Tag Archives: #HIV

Study Reveals Regulation Mechanism of Integrin α4β7 Mediated HIV-1 Virus Infection (Biology)

A research group led by Prof. LI Guohui from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), in collaboration with Prof. CHEN Jianfeng’s group from Shanghai Institute of Biochemistry and Cell Biology of CAS, revealed the regulation mechanism of integrin α4β7 mediated human immunodeficiency virus 1 (HIV-1) infection.

This study was published in Signal Transduction and Targeted Therapy on July 16.

Integrin α4β7, an important cell surface adhesion molecule, is responsible for mediating lymphocytes from blood circulation into the intestine and central nervous system. The abnormality of its function is closely related to human autoimmune diseases.

Previous studies have shown that intestinal homing CD4+ T cells expressing integrin α4β7 are the early targets of HIV-1 virus infection, which plays an important role in the pathogenesis of HIV-1 infection.

The binding between the envelope protein gp120 located on the surface of the HIV-1 virus and the receptors on the surface of CD4+ T cells is a key step for HIV-1 to infect T cells.

In this study, the researchers investigated the interaction between integrin α4β7 and gp120. They found that specific intestinal chemokines could stimulate integrin α4β7 in a relatively stretched condition, leading to a highly activated conformation state, and it enabled integrin α4β7 to bind the HIV-1 envelope protein gp120. While, the inactive integrin α4β7 exhibited no binding ability with HIV-1 envelope protein gp120.

Moreover, they indicated that the interactions between the metal ion-dependent adhesion site (MIDAS) in the integrin β7 subunit and the highly conserved tripeptide LDI in the HIV-1 envelope protein gp120 were the key site for integrin α4β7 mediated HIV-1 infection.

In addition, they also found that the interactions between integrin α4β7 and HIV-1 envelope protein gp120 might activate multiple intracellular signaling pathways, which further regulated HIV-1 virus replication and T cell function.

“This study would provide new strategies and ideas for the prevention and treatment of HIV-1 infection and the screening of related drugs,” said Prof. LI.

The research was supported by the National Natural Science Foundation of China.

Featured image credit: C. Goldsmith Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus 


Reference: Wang, S., Lin, C., Li, Y. et al. Distinct chemokines selectively induce HIV-1 gp120-integrin α4β7 binding via triggering conformer-specific activation of α4β7. Sig Transduct Target Ther 6, 265 (2021). https://doi.org/10.1038/s41392-021-00582-8


Provided by Chinese Academy of Sciences

Study Uncovers Stem Cells Ability to Restore Immunity And Repair Gut Damage Caused by HIV (Medicine)

In a groundbreaking study, a team of UC Davis researchers has discovered a special type of stem cell that can reduce the amount of the virus causing AIDS, boosting the body’s antiviral immunity and repairing and restoring the gut’s lymphoid follicles damaged by the simian immunodeficiency virus (SIV), the equivalent of the human immunodeficiency virus (HIV) in non-human primates.

The study, published June 22 in JCI Insight, showed the mechanism through which mesenchymal stem/stromal cells (MSCs) enhance the body’s immune response to the virus. It also provides a roadmap for developing multi-pronged HIV eradication strategies.

“Impaired immune functions in HIV infection and incomplete immune recovery pose obstacles for eradicating HIV,” said Satya Dandekar, senior author of this paper. “Our objective was to develop strategies to boost immunity against the virus and empower the host immune system to eradicate the virus. We sought to repair, regenerate and restore the lymphoid follicles that are damaged by the viral infection.”

The lymphoid tissue in the gut is an early site for viral replication and the establishment of viral reservoirs. Dandekar’s group has previously shown that an HIV infection causes severe loss of gut mucosal T immune cells and disrupts the gut epithelial barrier lining, leading to a leaky gut.

“The lymphoid follicles are organized structures where the long-term immune attack is launched against pathogens by generating antibody response targeting the virus. These important regions are functionally impaired very early following HIV infection,” Dandekar said.

While antiretroviral drugs effectively suppress viral replication, they do not repair the damage caused by the virus to the immune system. On their own, these drugs cannot restore the functionality of the lymphoid follicles damaged by HIV infection.

Can stem cells counteract the gut damage caused by HIV?

The researchers administered bone marrow-derived MSC in a rhesus macaque model of AIDS that had impaired immunity and disrupted gut functions due to the viral infection.

