CD4 T cells
Encouraging First-in-Human Results for a Promising HIV Vaccine
Posted on by Lawrence Tabak, D.D.S., Ph.D.
In recent years, we’ve witnessed some truly inspiring progress in vaccine development. That includes the mRNA vaccines that were so critical during the COVID-19 pandemic, the first approved vaccine for respiratory syncytial virus (RSV), and a “universal flu vaccine” candidate that could one day help to thwart future outbreaks of more novel influenza viruses.
Inspiring progress also continues to be made toward a safe and effective vaccine for HIV, which still infects about 1.5 million people around the world each year [1]. A prime example is the recent first-in-human trial of an HIV vaccine made in the lab from a unique protein nanoparticle, a molecular construct measuring just a few billionths of a meter.
The results of this early phase clinical study, published recently in the journal Science Translational Medicine [2] and earlier in Science [3], showed that the experimental HIV nanoparticle vaccine is safe in people. While this vaccine alone will not offer HIV protection and is intended to be part of an eventual broader, multistep vaccination regimen, the researchers also determined that it elicited a robust immune response in nearly all 36 healthy adult volunteers.
How robust? The results show that the nanoparticle vaccine, known by the lab name eOD-GT8 60-mer, successfully expanded production of a rare type of antibody-producing immune B cell in nearly all recipients.
What makes this rare type of B cell so critical is that it is the cellular precursor of other B cells capable of producing broadly neutralizing antibodies (bnAbs) to protect against diverse HIV variants. Also very good news, the vaccine elicited broad responses from helper T cells. They play a critical supportive role for those essential B cells and their development of the needed broadly neutralizing antibodies.
For decades, researchers have brought a wealth of ideas to bear on developing a safe and effective HIV vaccine. However, crossing the finish line—an FDA-approved vaccine—has proved profoundly difficult.
A major reason is the human immune system is ill equipped to recognize HIV and produce the needed infection-fighting antibodies. And yet the medical literature includes reports of people with HIV who have produced the needed antibodies, showing that our immune system can do it.
But these people remain relatively rare, and the needed robust immunity clocks in only after many years of infection. On top of that, HIV has a habit of mutating rapidly to produce a wide range of identity-altering variants. For a vaccine to work, it most likely will need to induce the production of bnAbs that recognize and defend against not one, but the many different faces of HIV.
To make the uncommon more common became the quest of a research team that includes scientists William Schief, Scripps Research and IAVI Neutralizing Antibody Center, La Jolla, CA; M. Juliana McElrath, Fred Hutchinson Cancer Center, Seattle; and Kristen Cohen, a former member of the McElrath lab now at Moderna, Cambridge, MA. The team, with NIH collaborators and support, has been plotting out a stepwise approach to train the immune system into making the needed bnAbs that recognize many HIV variants.
The critical first step is to prime the immune system to make more of those coveted bnAb-precursor B cells. That’s where the protein nanoparticle known as eOD-GT8 60-mer enters the picture.
This nanoparticle, administered by injection, is designed to mimic a small, highly conserved segment of an HIV protein that allows the virus to bind and infect human cells. In the body, those nanoparticles launch an immune response and then quickly vanish. But because this important protein target for HIV vaccines is so tiny, its signal needed amplification for immune system detection.
To boost the signal, the researchers started with a bacterial protein called lumazine synthase (LumSyn). It forms the scaffold, or structural support, of the self-assembling nanoparticle. Then, they added to the LumSyn scaffold 60 copies of the key HIV protein. This louder HIV signal is tailored to draw out and engage those very specific B cells with the potential to produce bnAbs.
As the first-in-human study showed, the nanoparticle vaccine was safe when administered twice to each participant eight weeks apart. People reported only mild to moderate side effects that went away in a day or two. The vaccine also boosted production of the desired B cells in all but one vaccine recipient (35 of 36). The idea is that this increase in essential B cells sets the stage for the needed additional steps—booster shots that can further coax these cells along toward making HIV protective bnAbs.
The latest finding in Science Translational Medicine looked deeper into the response of helper T cells in the same trial volunteers. Again, the results appear very encouraging. The researchers observed CD4 T cells specific to the HIV protein and to the LumSyn in 84 percent and 93 percent of vaccine recipients. Their analyses also identified key hotspots that the T cells recognized, which is important information for refining future vaccines to elicit helper T cells.
