Computational model uncovers progression of HIV infection in brain

University of Alberta research team successfully uncovered the progression of HIV infection in the brain using a new mathematical model. The team is utilizing this model to develop a nasal spray to administer  antiretroviral medication effectively. Their research is published in Journal of Neurovirology.

Research was done by PhD student Weston Roda and Prof. Michael Li. They used data from patients who died five to 15 years after they were infected, as well as known biological processes for the HIV virus to build the model that predicts the growth and progression of HIV in the brain, from the moment of infection onward. It is the first model of an infectious disease in the brain.

“The nature of the HIV virus allows it to travel across the blood-brain barrier in infected macrophage–or white blood cell–as early as two weeks after infection. Antiretroviral drugs, the therapy of choice for HIV, cannot enter the brain so easily,” said Roda. This creates what is known as a viral reservoir, a place in the body where the virus can lay dormant and is relatively inaccessible to drugs.

Prior to this study, scientists could only study brain infection at autopsy. The new model allows scientists to backtrack, seeing the progression and development of HIV infection in the brain. Using this information, researchers can determine what level of effectiveness is needed for antiretroviral therapy in the brain to decrease active infection.

“The more we understand and can target treatment toward viral reservoirs, the closer we get to developing total suppression strategies for HIV infection,” said Roda. A research team led by Chris Power, Roda’s co-supervisor who is a professor in the Division of Neurology, is planning clinical trials for a nasal spray that would get the drugs into the brain faster, with critical information on dosage and improvement rate provided by Roda’s model.

“Our next steps are to understand other viral reservoirs, like the gut, and develop models similar to this one, as well as understand latently infected cell populations in the brain,” said Roda. “With the antiretroviral therapy, infected cells can go into a latent stage. The idea is to determine the size of the latently infected population so that clinicians can develop treatment strategies”

Citation: Roda, Weston C., Michael Y. Li, Michael S. Akinwumi, Eugene L. Asahchop, Benjamin B. Gelman, Kenneth W. Witwer, and Christopher Power. “Modeling brain lentiviral infections during antiretroviral therapy in AIDS.” Journal of NeuroVirology, 2017.
doi:10.1007/s13365-017-0530-3.
Adapted from press release by University of Alberta.

New technique of cellular vaccination against HIV

Scientists at The Scripps Research Institute have found a way to tether HIV-fighting antibodies to immune cells, creating a cell population resistant to the virus. Researchers have used membrane-tethered, receptor blocking antibodies to achieve this outcome.

Here, cells protected from rhinovirus by membrane-tethered,
receptor-blocking antibodies survive well and form colonies.
Credit: Jia Xie, Lerner lab, The Scripps Research Institute.

Their experiments under lab conditions show that these resistant cells can quickly replace diseased cells, potentially curing the disease in a person with HIV. “This protection would be long term,” said Jia Xie, senior staff scientist at TSRI and first author of the study published today in the journal Proceedings of the National Academy of Sciences.

The new TSRI technique offers a significant advantage over therapies where antibodies float freely in the bloodstream at a relatively low concentration. Instead, antibodies in the new study hang on to a cell’s surface, blocking HIV from accessing a crucial cell receptor  called CD4, and thereby preventing spreading of infection. With the antibodies monopolizing that site, the virus cannot enter the cell to spread infection. “This is really a form of cellular vaccination,” said study senior author Richard Lerner, M.D.

The scientists further confirmed that these tethered antibodies blocked HIV more effectively than free-floating, soluble antibodies in experiments led by study co-authors Devin Sok of the International AIDS Vaccine Initiative (IAVI) and TSRI Professor Dennis R. Burton.

Citation: Xie, Jia, Devin Sok, Nicholas C. Wu, Tianqing Zheng, Wei Zhang, Dennis R. Burton, and Richard A. Lerner. “Immunochemical engineering of cell surfaces to generate virus resistance.” Proceedings of the National Academy of Sciences, 2017, 201702764.
doi:10.1073/pnas.1702764114.
Adapted from press release by The Scripps Research Institute.