“We are starting to recognize the great potential of these stem cells in the context of infectious diseases. We have yet to discover how these stem cells can impact chronic viral infections such as AIDS,” Dandekar said. She is a professor at and the chairperson of the Department of Medical Microbiology and Immunology at UC Davis and affiliated with the California National Primate Research Center.

The study found that the MSCs can modulate, alter and remodel the damaged mucosal site. There were immediate benefits, with a rapid rise in antibodies and T-immune cells targeting the virus. The stem cells were instrumental in the recovery and restoration of these lymphoid follicles.

MSCs also offer an opportunity for an innovative, multi-pronged HIV cure strategy by complementing current HIV treatments.

“Stem cells are good synergistic partner components with drugs. The antiretroviral drugs can stop the fire of the viral infection but cannot restore the forest of the lymphoid tissue compartment. The MSCs would rejuvenate the field and bring back immune vitality,” Dandekar said.

Even without the use of antiviral drugs, MSCs were able to increase the host’s antiviral response by repairing the lymphoid follicles, restoring the mucosal immunity and reviving what has been targeted by the virus very early on.

MSC treatments

MSC treatments require well defined cell quality controls and specific delivery mechanisms. The UC Davis Stem Cell Program, a center for excellence for stem cell research, is leading multiple clinical trials on MSC use in treating diseases such as spina bifida and Huntington’s disease. Findings from this study provide a scientific basis for investigating MSC in treating HIV and other infectious diseases in the clinical setting.

Co-authors on this study are Mariana G. Weber, Chara J. Walters-Laird, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Juan Arredondo, Amir Kol, Sonny R. Elizaldi, Smita S. Iyer and Alice Tarantal at UC Davis, and Bipin Balan at Università di Palermo, Italy.

This work was supported by National Institutes of Health grants (R01AI 153025, R21 AI 116415, R21AI34368, and OD P51 OD011107) and from the National Council for Scientific and Technological Development (CNPq), Brazil.

Featured image: HIV disrupts the lymphoid immune battleground © UC Davis Health


Article: Weber et al. (2021) Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection. JCI Insight. 6(12), Doi:10.1172/jci. insight.149033.


Provided by UC Davis Health

How HIV Infection Shrinks The Brain’s White Matter? (Neuroscience)

Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.

It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.

Earlier work by a team from the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found that antiretroviral therapy (ART)—the lifesaving suite of drugs that many people with HIV use daily—can reduce white matter, but it wasn’t clear how the virus itself contributed to this loss. 

In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature. 

The work is published in the journal Glia.

“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”

“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”

Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.

In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.

Scientists had hypothesized that HIV’s impact on the brain arose indirectly through the activity of these immune cells since the virus doesn’t infect neurons or oligodendrocytes. To learn more about how this might affect white matter specifically, the researchers took the fluid in which macrophages infected with HIV were growing and applied it to rat oligodendrocyte precursor cells, which mature into oligodendrocytes. While this treatment didn’t kill the precursor cells, it did block them from maturing into oligodendrocytes. Myelin production was subsequently also reduced.

“Immune cells that are infected with the virus secrete harmful substances, which normally target invading organisms, but can can also kill nearby cells, such as neurons, or stop them from differentiating,” Grinspan says. “So the next step was to figure out what was being secreted to cause this effect on the oligodendrocytes.” 

The researchers had a clue to go on: Glutamate, a neurotransmitter, is known to have neurotoxic effects when it reaches high levels. “If you have too much glutamate, you’re in big trouble,” says Grinspan. Sure enough, when the researchers applied a compound that blunts glutamate levels to HIV-infected macrophages before the transfer of the growth medium to oligodendrocyte precursors, the cells were able to mature into oligodendrocytes. The result suggests that glutamate secreted by the infected macrophages was the culprit behind the precursor cells getting “stuck” in their immature form.

There was another mechanism, however, that the researchers suspected might be involved: the integrated stress response. This response integrates signals from four different signaling pathways, resulting in changes in gene expression that serve to protect the cell from stress or to prompt the cell to die, if the stress is overwhelming. Earlier findings from Jordan-Sciutto’s lab had found the integrated stress response was activated in other types of brain cells in patients who had cognitive impairment associated with HIV infection, so the team looked for its involvement in oligodendrocytes as well. 

Indeed, they found evidence that the integrated stress response was activated in cultures of oligodendrocyte precursor cells. 