The team reports that they’re now collaborating with Moderna, the developer of one of the two successful mRNA-based COVID-19 vaccines, on an mRNA version of eOD-GT8 60-mer. That’s exciting because mRNA vaccines are much faster and easier to produce and modify, which should now help to move this line of research along at a faster clip.
Indeed, two International AIDS Vaccine Initiative (IAVI)-sponsored clinical trials of the mRNA version are already underway, one in the U.S. and the other in Rwanda and South Africa [4]. It looks like this team and others are now on a promising track toward following the basic science and developing a multistep HIV vaccination regimen that guides the immune response and its stepwise phases in the right directions.
As we look back on more than 40 years of HIV research, it’s heartening to witness the progress that continues toward ending the HIV epidemic. This includes the recent FDA approval of the drug Apretude, the first injectable treatment option for pre-exposure prevention of HIV, and the continued global commitment to produce a safe and effective vaccine.
References:
[1] Global HIV & AIDS statistics fact sheet. UNAIDS.
[2] A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Cohen KW, De Rosa SC, Fulp WJ, deCamp AC, Fiore-Gartland A, Laufer DS, Koup RA, McDermott AB, Schief WR, McElrath MJ. Sci Transl Med. 2023 May 24;15(697):eadf3309.
[3] Vaccination induces HIV broadly neutralizing antibody precursors in humans. Leggat DJ, Cohen KW, Willis JR, Fulp WJ, deCamp AC, Koup RA, Laufer DS, McElrath MJ, McDermott AB, Schief WR. Science. 2022 Dec 2;378(6623):eadd6502.
[4] IAVI and Moderna launch first-in-Africa clinical trial of mRNA HIV vaccine development program. IAVI. May 18, 2022.
Links:
Progress Toward an Eventual HIV Vaccine, NIH Research Matters, Dec. 13, 2022.
NIH Statement on HIV Vaccine Awareness Day 2023, Auchincloss H, Kapogiannis, B. May, 18, 2023.
HIV Vaccine Development (National Institute of Allergy and Infectious Diseases/NIH)
International AIDS Vaccine Initiative (IAVI) (New York, NY)
William Schief (Scripps Research, La Jolla, CA)
Julie McElrath (Fred Hutchinson Cancer Center, Seattle, WA)
McElrath Lab (Fred Hutchinson Cancer Center, Seattle, WA)
NIH Support: National Institute of Allergy and Infectious Diseases
Finding HIV’s ‘Sweet Spot’
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Each year, about 30,000 people in the United States contract the human immunodeficiency virus (HIV), the cause of AIDS [1]. Thankfully, most can control their HIV infections with antiretroviral therapy and will lead productive, high-quality lives. Many will even reach a point where they have no detectable levels of virus circulating in their blood. However, all must still worry that the undetectable latent virus hidden in their systems could one day reactivate and lead to a range of serious health complications.
Now, an NIH-funded team has found that patterns of sugars at the surface of our own human immune cells affect their vulnerability to HIV infection. These data suggest it may be possible to find the infected immune cells harboring the last vestiges of virus by reading the sugar profiles on their surfaces. If so, it would move us a step closer to eliminating latent HIV infection and ultimately finding a cure for this horrible virus.
These fascinating new findings come from a team led by Nadia Roan, Gladstone Institutes, San Francisco and Mohamed Abdel-Mohsen, The Wistar Institute, Philadelphia, PA. Among its many areas of study, the Roan lab is interested in why HIV favors infecting specific subsets of a special type of immune cell called memory CD4 T cells. These cells come in different varieties. They also play important roles in the immune system’s ability to recall past infections and launch a rapid response to an emerging repeat infection.
For years, her team and others have tried to understand the interplay between HIV and human immune cells primarily by studying the proteins present at the cell surface. But living cells and their proteins also are coated in sugars and, the presence or absence of these carbohydrates is essential to their biochemistry.
In the new study, published in the journal eLife, the researchers included for the first time the patterns of these sugars in their study of cell surface proteins [2]. They, like many labs, hadn’t done so previously for technical reasons: it’s much easier to track these proteins than sugars.
To overcome this technical hurdle, Roan’s team turned to an approach that it uses for quantifying levels of proteins on the surface of single cells. The method, called CyTOF, uses metal-studded antibodies that stick to proteins, uniquely marking precise patterns of selected proteins, in this case, on individual HIV-infected cells.