Animal study shows combination of antibodies are effective in HIV

Without antiretroviral drug treatment, the majority of people infected with HIV ultimately develop AIDS, as the virus changes and evolves beyond the body’s ability to control it. But a small group of infected individuals called elite controllers possess immune systems capable of defeating the virus. They accomplish this by manufacturing broadly neutralizing antibodies, which can take down multiple forms of HIV.

Now a study using antibodies from one of these elite controllers has shown that a combination of three such antibodies can completely suppress the virus in HIV-infected mice. The findings, from the laboratory of Michel Nussenzweig, who is Zanvil A. Cohn and Ralph M. Steinman Professor at Rockefeller University and head of the Laboratory of Molecular Immunology, are reported in Science Translational Medicine.

“Some people with HIV produce these antibodies, but most of the time the virus eventually escapes them through mutations in the antibody’s corresponding epitope,” says postdoctoral fellow Natalia Freund, the study’s first author. The epitope is the part of the virus that antibodies recognize and attach themselves to, and this ability to mutate makes HIV particularly tricky to tame. It ensures that once the virus is in their bodies, people remain infected forever, and this may be the biggest roadblock in developing immune therapies to overcome the virus.

“What we’ve shown in this study is that after several rounds of escape from these particular antibodies, the virus seems to run out of options,” Natalia Freund adds. “In this particular case, HIV eventually loses this arms race.”

An elite controller’s immune system can defeat the virus by coming up with new broadly neutralizing antibodies, and also by producing cytotoxic T cells immune cells that can recognize and destroy infected cells to immobilize the virus. The patient whose HIV response created antibodies for the study has been working with the Rockefeller team for ten years, contributing his blood serum for their research. He was infected at least three decades ago, and has developed three different types of broadly neutralizing antibodies that bind to three different sites on the virus.

The remarkable thing about his antibodies is that they seem to complement each other’s activity, completely shutting down HIV.

The investigators gave the three antibodies, called BG18, NC37, and BG1, to HIV-infected mice whose immune systems had been modified to more closely resemble those of humans. They found that the trio rendered the virus undetectable in two-thirds of the mice three weeks after it was administered.

“This study validates the approach of using three different antibodies to control HIV infection,” Freund concludes, “pointing the way toward a potential new treatment for people infected with HIV.”

Citation: Freund, Natalia T., Haoqing Wang, Louise Scharf, Lilian Nogueira, Joshua A. Horwitz, Yotam Bar-On, Jovana Golijanin, Stuart A. Sievers, Devin Sok, Hui Cai, Julio C. Cesar Lorenzi, Ariel Halper-Stromberg, Ildiko Toth, Alicja Piechocka-Trocha, Harry B. Gristick, Marit J. van Gils, Rogier W. Sanders, Lai-Xi Wang, Michael S. Seaman7, Dennis R. Burton, Anna Gazumyan, Bruce D. Walker, Anthony P. West Jr, Pamela J. Bjorkman and Michel C. Nussenzweig. “Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller.” Science Translational Medicine 9, no. 373 (2017): eaal2144.
DOI: 10.1126/scitranslmed.aal2144
Research funding: Robertson Foundation, Bill and Melinda Gates Foundation, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, National Institutes of Health, Gordon and Betty Moore Foundation, California HIV/AIDS Research Program.
Adapted from press release by Rockefeller University.

Increased risk of cardiovascular events in HIV patients

Current methods to predict the risk of heart attack and stroke vastly underestimate the risk in individuals with HIV, which is nearly double that of the general population, reports a new Northwestern Medicine study. “The actual risk of heart attack for people with HIV was roughly 50 percent higher than predicted by the risk calculator many physicians use for the general population,” said first author Dr. Matthew Feinstein, a cardiovascular disease fellow at Northwestern University Feinberg School of Medicine. The study was published in JAMA Cardiology.