Taking this information with what they had found out about glutamate, “Lindsay was able to tie these two things together,” Jordan-Sciutto says. She demonstrated that HIV-infected macrophages secreted glutamate, which activated the integrated stress response by turning on a pathway governed by an enzyme called PERK. “If you blocked glutamate, you prevented the activation of the integrated stress response,” Jordan-Sciutto says.

To take these findings further, and potentially test out new drug targets to address HIV-related cognitive impairments, the team hopes to use a well-characterized rat model of HIV infection.  

“HIV is a human disease, so it’s a hard one to model,” says Grinspan. “We want to find out if this model recapitulates human disease more accurately than others we’ve used in the past.”

By tracking white matter in this animal model and comparing it to imaging studies done on patients with HIV, they hope to get at a better understanding of what factors shape white matter loss. They’re particularly interested in looking at a cohort of adolescents being treated at CHOP, as teens are a group in whom HIV infection rates are climbing.

Ultimately, the researchers want to discern the effects of the virus from the drugs used to treat it in order to better evaluate the risks of each. 

“When we put people on ART, especially kids or adolescents, it’s important to understand the implications of doing that,” says Jordan-Sciutto. “Antiretrovirals may prevent the establishment of a viral reservoir in the central nervous system, which would be wonderful, but we also know that the drugs can cause harm, particularly to white matter.

“And then of course we can’t forget the 37 million HIV-infected individuals who live outside the United States and may not have access to antiretrovrials like the patients here,” she says. “We want to know how we can help them too.”

Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies.

Judith Grinspan is research scientist at the Children’s Hospital of Philadelphia and research professor of neurology at the the Perelman School of Medicine at the University of Pennsylvania.

Lindsay Roth, who recently earned her doctoral degree from the Biomedical Graduate Group at the University of Pennsylvania, was first author on the paper. 

Roth, Grinspan, and Jordan-Sciutto’s coauthor was Çagla Akay-Espinoza, from Penn’s School of Dental Medicine.

The study was supported by the National Institutes of Health (grants MH098742, MH118121, and MH109382) and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children’s Hospital of Philadelphia (grants HD26979 and GM008076).

Featured image: A confocal microscope image shows an oligodendrocyte in cell culture, labeled to show the cell nucleus in blue and myelin proteins in red, green, and yellow. Researchers from Penn and CHOP have shown that HIV infection prevents oligodendrocytes from maturing, leading to a reduction in white matter in the brain. (Image: Raj Putatunda)


Provided by Penn Today

How HIV Infection Shrinks the Brain’s White Matter? (Medicine)

Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.

It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.

Earlier work by a team from the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found that antiretroviral therapy (ART)—the lifesaving suite of drugs that many people with HIV use daily—can reduce white matter, but it wasn’t clear how the virus itself contributed to this loss. 

In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature. 

The work is published in the journal Glia.

“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”

“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”

Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.

In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.

Scientists had hypothesized that HIV’s impact on the brain arose indirectly through the activity of these immune cells since the virus doesn’t infect neurons or oligodendrocytes. To learn more about how this might affect white matter specifically, the researchers took the fluid in which macrophages infected with HIV were growing and applied it to rat oligodendrocyte precursor cells, which mature into oligodendrocytes. While this treatment didn’t kill the precursor cells, it did block them from maturing into oligodendrocytes. Myelin production was subsequently also reduced.

“Immune cells that are infected with the virus secrete harmful substances, which normally target invading organisms, but can can also kill nearby cells, such as neurons, or stop them from differentiating,” Grinspan says. “So the next step was to figure out what was being secreted to cause this effect on the oligodendrocytes.” 

The researchers had a clue to go on: Glutamate, a neurotransmitter, is known to have neurotoxic effects when it reaches high levels. “If you have too much glutamate, you’re in big trouble,” says Grinspan. Sure enough, when the researchers applied a compound that blunts glutamate levels to HIV-infected macrophages before the transfer of the growth medium to oligodendrocyte precursors, the cells were able to mature into oligodendrocytes. The result suggests that glutamate secreted by the infected macrophages was the culprit behind the precursor cells getting “stuck” in their immature form.

There was another mechanism, however, that the researchers suspected might be involved: the integrated stress response. This response integrates signals from four different signaling pathways, resulting in changes in gene expression that serve to protect the cell from stress or to prompt the cell to die, if the stress is overwhelming. Earlier findings from Jordan-Sciutto’s lab had found the integrated stress response was activated in other types of brain cells in patients who had cognitive impairment associated with HIV infection, so the team looked for its involvement in oligodendrocytes as well. 