In collaboration with Abdel-Mohsen, a glycobiology expert, they adapted this method for cell surface sugars. They did it by adding molecules called lectins, which stick to sugar molecules with specific shapes and compositions.
With this innovation, Roan and team report that they learned to characterize and quantify levels of 34 different proteins on the cell surface simultaneously with five types of sugars. Their next questions were: Could those patterns of cell-surface sugars help them differentiate between different types of immune cells? If so, might those patterns help to define a cell’s susceptibility to HIV?
The answer appears to be yes to both questions. Their studies revealed tremendous diversity in the patterns of sugars at the cells surfaces. Those patterns varied depending on a cell’s tissue of origin—in this case, from blood, tonsil, or the reproductive tract. The patterns also varied depending on the immune cell type—memory CD4 T cells versus other T cells or antibody-producing B cells.
Those sugar and protein profiles offered important clues as to which cells HIV prefers to infect. More specifically, compared to uninfected memory CD4 T cells, the infected ones had higher surface levels of two sugars, known as fucose [3] and sialic acid [4]. What’s more, during HIV infection, levels of both sugars increased.
Scientists already knew that HIV changes the proteins that the infected memory CD4 T cell puts on its surface, a process known as viral remodeling. Now it appears that something similar happens with sugars, too. The new findings suggest the virus increases levels of sialic acid at the cell surface in ways that may help the virus to survive. That’s especially intriguing because sialic acid also is associated with a cell’s ability to avoid detection by the immune system.
The Roan and Abdel-Mohsen labs now plan to team up again to apply their new method to study latent infection. They want to find sugar-based patterns that define those lingering infected cells and see if it’s possible to target them and eliminate the lingering HIV.
What’s also cool is this study indicates that by performing single-cell analyses and sorting cells based on their sugar and protein profiles, it may be possible to discover distinct new classes of immune and other cells that have eluded earlier studies. As was the case with HIV, this broader protein-sugar profile could hold the key to gaining deeper insights into disease processes throughout the body.
References:
[1] Diagnoses of HIV infection in the United States and dependent areas, 2020. HIV Surveillance Report, May 2020; 33; Centers for Disease Control and Prevention.
[2] Single-cell glycomics analysis by CyTOF-Lec reveals glycan features defining cells differentially susceptible to HIV. Ma T, McGregor M, Giron L, Xie G, George AF, Abdel-Mohsen M, Roan NR.eLife 2022 July 5;11:e78870
[3] Biological functions of fucose in mammals. Schneider M, Al-Shareffi E, Haltiwanger RS. Glycobiology. 2016 Jun;26(6):543.
[4] Sialic acids and other nonulosonic acids. Lewis AL, Chen X, Schnaar RL, Varki A. In Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022.
Links:
HIV/AIDS (National Institute of Allergy and Infectious Diseases/NIH)
Roan Lab (University of California, San Francisco)
Mohamed Abdel-Mohsen (The Wistar Institute, Philadelphia, PA)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Institute of Neurological Disorders and Stroke
Immune T Cells May Offer Lasting Protection Against COVID-19
Posted on by Dr. Francis Collins
Much of the study on the immune response to SARS-CoV-2, the novel coronavirus that causes COVID-19, has focused on the production of antibodies. But, in fact, immune cells known as memory T cells also play an important role in the ability of our immune systems to protect us against many viral infections, including—it now appears—COVID-19.
An intriguing new study of these memory T cells suggests they might protect some people newly infected with SARS-CoV-2 by remembering past encounters with other human coronaviruses. This might potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill with COVID-19.
The findings, reported in the journal Nature, come from the lab of Antonio Bertoletti at the Duke-NUS Medical School in Singapore [1]. Bertoletti is an expert in viral infections, particularly hepatitis B. But, like so many researchers around the world, his team has shifted their focus recently to help fight the COVID-19 pandemic.
Bertoletti’s team recognized that many factors could help to explain how a single virus can cause respiratory, circulatory, and other symptoms that vary widely in their nature and severity—as we’ve witnessed in this pandemic. One of those potential factors is prior immunity to other, closely related viruses.
SARS-CoV-2 belongs to a large family of coronaviruses, six of which were previously known to infect humans. Four of them are responsible for the common cold. The other two are more dangerous: SARS-CoV-1, the virus responsible for the outbreak of Severe Acute Respiratory Syndrome (SARS), which ended in 2004; and MERS-CoV, the virus that causes Middle East Respiratory Syndrome (MERS), first identified in Saudi Arabia in 2012.