The higher risk for heart attack about 1.5 to two times greater exists even in people whose virus is undetectable in their blood because of antiretroviral drugs. Accurately predicting an individual’s risk helps determine whether he or she should take medications such as statins to reduce the risk of heart attack or stroke.

The study was conducted using a large, multi-center clinical cohort of HIV-infected individuals receiving care at one of five participating sites around the country. Researchers analyzed data from approximately 20,000 HIV-infected individuals. They compared predicted rates of heart attacks based on data from the general population to the actual rates of heart attacks observed in this cohort.

Scientists believe that primary driver of the higher risk is the HIV-related chronic inflammation. Plaque buildup occurs 10 to 15 years earlier in HIV patients than in the uninfected population. In addition to inflammation and other effects from the virus as factors in higher heart attack and stroke rates, senior study author Dr. Heidi Crane also pointed to higher rates of traditional risk factors like smoking.

“Despite these differences, we found that risk scores developed in the general population — while not as accurate as we would like are still useful in assessing risk in HIV populations,” said Crane, associate professor of medicine at the University of Washington. “More research is needed to develop better ways to assess risk in HIV. “

Feinstein and colleagues hope to collaborate with a large multi-center HIV cohort to develop a new algorithm. They attempted to do it with this study, but 20,000 patients weren’t enough for an accurate predictor. The current tool for predicting heart attack risk for the general population is based on more than 200,000 patients.

“Regardless of age, sex or race, the risks are higher in people with HIV,” Feinstein said. Of HIV-infected groups, the study found the current predictor tool was least accurate in African American men and women and most effective for Caucasian men.

A clinical trial is underway at Northwestern Medicine to evaluate how well common medications for heart disease prevention and treatment, such as statin medications, work to prevent heart disease in the HIV-infected population.

Citation: Feinstein, Matthew J., Robin M. Nance, Daniel R. Drozd, Hongyan Ning, Joseph A. Delaney, Susan R. Heckbert, Matthew J. Budoff, William C. Mathews, Mari M. Kitahata, Michael S. Saag, Joseph J. Eron, Richard D. Moore, Chad J. Achenbach, Donald M. Lloyd-Jones and Heidi M. Crane. “Assessing and Refining Myocardial Infarction Risk Estimation Among Patients With Human Immunodeficiency Virus: A Study by the Centers for AIDS Research Network of Integrated Clinical Systems”. JAMA Cardiology 2016 vol: 43 (1) pp: 27-34
DOI: 10.1001/jamacardio.2016.4494
Research funding: National Institutes of Health, American Heart Association.
Adapted from press release by Northwestern University.

HIV treatment with immunotherapy using VRC01 shows promise and limitations

Immunotherapy has revolutionized treatment options in oncology, neurology, and many infectious diseases and now there is fresh hope that the same method could be used to treat or functionally cure HIV, according to two related studies from Perelman School of Medicine at the University of Pennsylvania, the University of Alabama at Birmingham (UAB), and the National Institutes of Health (NIH).

Published online today in the New England Journal of Medicine, the research offers new insights into how immunotherapy could be used to develop a functional cure for HIV and eliminate the need for people living with the virus to take a daily regimen of medications.

The study, which examined chronically HIV-infected participants, found that injections of one broadly neutralizing HIV antibody (bNAb), known as VRC01, were safe, generated high levels of the antibody, and modestly delayed the time of HIV viral rebound compared to historical controls. However, suppression did not surpass 8 weeks in the majority of participants. By demonstrating that HIV-specific antibodies could be successfully administered as long-acting agents to suppress or even kill HIV-infected cells, this method is a first step toward the ultimate goal of durable suppression of HIV in the absence of antiretroviral therapy (ART).

Currently, most people living with HIV take a once-daily combination of antiretroviral therapy (ART), which prolongs life expectancy and improves overall health, but cannot completely eradicate the virus. Adherence to a daily HIV medication continues to be a challenge for many people living with HIV, especially in resource-limited settings. However, the vast majority of people living with HIV experience rapid rebound if absence of antiretroviral therapy (ART) is stopped or interrupted, making those people sicker and more likely to spread the virus to others.

