Tag Archives: HIV-1

First-in-human nanoparticle HIV vaccine induces broad and publicly targeted helper T cell responses

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Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.

Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.

We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”

Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study

However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.

“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.

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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.

McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.

Findings from the study include:

  • Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
  • Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
  • Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
  • Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
  • LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
  • CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
  • CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.

This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.

Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).

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Source:
Journal reference:

Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine. doi.org/10.1126/scitranslmed.adf3309.

Novel gene-editing strategy harnesses an unusual protective ability to eliminate HIV-1 infection

Genetic alterations that give rise to a rare, fatal disorder known as MOGS-CDG paradoxically also protect cells against infection by viruses. Now, scientists at the Lewis Katz School of Medicine at Temple University have harnessed this unusual protective ability in a novel gene-editing strategy aimed at eliminating HIV-1 infection with no adverse effects on cell mortality.

The new approach, described online April 28 in the journal Molecular Therapy – Nucleic Acids, is based on a combination of two gene-editing constructs, one that targets HIV-1 DNA and one that targets a gene called MOGS – defects in which cause MOGS-CDG. In cells from persons infected with HIV-1, the Temple researchers show that disrupting the virus’s DNA while also deliberately altering MOGS blocks the production of infectious HIV-1 particles. The discovery opens up new avenues in the development of a cure for HIV/AIDS.

Proper MOGS function is essential for glycosylation, a process by which some cellular proteins synthesized in the body are modified to make them stable and functional. Glycosylation, however, is leveraged by certain kinds of infectious viruses. In particular, viruses like HIV, influenza, SARS-CoV-2, and hepatitis C, which are surrounded by a viral envelope, rely on glycosylated proteins to enter host cells.

In the new study, lead investigators Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine, and Rafal Kaminski, PhD, Assistant Professor at the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine designed a genetic approach to exclusively turn on CRISPR to impede MOGS gene expression through DNA editing within immune cells that harbor replication competent, HIV-1. Their novel approach is expected to avoid any impact on the health of uninfected cells that retain normal MOGS gene function. Stimulation of the apparatus in HIV-1 infected cells disrupted the glycan structure of the HIV-1 envelope protein, culminating in the production of non-infectious virus particles.

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“This approach is conceptually very interesting,” said Dr. Khalili, who is also senior investigator on the new study. “By mitigating the ability of the virus to enter cells, which requires glycosylation, MOGS may offer another target, in addition to the integrated viral DNA for developing the next generation of CRISPR gene-editing technology for HIV elimination.”

Dr. Kaminski, Dr. Khalili, and Tricia H. Burdo, PhD, Professor and Vice Chair in the Department of Microbiology, Immunology, and Inflammation and the Center for Neurovirology and Gene Editing at Temple and an expert in the use of non-human primate models for HIV-1, have been working together to further assess the efficacy and safety of CRISPR-MOGS strategy in preclinical studies. In previous work, the team demonstrated that CRISPR-based technology can successfully remove viral DNA from the cells of infected non-human primates.

Other researchers who contributed to the study include Hong Liu, Chen Chen, Shuren Liao, and Shohreh Amini, Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University; Danielle K. Sohaii, Conrad R.Y. Cruz, and Catherine M. Bollard, Center for Cancer and Immunology Research, Children’s National Health System, The George Washington University; Thomas J. Cradick and Jennifer Gordon, Excision Biotherapeutics, San Francisco, CA; Anand Mehta, Stephane Grauzam, and James Dressman, Department of Cell and Molecular Pharmacology, Medical University of South Carolina; and Carlos Barrero and Magda Florez, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University.

The research was supported in part by grants from the National Institutes of Health and the W.W. Smith Charitable Trust.

Source:
Journal reference:

Liu, H., et al. (2023) Strategic Self-Limiting Production of Infectious HIV Particles by CRISPR in Permissive Cells. Molecular Therapy — Nucleic Acids. doi.org/10.1016/j.omtn.2023.04.027.

Analysis of rebound virus suggests two separate reservoirs of latent HIV in patients

When people living with HIV take antiviral therapy (ART), their viral loads are driven so low that a standard blood test cannot detect the virus. However, once ART is stopped, detectable HIV re-emerges with new cells getting infected. This is called “rebound” virus, and the cells that release the virus to re-ignite the infection come from a small population of HIV-infected CD4+ T cells that had remained dormant in blood and lymph tissue while individuals were on ART.