Indeed, they found evidence that the integrated stress response was activated in cultures of oligodendrocyte precursor cells. 

Taking this information with what they had found out about glutamate, “Lindsay was able to tie these two things together,” Jordan-Sciutto says. She demonstrated that HIV-infected macrophages secreted glutamate, which activated the integrated stress response by turning on a pathway governed by an enzyme called PERK. “If you blocked glutamate, you prevented the activation of the integrated stress response,” Jordan-Sciutto says.

To take these findings further, and potentially test out new drug targets to address HIV-related cognitive impairments, the team hopes to use a well-characterized rat model of HIV infection.  

“HIV is a human disease, so it’s a hard one to model,” says Grinspan. “We want to find out if this model recapitulates human disease more accurately than others we’ve used in the past.”

By tracking white matter in this animal model and comparing it to imaging studies done on patients with HIV, they hope to get at a better understanding of what factors shape white matter loss. They’re particularly interested in looking at a cohort of adolescents being treated at CHOP, as teens are a group in whom HIV infection rates are climbing.

Ultimately, the researchers want to discern the effects of the virus from the drugs used to treat it in order to better evaluate the risks of each. 

“When we put people on ART, especially kids or adolescents, it’s important to understand the implications of doing that,” says Jordan-Sciutto. “Antiretrovirals may prevent the establishment of a viral reservoir in the central nervous system, which would be wonderful, but we also know that the drugs can cause harm, particularly to white matter.

“And then of course we can’t forget the 37 million HIV-infected individuals who live outside the United States and may not have access to antiretrovrials like the patients here,” she says. “We want to know how we can help them too.”

Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies.

Judith Grinspan is research scientist at the Children’s Hospital of Philadelphia and research professor of neurology at the the Perelman School of Medicine at the University of Pennsylvania.

Lindsay Roth, who recently earned her doctoral degree from the Biomedical Graduate Group at the University of Pennsylvania, was first author on the paper. 

Roth, Grinspan, and Jordan-Sciutto’s coauthor was Çagla Akay-Espinoza, from Penn’s School of Dental Medicine.

The study was supported by the National Institutes of Health (grants MH098742, MH118121, and MH109382) and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children’s Hospital of Philadelphia (grants HD26979 and GM008076).

Featured image: A confocal microscope image shows an oligodendrocyte in cell culture, labeled to show the cell nucleus in blue and myelin proteins in red, green, and yellow. Researchers from Penn and CHOP have shown that HIV infection prevents oligodendrocytes from maturing, leading to a reduction in white matter in the brain. (Image: Raj Putatunda)


Reference: Lindsay Roth, Cagla Akay-Espinoza, Judith B. Grinspan, Kelly L. Jordan-Sciutto, “HIV-induced neuroinflammation inhibits oligodendrocyte maturation via glutamate-dependent activation of the PERK arm of the integrated stress response”, Glia, 31 May 2021. https://doi.org/10.1002/glia.24033


Provided by Penn Today

Newly Identified Antibody Can Be Targeted by HIV Vaccines (Medicine)

A newly identified group of antibodies that binds to a coating of sugars on the outer shell of HIV is effective in neutralizing the virus and points to a novel vaccine approach that could also potentially be used against SARS-CoV-2 and fungal pathogens, researchers at the Duke Human Vaccine Institute report.

In a study appearing online May 20 in the journal Cell, the researchers describe an immune cell found in both monkeys and humans that produces a unique type of anti-glycan antibody. This newly described antibody has the ability to attach to the outer layer of HIV at a patch of glycans — the chain-like structures of sugars that are on the surfaces of cells, including the outer shells of viruses. 

“This represents a new form of host defense,” said senior author Barton Haynes, M.D., director of the Duke Human Vaccine Institute (DHVI). “These new antibodies have a special shape and could be effective against a variety of pathogens. It’s very exciting.”

Haynes and colleagues — including lead author Wilton Williams, Ph.D., director of the Viral Genetics Analysis Core at DHVI and co-author Priyamvada Acharya, Ph.D., director of the Division of Structural Biology at DHVI — found the antibody during a series of studies exploring whether there might be an immune response targeted to glycans that cover the outer surface of HIV. 

More than 50% of the virus’s outer layer is comprised of glycans. Haynes said it has long been a tempting approach to unleash anti-glycan antibodies to break down these sugar structures, triggering immune B-cell lymphocytes to produce antibodies to neutralize HIV.