Through broadly neutralizing HIV antibody (bNAb) immunotherapy, people living with HIV could potentially receive an injection of antibodies or another immunological intervention that would suppress the virus. The injection would remove HIV from a person’s blood and enable control of the virus without a daily absence of antiretroviral therapy (ART) regimen.

“For the near future, it is unlikely that we will be able to fully eradicate HIV once a person has been infected. But a functional cure is a reasonable intermediate goal,” Tebas said. A functional HIV cure means that while the virus would still exist in a person’s body in extremely small amounts, virus replication would be durably suppressed, disease progression drastically slowed, and symptoms of infection stopped – all without the need for daily medications.

“The goal of immunotherapy is to eliminate the need to take a pill every single day while simultaneously chipping away at the latent reservoir of virus-infected cells. However, we are still years away from that goal. And even if a person is able to be functionally cured of HIV, long-term follow-up will be essential to ensure that the virus doesn’t return to high levels,” Tebas said.

The bNAb tested in this trial did not provide long-lasting virus control in participants. Investigators tested historical blood samples from trial participants that were stored at both Penn and UAB’s Centers for AIDS Research (CFAR) in order to determine if there was pre-existing resistance to bNAb immunotherapy and reveal its limitations as a potential cure. They found that the trial participants with the shortest times of HIV suppression harbored viruses that were resistant to the broadly neutralizing HIV antibody (bNAb).

Bar notes that this study was a collaborative effort between several institutions. “The close collaboration between the Penn and UAB CFARs with the AIDS Clinical Trials Group (ACTG) enabled us to characterize the pre-existing resistance and identify it as a key barrier to developing broadly neutralizing HIV antibody (bNAb) immunotherapy as an HIV cure. Continued collaboration between CFARs and the ACTG will be instrumental as we continue to move this research forward.”

Future trials that are now in development will test whether combinations of more potent broadly neutralizing HIV antibody (bNAb) can provide durable virus suppression and potentially reduce the size of the persistent reservoir.

Citation: Katharine J. Bar, Michael C. Sneller, Linda J. Harrison, J. Shawn Justement, Edgar T. Overton, Mary E. Petrone, D. Brenda Salantes, Catherine A. Seamon, Benjamin Scheinfeld, Richard W. Kwan, Gerald H. Learn, Michael A. Proschan, Edward F. Kreider, Jana Blazkova, Mark Bardsley, Eric W. Refsland, Michael Messer, Katherine E. Clarridge, Nancy B. Tustin, Patrick J. Madden, KaSaundra Oden, Sijy J. O’Dell, Bernadette Jarocki, Andrea R. Shiakolas, Randall L. Tressler, Nicole A. Doria-Rose, Robert T. Bailer, Julie E. Ledgerwood, Edmund V. Capparelli, Rebecca M. Lynch, Barney S. Graham, Susan Moir, Richard A. Koup, John R. Mascola, James A. Hoxie, Anthony S. Fauci, Pablo Tebas, and Tae-Wook Chun. “Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption” New England Journal of Medicine. 2016 pp: NEJMoa1608243
DOI: http://dx.doi.org/10.1056/NEJMoa1608243
Research funding: NIH/National Institute of Allergy and Infectious Diseases
Adapted from press release by University of Pennsylvania

Ibalizumab, a monoclonal antibody for treating Multidrug resistant HIV infection

A new biologic medication – the first for HIV – is showing promise in treating patients with multidrug resistance, according to phase 3 research being presented at IDWeek 2016™. Administered intravenously once every two weeks, ibalizumab is a biologic medication called a monoclonal antibody, a genetically engineered molecule that coats immune system cells to protect them from HIV entry. Eighty three percent of patients with multi-drug resistant HIV (MDR HIV) had a virologic response to the drug, according to the study.