It’s a problem called latency, and overcoming it remains a major goal for researchers trying to create curative therapies for HIV-;the special focus of the UNC HIV Cure Center.

Now, scientists led by virologist Ron Swanstrom, PhD, Director of the UNC Center for AIDS Research and the Charles P. Postelle, Jr. Distinguished Professor of Biochemistry & Biophysics at the UNC School of Medicine, describe another layer to the challenge of HIV latency and published their work in Nature Microbiology.

Swanstrom and colleagues, with collaborators at UCSF, Yale, the University of Gothenburg in Sweden, and others, provide indirect evidence for the existence of a distinct latent reservoir of CD4+ T cells in the central nervous system (CNS). They accomplished this by analyzing rebound virus in the cerebral spinal fluid (CSF) during the period when people had just stopped taking ART.

Our analysis of rebound virus suggests latently infected T cells in the CNS are separate from the latent reservoir in the blood. Our analysis allows us to infer the presence of a distinct pool of latently infected cells in the CNS waiting to reinitiate infection once ART is interrupted.”

Dr. Ron Swanstrom, senior author of the study

The researchers compared the genetic sequences of rebound virus particles when ART was discontinued in 11 human participants. This approach allowed the scientists to assess the similarities between viral populations in the blood and CSF to determine whether they were part of a common latent reservoir. In many cases, the viral populations were not the same, which suggested they can represent different populations of latently infected cells.

The researchers also studied details of viral replication to determine if rebound virus had been selected for replication in CD4+ T cells – the primary home of the virus – or had evolved to replicate in central nervous system myeloid cells, such as macrophages and microglia. All rebound viruses tested were adapted to growth in T cells. For several participants, the researchers also compared viral populations in blood and CSF before ART initiation and after ART was stopped.

These experiments provide further evidence that HIV-infected CD4+ T cells can cross over from blood into the CNS, but also that some latently infected cells may be resident in the CNS during therapy. Any curative therapy would need to activate this dormant reservoir, as well as the latent reservoir in the blood and lymph tissue.

Source:
Journal reference:

Swanstrom, R., et al. (2022) Rebound virus in the cerebrospinal fluid reveals a possible HIV-1 reservoir. Nature Microbiology. doi.org/10.1038/s41564-022-01309-3.

Miracles Start in the Lab: the quest to find a vaccine to cure AIDS

Thought LeadersDr. Larry CoreyProfessor and President and Director EmeritusFred Hutch Cancer Center

To commemorate World AIDS Day, News Medical spoke to Dr. Larry Corey, an internationally renowned expert in virology, immunology, and vaccine development, and the former president and director of Fred Hutch, about his work within the field of HIV/AIDS research and vaccine development. 

Please can you introduce yourself and tell us about your background in virology, immunology, and vaccine development?  

I’m Dr. Larry Corey. I am a Professor at the University of Washington and Fred Hutchinson Cancer Center. I am a virologist by training. I have worked in the field of HIV since the inception of the recognition of the virus. Initially, I was the leader of the US government’s AIDS Clinical Trials Group, which was devoted to antiviral chemotherapy. I was lucky early in my career to be involved in developing the first effective antiviral drug called Acyclovir, which was for herpes virus infections, especially genital herpes.

I switched my interests in the late 1990s from therapy to try and develop an HIV vaccine and founded the HIV Vaccine Trials Network with my friend and colleague Tony Fauci. We’ve worked together to develop an HIV vaccine and set up a network within the US of investigators to tackle the immunology of HIV, which has been very formidable. The network has been where probably 80 or 90% of the HIV vaccine clinical trials have been conducted worldwide over the last 20 years.

How have you seen the field of HIV/AIDS research change in this time? How have patient outcomes changed?

HIV is still a pandemic illness. We still have 1.4 million new infections each year. We have a growing number of people living with AIDS, and it is still a perfect storm. You acquire it subclinically, transmit it subclinically, and get it from people you don’t suspect have it. We still need better prevention methods.