“Of course, it’s not that simple,” Haynes said.

Instead, HIV is cloaked in sugars that look like the host’s glycans, creating a shield that makes the virus appear to be part of the host rather than a deadly pathogen. 

But the newly identified group of anti-glycan antibodies — referred by the Duke team as Fab-dimerized glycan-reactive (FDG) antibodies — had gone undiscovered as a potential option. 

To date, there was only one report of a similar anti-glycan HIV antibody with an unusual structure that was found 24 years ago (termed 2G12). The Duke team has now isolated several FDG antibodies and found that they display a rare, never-before-seen structure that resembled 2G12. This structure enables the antibody to lock tightly onto a specific, dense patch of sugars on HIV, but not on other cellular surfaces swathed in host glycans.

“The structural and functional characteristics of these antibodies can be used to design vaccines that target this glycan patch on HIV, eliciting a B-cell response that neutralizes the virus,” Williams said.

“These antibodies are actually much more common in blood cells than other neutralizing antibodies that target specific regions of the HIV outer layer,” Williams said. “That’s an exciting finding, because it overcomes one of the biggest complexities associated with other types of broadly neutralizing antibodies.”

Williams said the FDG antibodies also bind to a pathogenic yeast called Candida albicans, and to viruses, including SARS-CoV-2, which causes COVID-19. Additional studies will explore ways of harnessing the antibody and deploying it against these pathogens. 

In addition to Haynes, Williams and Acharya, study authors include R. Ryan Meyerhoff, R.J. Edwards, Hui Li, Kartik Manne, Nathan I. Nicely, Rory Henderson, Ye Zhou, Katarzyna Janowska, Katayoun Mansouri, Sophie Gobeil, Tyler Evangelous, Bhavna Hora, Madison Berry, A. Yousef Abuahmad, Jordan Sprenz, Margaret Deyton, Victoria Stalls, Megan Kopp, Allen L. Hsu, Mario J. Borgnia, Guillaume Stewart-Jones, Matthew S. Lee, Naomi Bronkema, M. Anthony Moody, Kevin Wiehe, Todd Bradley, S. Munir Alam, Robert J. Parks, Andrew Foulger, Thomas Oguin, Gregory D. Sempowski, Mattia Bonsignori, Celia C. LaBranche, David C. Montefiori, Michael Seaman, Sampa Santra, John Perfect, Joseph R. Francica, Geoffrey M. Lynn, Baptiste Aussedat, William E. Walkowicz, Richard Laga, Garnett Kelsoe, Kevin O. Saunders, Daniela Fera, Peter D. Kwong, Robert A. Seder, Alberto Bartesaghi and George M. Shaw.

The study received funding support from the Consortia for HIV/AIDS Vaccine Development, the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, Division of AIDS (UM1-AI44371).


Reference: Wilton B. Williams, R. Ryan Meyerhoff et al., “Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies”, Cell, 2021. DOI: https://doi.org/10.1016/j.cell.2021.04.042


Provided by Duke Health news

New Combination Immunotherapy Plus ART Expand Innate Cells Critical to Controlling HIV (Medicine)

Yerkes National Primate Research Center researchers in collaboration with Institut Pasteur have determined a combination immunotherapy of Interleukin-21 (IL-21) and interferon alpha (IFN?) when added to antiviral therapy (ART) is effective in generating highly functional natural killer (NK) cells that can help control and reduce simian immunodeficiency virus (SIV) in animal models. This finding, published online today in Nature Communications, is key for developing additional treatment options to control HIV/AIDS, which impacts 38 million people worldwide.

ART is the current leading treatment for HIV/AIDS. It is capable of reducing the virus to undetectable levels, but is not a cure and is hampered by issues such as cost, adherence to medication treatment plan and social stigma.

To reduce reliance on ART, the Yerkes, Emory and Institut Pasteur research team worked with 16 SIV-positive, ART-treated rhesus macaques. In most nonhuman primates (NHPs), including rhesus macaques, untreated SIV infection progresses to AIDS-like disease and generates NK cells with impaired functionality. This is in contrast to natural primate hosts of SIV, which do not progress to AIDS-like disease (Huot et al., Nature Communications, 2021). Determining why natural hosts do not progress or how to stop the progression is a critical step in halting HIV in humans.

The researchers compared ART-only treated animals with animals that received ART, IL-21 and IFN? to evaluate how the ART plus combination immunotherapy affected the amount of virus in the animals’ tissue.