When taken as directed, combination treatment called antiretroviral therapy (ART) is highly successful in combatting HIV. However, of the 1.2 million Americans who have HIV, about 10,000 have MDR HIV, meaning they are resistant to all medications used to treat HIV.

“This is the first drug in a long time for patients with multidrug resistance,” said Jacob Lalezari, MD, lead author of the study and medical director for Quest Research, a division of eStudySite, San Franscisco. “This therapy showed good activity in patients who were resistant to everything else, which is very exciting for these vulnerable patients and those who care for them.” He noted that ibalizumab is the first of what promises to be many long-acting anti-viral treatments. While most ART therapy is once a day, researchers are testing medications that are taken less frequently, which will make it easier for patients to take them as prescribed.

The study included 40 patients with MDR-HIV who had been infected with HIV for an average of 21 years and had been treated with many medications. More than one in four (28 percent) had been treated with 10 or more HIV medications. All were given ibalizumab: 35 percent required an additional investigational medication due to resistance to all HIV medications. Most patients benefitted after seven days of treatment: 24 (60 percent) achieved a significant decrease in viral load of 1.0 log10 or greater and 33 (83 percent) achieved a decrease in viral load of 0.5 log10. The average decrease in viral load after seven days of treatment was 1.1 log10. During the control period at the beginning of the study before ibalizumab was added, only one patient (3 percent) had achieved a significant decrease in viral load on the existing ART regime. After one week, all patients continued with ibalizumab and began taking optimizing HIV medications as part of the ART regimen. The combination therapy varied by patient.

“This drug benefits a small but challenging population of HIV patients who are highly treatment experienced,” said Daniel R. Kuritzkes, MD, chief of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston. “This will not be a first- or second-line therapy for those who are infected with HIV, but it may be helpful for certain patients.”

The bi-weekly regimen is beneficial for these patients, said Dr. Lalezari. “There’s higher compliance because they have a place where they can go and are cared for, and it really works for them,” he said.
Some patients are infected with a multidrug resistant form of HIV, but most others develop resistance after periods of time when they are unable to take their ART medication as directed, he said.

Research presented at  IDWeek 2016™.
Research funding by TaiMed Biologics, the manufacturer of ibalizumab.
Adapted from press release by Infectious Diseases Society of America

Researchers focus on using Nanoparticles to improve drug delivery in HIV patients

New research led by the University of Liverpool aims to improve the administration and availability of drug therapies to HIV patients through the use of nanotechnology.  The research, conducted by the collaborative nanomedicine research programme led by Pharmacologist Professor Andrew Owen and Materials Chemist Professor Steve Rannard, examined the use of nanotechnology to improve the delivery of drugs to HIV patients.

Currently, the treatment of HIV requires daily oral dosing of HIV drugs, and chronic oral dosing has significant complications that arise from the high pill burden experienced by many patients across populations with varying conditions leading to non-adherence to therapies.

Recent evaluation of HIV patient groups have shown a willingness to switch to nanomedicine alternatives if benefits can be shown. Research efforts by the Liverpool team have focused on the development of new oral therapies, using Solid Drug Nanoparticle (SDN) technology which can improve drug absorption into the body, reducing both the dose and the cost per dose and enabling existing healthcare budgets to treat more patients.

Presently, no clinically available oral nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available. The programme examined one current paediatric formulation that utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral.

Through the use of a rapid small-scale nanomedicine screening approach developed at Liverpool, the researchers were able to generate a novel water dispersible nanotherapy, hence removing the need to use alcohol in the paediatric medicine.

The research, funded by the UK Engineering and Physical Sciences Research Council is in ongoing human trials, and the preclinical development has been published in Nature Communications today (Friday, 21 October 2016).

Publication: Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies.
DOI: http://dx.doi.org/10.1038/ncomms13184
Authors:Marco Giardiello et.al,
Journal: Nature Communications – News
Adapted from press release by University of Liverpool