All six previously known coronaviruses spark production of both antibodies and memory T cells. In addition, studies of immunity to SARS-CoV-1 have shown that T cells stick around for many years longer than acquired antibodies. So, Bertoletti’s team set out to gain a better understanding of T cell immunity against the novel coronavirus.
The researchers gathered blood samples from 36 people who’d recently recovered from mild to severe COVID-19. They focused their attention on T cells (including CD4 helper and CD8 cytotoxic, both of which can function as memory T cells). They identified T cells that respond to the SARS-CoV-2 nucleocapsid, which is a structural protein inside the virus. They also detected T cell responses to two non-structural proteins that SARS-CoV-2 needs to make additional copies of its genome and spread. The team found that all those recently recovered from COVID-19 produced T cells that recognize multiple parts of SARS-CoV-2.
Next, they looked at blood samples from 23 people who’d survived SARS. Their studies showed that those individuals still had lasting memory T cells today, 17 years after the outbreak. Those memory T cells, acquired in response to SARS-CoV-1, also recognized parts of SARS-CoV-2.
Finally, Bertoletti’s team looked for such T cells in blood samples from 37 healthy individuals with no history of either COVID-19 or SARS. To their surprise, more than half had T cells that recognize one or more of the SARS-CoV-2 proteins under study here. It’s still not clear if this acquired immunity stems from previous infection with coronaviruses that cause the common cold or perhaps from exposure to other as-yet unknown coronaviruses.
What’s clear from this study is our past experiences with coronavirus infections may have something important to tell us about COVID-19. Bertoletti’s team and others are pursuing this intriguing lead to see where it will lead—not only in explaining our varied responses to the virus, but also in designing new treatments and optimized vaccines.
Reference:
[1] SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Le Bert N, Tan AT, Kunasegaran K, et al. Nature. 2020 July 15. [published online ahead of print]
Links:
Coronavirus (COVID-19) (NIH)
Overview of the Immune System (National Institute of Allergy and Infectious Diseases/NIAID)
Bertoletti Lab (Duke-NUS Medical School, Singapore)
Snapshots of Life: Finding Where HIV Hides
Posted on by Dr. Francis Collins
Credit: Nadia Roan, University of California, San Francisco
Researchers have learned a tremendous amount about how the human immunodeficiency virus (HIV), which causes AIDS, infects immune cells. Much of that information comes from studying immune cells in the bloodstream of HIV-positive people. Less detailed is the picture of how HIV interacts with immune cells inside the lymph nodes, where the virus can hide.
In this image of lymph tissue taken from the neck of a person with uncontrolled HIV infection, you can see areas where HIV is replicating (red) amid a sea of immune cells (blue dots). Areas of greatest HIV replication are associated with a high density of a subtype of human CD4 T-cells (yellow circles) that have been found to be especially susceptible to HIV infection.
Simplifying HIV Treatment: A Surprising New Lead
Posted on by Dr. Francis Collins
Caption: PET/CT imaging reveals a surprisingly high concentration (yellow, light green) of key immune cells called CD4 T cells in the colon (left) of an SIV-infected animal that received antibody infusions along with antiviral treatment. Fewer immune cells were found in the small intestine (right), while the liver (lower left) shows a high level of non-specific signal (orange).
Credit: Byrareddy et al., Science (2016).
The surprising results of an animal study are raising hopes for a far simpler treatment regimen for people infected with the AIDS-causing human immunodeficiency virus (HIV). Currently, HIV-infected individuals can live a near normal life span if, every day, they take a complex combination of drugs called antiretroviral therapy (ART). The bad news is if they stop ART, the small amounts of HIV that still lurk in their bodies can bounce back and infect key immune cells, called CD4 T cells, resulting in life-threatening suppression of their immune systems.
Now, a study of rhesus macaques infected with a close relative of HIV, the simian immunodeficiency virus (SIV), suggests there might be a new therapeutic option that works by a mechanism that has researchers both excited and baffled [1]. By teaming ART with a designer antibody used to treat people with severe bowel disease, NIH-funded researchers report that they have been able to keep SIV in check in macaques for at least two years after ART is stopped. More research is needed to figure out exactly how the new strategy works, and whether it would also work for humans infected with HIV. However, the findings suggest there may be a way to achieve lasting remission from HIV without the risks, costs, and inconvenience associated with a daily regimen of drugs.