“Our results indicate the ART plus combo-treated rhesus monkeys showed enhanced antiviral NK cell responses,” says first author Justin Harper, PhD. “These robust NK cell responses helped clear cells in the lymph nodes (LN), which are known for harboring the virus and enabling its replication and, therefore, the virus’ persistence. Targeting areas where the virus seeks refuge and knowing how to limit replication facilitate controlling HIV,” Harper continues. Harper is a senior research specialist and lab manager of the Paiardini research lab.

HIV treatment has historically focused on the role of T cells in immunity. “This proof-of-concept study in rhesus monkeys, which progress to AIDS-like disease in the absence of ART, demonstrates how certain NK cell activity can contribute to controlling the virus,” says Mirko Paiardini, PhD. “This opens the door to designing additional treatment strategies to induce SIV and HIV remission in the absence of ART, and, ultimately, reducing the burden HIV is to individuals, families and the world,” he adds. Paiardini is an associate professor of Pathology and Laboratory Medicine at Emory University and a researcher at Yerkes.

This study was done in close collaboration with Michaela Müller-Trutwin, PhD, and Nicolas Huot, PhD, at Institut Pasteur. Muller-Trutwin is professor and head of the HIV, Inflammation and Persistence unit, and Huot is a post-doctoral fellow in Muller-Trutwin’s laboratory. The Yerkes/Emory research team also included Luca Micci, PhD, Steve Bosinger, PhD, Guido Silvestri, MD, and Kirk Easley, MS.

The research reported in this release is supported in part by the Yerkes National Primate Research Center base grant from the NIH Office of the Director, Office of Research Infrastructure Programs. The National Institute of Allergy and Infectious Diseases, National Center for Research Resources (through 2015) and National Cancer Institute provided additional funding as did the French National Agency of Research on AIDS and Viral Hepatitis (ANRS) and the Fondation J. Beytout.

Featured image:  Cartoon schematic of study design as detailed in the Results and Methods. Plasma viral loads (SIV-RNA copies/mL) were longitudinally measured by qRT-PCR with individual © Authors


Reference: Harper, J., Huot, N., Micci, L. et al. IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques. Nat Commun 12, 2866 (2021). https://doi.org/10.1038/s41467-021-23189-7


Provided by Emory Health Sciences

New Pre-Clinical Model Could Hold the Key to Better HIV Treatments (Medicine)

A team led by researchers at Weill Cornell Medicine and Children’s National Hospital has developed a unique pre-clinical model that enables the study of long-term HIV infection, and the testing of new therapies aimed at curing the disease.

Ordinary mice cannot be infected with HIV, so previous HIV mouse models have used mice that carry human stem cells or CD4 T cells, a type of immune cell that can be infected with HIV. But these models tend to have limited utility because the human cells soon perceive the tissues of their mouse hosts as “foreign,” and attack—making the mice gravely ill.

By contrast, the new mouse model, described in a paper in the Journal of Experimental Medicine on May 14, avoids this problem by using a subset of human CD4 cells that mostly excludes the cells that would attack mouse tissue. The researchers showed that the mice can usefully model the dynamics of long-term HIV infection, including the virus’s response to experimental therapies.

“We expect this to be a valuable and widely used tool for studying the basic science of HIV infection, and for speeding the development of better therapies,” said co-first author Dr. Chase McCann. During the study, Dr. McCann was a Weill Cornell Graduate School student in the laboratory of senior author Dr. Brad Jones, associate professor of immunology in medicine in the Division of Infectious Diseases at Weill Cornell Medicine. Dr. McCann, who was supported at Weill Cornell by a Clinical and Translational Science Center (CTSC) TL1 training award, is now the Cell Therapy Lab Lead in the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, DC. The other co-first authors of the study are Dr. Christiaan van Dorp of Los Alamos National Laboratory and Dr. Ali Danesh, a senior research associate in medicine at Weill Cornell Medicine.

The invention of the new mouse model is part of a wider effort to develop and test cell therapies against HIV infection. Cell therapies, such as those using the patient’s own engineered T cells, are increasingly common in cancer treatment and have achieved some remarkable results. Many researchers hope that a similar strategy can work against HIV and can potentially be curative. But the lack of good mouse models has hampered the development of such therapies.

