.B., M.Med., M.P.H., co-founder of the Rakai Health Science Program and professor at Makerere University School of Public Health in Kampala, Uganda.

HIV incidence dropped the most — by 57­­ percent — among circumcised men, likely because both their own circumcision and ART taken by their female sexual partners living with HIV protected these men from the virus. HIV incidence declined by 54 percent among all men but by only 32 percent among all women. According to the investigators, this difference probably occurred because a greater percentage of women living with HIV than men living with HIV took ART, and because nearly two-thirds of men chose the extra preventive benefit of circumcision. The researchers suggest addressing this gender imbalance by influencing more men living with HIV to take ART and by giving HIV-uninfected women HIV prevention tools that they can control unilaterally, such as pre-exposure prophylaxis (PrEP). The scientists anticipate that the RCCS will add PrEP to its combination HIV prevention package as the study continues.

“We expect that this multifaceted approach to HIV prevention will work as well in other populations as it has in rural Uganda,” said Dr. Grabowski. “Our results make a strong case for further expanding ART and male circumcision for HIV prevention in Rakai District and beyond. Additional proven HIV prevention interventions, such as PrEP, should be added to the mix to reduce HIV infections in women and other high-risk groups.”

The Rakai Health Sciences Program is an independent research organization whose collaborators include the Uganda Virus Research Institute of the Ministry of Health in Kampala, the NIAID Division of Intramural Research-supported International Center for Excellence in Research in Rakai, the U.S. Centers for Disease Control and Prevention partnership with Uganda (CDC-Uganda), Makerere University and the Johns Hopkins University Bloomberg School of Public Health.

The RCCS and the new analysis were funded by NIAID, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all part of NIH; as well as by the World Bank, the Doris Duke Charitable Foundation, the Bill & Melinda Gates Foundation, the Johns Hopkins University Center for AIDS Research and PEPFAR.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

Reference

MK Grabowski, et al. Combination HIV prevention and HIV incidence in Uganda. NEJM DOI: 10.1056/NEJMoa1702150 (2017).

Three Decades of Responding to Infectious Disease Outbreaks

NIAID Director Anthony S. Fauci, M.D., Highlights Lessons from AIDS to Zika

November 14, 2017

 

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Map showing global examples of emerging and re-emerging infectious diseases.

 

Soon after his appointment in 1984 as director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, Anthony S. Fauci, M.D., testified before Congress showing a world map annotated with a single emerging infectious disease threat, HIV/AIDS. Since then, diseases and pathogens including chikungunya, H1N1 influenza, severe acute respiratory syndrome (SARS), West Nile, Ebola and Zika viruses were added, providing a powerful visual reminder of the enduring need to anticipate, detect and manage new and emerging infectious diseases around the globe. In an essay in Annals of Internal Medicine published online today, Dr. Fauci reflects on the ways efforts have been marshalled to address infectious disease outbreaks of the past three decades.

Initial responses to a newly recognized disease, now known as HIV/AIDS, in the early 1980s were criticized as being too slow, the essay notes. “The insidious emergence of HIV/AIDS and the lack of due attention by policymakers illustrate how some outbreaks that start subtly can grow to global proportions if they are not aggressively addressed early on,” Dr. Fauci writes. Between the early 1980s and the early 1990s, federal funding for HIV/AIDS research increased markedly, reaching $1 billion by the end of 1992. The accelerated government response supported both research and research infrastructure, and yielded advances in countering the HIV/AIDS pandemic domestically and internationally. Ultimately, notes Dr. Fauci, sustained support for scientific research coupled with political and community engagement helped transform HIV/AIDS from a nearly universally fatal disease to a condition that can be managed with appropriate treatment.

In contrast to HIV/AIDS, when outbreaks of respiratory diseases caused by SARS coronavirus and influenza viruses have occurred, they generated immediate widespread public attention and prompted concerted responses by presidential administrations and Congress. For example, the 2009 influenza pandemic began in April and an experimental vaccine entered clinical trials by August. However, despite intense efforts to test and manufacture the new vaccine, adequate supplies to protect the broad U.S. population were not available until early winter, after the outbreak had peaked. “This experience,” writes Dr. Fauci, “served as a striking reminder of the inadequacy of our pandemic preparedness capabilities and underscored the need, now being actively pursued, to develop platform technologies that can be applied rapidly to develop vaccines for evolving outbreaks.”

The essay also considers how presidential administrations have responded to the appearance of pathogens ranging from West Nile virus and Ebola to, most recently, the arrival of Zika virus in the Americas. “Leadership at the NIAID has learned many valuable lessons through experiences during the prior administrations with regard to optimal responses to such outbreaks,” Dr. Fauci concludes. “It is critical to apply these lessons to the infectious disease threats that we will inevitably face in the current administration and beyond.”

ARTICLE:

CI Paules, et al. What recent history has taught us about responding to emerging infectious disease threats. Annals of Internal Medicine DOI: 10.7326/M17-2496 (2017).

WHO:

NIAID Director Anthony S. Fauci, M.D., is available to discuss his paper.

 Content last reviewed on November 14, 2017


Published courtesy of the National Institute of Allergy and Diseases