Antiretrovirals have saved more lives than any other medical procedure or medical group of therapies in the last 50 or 60 years. We went from a disease that killed everybody to now a disease that, if you take the pills, you can live a normal lifespan essentially. That’s an amazing feat that occurred in the decade from the virus’s isolation.

Image Credit: PENpics Studio/Shutterstock.com

Image Credit: PENpics Studio/Shutterstock.com

HIV research has markedly changed and become markedly more sophisticated. We’re cloning B-cells in the germ lines. We’re doing things you couldn’t conceive 40 years ago. Certainly, a vaccine will be needed to end AIDS and have my granddaughters grow up like I grew up, not worrying about AIDS.

Patient outcomes for treatment have markedly changed. You can live normal lives. But we haven’t made as many inroads in prevention. The reason is that we don’t have a vaccine. When you look at how to prevent disease acquisition on a population basis, it’s only been with a vaccine. So, as hard as it is, the vaccine effort must continue.

In your lab, you study genetically modified T cells to treat HIV-1. How have recent advancements in cancer treatment influenced the treating HIV/AIDS? How can immunological approaches treat chronic viral infections?

In oncology, using the cell as an anti-tumor drug in CAR T-cell therapy is the biggest advance. The lab is trying to take those approaches used in cancer and employ them against HIV through these adopted transfer experiments. We think we’ve had some successes, so that’s our area of interest at the moment.

You are also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network. How has the COVID-19 pandemic impacted HIV/AIDS research?

People working in HIV and the infrastructure from HIV helped the effort against COVID-19. RNA, used in the COVID-19 mRNA vaccines, can allow experiments to be conducted more quickly because it’s synthetic, and you can make a vaccine and get it into humans by doing an early clinical trial. From the idea to putting a jab in your arm, that’s still not happening as quickly with HIV as it did for COVID-19. Still, it is quicker, and we’re optimistic that this RNA technology will help us develop an HIV vaccine quicker.

The HVTN’s goal is to develop a safe, effective vaccine to prevent HIV globally. How close are we to actualizing this goal? From a global perspective, what would it mean to have an effective vaccine?

We make these vaccines that elicit broadly neutralizing antibodies. If we do, we’ll get there because we’ve already proven that broadly neutralizing antibodies can prevent HIV acquisition. Now the issue is how do we get to that target now that we know what the target is? You need to be optimistic. Miracles start in the lab.

The theme of this year’s World AIDS Day is “Equalize.” What does this theme mean to you personally? What needs to be done to address inequalities and help end AIDS?

Everybody wants to be healthy. I think equalize is a great word for World AIDS Day. I think HIV has always been a disease of the underdog.

Image Credit: fizkes/Shutterstock.com

Image Credit: fizkes/Shutterstock.com

But words have meaning and should be actionable. I think the word equalize is just another call to how we actualize the tools and maximize the use of the tools we have. COVID-19 has taught us that even if research invents a remarkably good vaccine, the process of implementing this on a population basis is complicated and needs to be equalized between the haves and the have-nots. The sociology and economics of health need to be equalized globally.

What is next for yourself and your research?

I’ve got my hands full trying to make an HIV vaccine.

Where can readers find more information?

About Dr. Larry Corey

Dr. Larry Corey is an internationally renowned expert in virology, immunology and vaccine development, and the former president and director of the Fred Hutchinson Cancer Research Center. His research focuses on herpes viruses, HIV, the novel coronavirus and other viral infections, including those associated with cancer. He is principal investigator of the HIV Vaccine Trials Network (HVTN), which conducts studies of HIV vaccines at over 80 clinical trials sites in 16 countries on five continents. Under his leadership, the HVTN has become the model for global, collaborative research. Dr. Corey is also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network (CoVPN) and co-leads the Network’s COVID-19 vaccine testing pipeline. The CoVPN is carrying out the large Operation Warp Speed portfolio of COVID-19 vaccines and monoclonal antibodies intended to protect people from COVID-19. 

Dr. Corey is a member of the US National Academy of Medicine and the American Academy of Arts and Sciences, and was the recipient of the Parran Award for his work in HSV-2, the American Society of Microbiology Cubist Award for his work on antivirals, and the University of Michigan Medical School Distinguished Alumnus Award. He is one of the most highly cited biomedical researchers in the last 20 years and is the author, coauthor or editor of over 1000 scientific publications.