Drs. Jones and McCann and their colleagues showed in the study that the cell-attacks-host problem found in prior mouse models is chiefly due to so-called “naïve” CD4 cells. These are CD4 cells that have not yet been exposed to targets, and apparently include a population of cells that can attack various mouse proteins. When the researchers excluded naïve CD4 cells and instead used only “memory” CD4 cells, which circulate in the blood as sentinels against infection following exposure to a specific pathogen, the cells survived indefinitely in the mice without causing major damage to their hosts.

The researchers observed that the human CD4 cells also could be infected and killed by HIV, or protected by standard anti-HIV drugs, essentially in the same way that they are in humans. Thus, they showed that the mice, which they termed “participant-derived xenograft” or PDX mice, served as a workable model for long-term HIV infection. This term is akin to the “patient-derived xenograft” PDX models used to study cancer therapies, while recognizing the contributions of people with HIV as active participants in research.

Lastly, the researchers used the new model to study a prospective new T-cell based therapy, very similar to one that is now being tested against cancers. They put memory CD4 T cells from a human donor into the mice to permit HIV infection, and then, after infection was established, treated the mice with another infusion of human T cells, these being CD8-type T cells, also called “killer T cells.”

The killer T cells were from the same human donor and could recognize a vulnerable structure on HIV—so that they attacked the virus wherever they found it within the mice. To boost the killer T cells’ effectiveness, the researchers supercharged them with a T cell-stimulating protein called IL-15.

The treatment powerfully suppressed HIV in the mice. And although, as often seen in human cases, the virus ultimately evolved to escape recognition by the killer T cells, the ease of use of the mouse model allowed the researchers to monitor and study these long-term infection and viral escape dynamics in detail.

“I think that the major impact of this model will be its acceleration of the development of T cell-based therapies that can overcome this problem of viral escape,” Dr. Jones said.

He and his laboratory are continuing to study such therapies using the new mouse model, with engineered T cells from Dr. McCann’s laboratory and others.

Featured image: Scanning electron micrograph of a human T lymphocyte (T cell) from a healthy donor’s immune system. Credit: National Institute of Allergy and Infectious Diseases/NIH


Provided by Weill Cornell Medicine

People Living With HIV More Likely to Get Sick With, Die From COVID-19 (Medicine)

Over the past year, studies have revealed that certain pre-existing conditions, such as cancer, diabetes and high blood pressure, can increase a person’s risk of dying from COVID-19. New research shows that individuals living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) — an estimated 38 million worldwide, according to the World Health Organization — have an increased risk of SARS-CoV-2 infection and fatal outcomes from COVID-19.

In a new studyPenn State College of Medicine researchers found that people living with HIV had a 24% higher risk of SARS-CoV-2 infection and a 78% higher risk of death from COVID-19 than people without HIV. They assessed data from 22 previous studies that included nearly 21 million participants in North America, Africa, Europe and Asia to determine to what extent people living with HIV/AIDS are susceptible to SARS-CoV-2 infection and death from COVID-19.

The majority of the participants (66%) were male and the median age was 56. The most common comorbidities among the HIV-positive population were hypertension, diabetes, chronic obstructive pulmonary disease and chronic kidney disease. The majority of patients living with HIV/AIDS (96%) were on antiretroviral therapy (ART), which helps suppress the amount of HIV detected in the body. 

“Previous studies were inconclusive on whether or not HIV is a risk factor for susceptibility to SARS-CoV-2 infection and poor outcomes in populations with COVID-19,” said Dr. Paddy Ssentongo, lead researcher and assistant professor at the Penn State Center for Neural Engineering. “This is because a vast majority of people living with HIV/AIDS are on ART, some of which have been used experimentally to treat COVID-19.”

According to the researchers, certain pre-existing conditions are common among people living with HIV/AIDS, which may contribute to the severity of their COVID-19 cases. The beneficial effects of antiviral drugs, such astenofovir and protease-inhibitors, in reducing the risk of SARS-CoV-2 infection and death from COVID-19 in people with living with HIV/AIDS remain inconclusive.

“As the pandemic has evolved, we’ve obtained sufficient information to characterize the epidemiology of HIV/SARS-CoV-2 coinfection, which could not be done at the beginning of the pandemic due to scarcity of data,” said Vernon Chinchilli, fellow researcher and chair of the Department of Public Health Sciences. “Our findings support the current Centers for Disease Control and Prevention guidance to prioritize persons living with HIV to receive a COVID-19 vaccine.”

Emily Heilbrunn, Anna Ssentongo and Jonathan Nunez of Penn State College of Medicine; Ping Du of Takeda Pharmaceuticals and Shailesh Advani of Georgetown University also contributed to this research. The researchers declare no conflicts of interest.

This research was supported by the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or FDA.

Featured image: Dr. Zeina Arnouk takes care of a patient in the COVID-19 unit at Penn State Health St. Joseph Medical Center. Image: Penn State Health


Reference: Ssentongo, P., Heilbrunn, E.S., Ssentongo, A.E. et al. Epidemiology and outcomes of COVID-19 in HIV-infected individuals: a systematic review and meta-analysis. Sci Rep 11, 6283 (2021). https://doi.org/10.1038/s41598-021-85359-3


Provided by Penn State

A Trait of the Rare Few Whose Bodies Naturally Control HIV: “Trained” Immune Cells (Medicine)

Scientists at the Ragon Institute of MGH, MIT and Harvard discover that “elite controllers” have myeloid dendritic cells that display characteristics of trained innate immune cells.

Immunity often calls to mind the adaptive immune response, made up of antibodies and T cells that learn to fight specific pathogens after infection or vaccination. But the immune system also has an innate immune response, which uses a set number of techniques to provide a swift, non-specialized response against pathogens or support the adaptive immune response.

In the past few years, however, scientists have found that certain parts of the innate immune response can, in some instances, also be trained in response to infectious pathogens, such as HIV. Xu Yu, MD, a Core Member of the Ragon Institute of MGH, MIT and Harvard, and colleagues recently published a study in the Journal of Clinical Investigation which showed that elite controllers, a rare subset of people whose immune system can control HIV without the use of drugs, have myeloid dendritic cells, part of the innate immune response, that display traits of a trained innate immune cell.

“Using RNA-sequencing technology, we were able to identify one long-noncoding RNA called MIR4435-2HG that was present at a higher level in elite controllers’ myeloid dendritic cells, which have enhanced immune and metabolic states,” says Yu. “Our research shows that MIR4435-2HG might be an important driver of this enhanced state, indicating a trained response.”

Myeloid dendritic cells’ primary job is to support T cells, which are key to the elite controllers’ ability to control HIV infection. Since MIR4435-2HG was found in higher levels only in cells from elite controllers, Yu explains, it may be part of a learned immune response to infection with HIV. Myeloid dendritic cells with increased MIR4435-2HG also had higher amounts of a protein called RPTOR, which drives metabolism. This increased metabolism may allow the myeloid dendritic cells to better support the T cells controlling the HIV infection.

“We used a novel sequencing technology, called CUT&RUN, to study the DNA of these cells,” says postdoctoral fellow Ciputra Hartana, MD, PhD, the paper’s first author. “It allowed us to study epigenetic modifications like MIR4435-2HG, which are molecules that bind to the DNA and change how, or if, the DNA is read by the cell’s machinery.”

The team found that MIR4435-2HG might work by attaching to the DNA near the location of the RPTOR gene. The bound MIR4435-2HG would then encourage the cell’s machinery to make more of the RPTOR protein, using the instructions found in the RPTOR gene. This type of epigenetic modification, a trained response to HIV infection, would allow the myeloid dendritic cells to stay in an increased metabolic state and therefore provide long-term support to the T cells fighting the virus.

“Myeloid dendritic cells are very rare immune cells, accounting for only 0.1-0.3% of cells found in human blood,” says Yu. “We were fortunate and thankful to have access to hundreds of millions of blood cells from the many study participants who have donated their blood to support our HIV research. These donations were key to making this discovery.”

Understanding exactly how elite controllers’ immune systems can control HIV is a key part of HIV cure research. If scientists can understand how elite controllers suppress this deadly virus, they may be able to develop treatments that allow other people living with HIV to replicate the same immune response, removing the need for daily medication to control the virus and achieving what is known as a functional cure.

Co-authors include Yelizaveta Rassadkina, Ce Gao, Bruce D. Walker, MD, and Mathias Lichterfeld, MD, PhD, of the Ragon Institute, and Enrique Martin-Gayo, PhD, of Universidad Autónoma de Madrid.

This work was supported by the National Institutes of Health, the Bill and Melinda Gates Foundation, the Ragon Institute and the Mark and Lisa Schwartz Family Foundation.


Reference: Ciputra Adijaya Hartana, … , Mathias Lichterfeld, Xu G. Yu, “Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers”, J Clin Invest. 2021;131(9):e146136. https://doi.org/10.1172/JCI146136


Provided by Massachusetts General Hospital