Researchers at Oregon Health & Science University have identified a gene that may interfere with the effectiveness of HIV vaccines in humans, paving the way for improved vaccine development for HIV and other diseases such as cancer and malaria. (OHSU/Kristin Torres Hicks)
Continuing the journey to develop an HIV vaccine, researchers at Oregon Health & Science University have identified a gene that could prevent the vaccine from being effective in humans.
The study, published Oct. 11 in the journal Science Immunology, removes another barrier to vaccine development not only for HIV but potentially other diseases such as malaria and cancer.
Dr. Daniel Mallory (Courtesy)
Daniel Marouli, Ph.D., assistant professor in the OHSU Vaccine and Gene Therapy Institute and lead author of the study, said the research team found that human cytomegalovirus (HCMV) has additional genes that may prevent certain immune responses. He said he checked to see if there were any. Prevent vaccines from working against HIV. Previous research by the team in non-human primates showed that a vaccine based on rhesus monkey CMV, called RhCMV, elicits a unique T-cell response not seen with other vaccines. Ta. They show that these unique immune responses are essential for rhesus CMV-based vaccines to be effective against SIV, the pathogen most commonly used in non-human primate HIV/AIDS models. I discovered it.
“To develop an equivalent vaccine for clinical trials, we need an HCMV-based vaccine that induces similar T-cell responses in humans,” Marouli said.
CMV in humans and rhesus macaques are similar, and OHSU researchers at the OHSU Vaccine and Gene Therapy Institute have shown in previous studies that rhesus macaque CMV needs to turn off specific genes to trigger these unique immune responses. I discovered something. This is the result of decades of research by a research team led by VGTI Associate Director Louis Picker, MD, Professor Klaus Frew, and Scott Hansen, PhD. The group has been working on this vaccine platform since the early 2000s, and in 2016 its OHSU startup, TomegaVax, was acquired by San Francisco-based Vir Biotechnology. The company is currently testing the platform in human clinical trials for HIV in collaboration with the National Institutes of Health and the Bill & Melinda Gates Foundation. Früh, Picker, and Hansen are corresponding authors of this new publication.
Malouli conducted his graduate studies at Früh in 2007, where he investigated attenuation strategies for rhesus macaque CMV-based vaccine vectors. He then joined Picker’s lab as a staff scientist to study how rhesus macaque CMV affects T-cell responses and refine the design of CMV vaccines so they can be tested in human clinical trials. . He currently has his own lab at OHSU’s VGTI.
For this study, the researchers inserted 41 human CMV-specific genes into rhesus macaque CMV and observed the immune responses of non-human primates.
“We found that rhesus CMV expressing a specific human CMV gene, UL18, elicits only the standard response, because UL18 interacts with inhibitory receptors on T cells that block reprogramming.” said Malouli.
As a result of this research, the team designed a human CMV-based HIV vaccine that does not contain UL18 or other genes that could interfere with the vaccine’s effectiveness in human patients, Frew said.
Dr. Klaus Frew (male)
“Our goal is to develop new types of vaccines, not just for HIV, but for cancer and other diseases,” Frew said.
Malouli added: “This CMV vector system invented at OHSU is unique. The potential applications of our vector system to other diseases are endless.”
Human clinical trials of an HIV vaccine that omit UL18 are currently underway by Vir Biotechnology and the NIH, with additional support from the Bill and Melinda Gates Foundation.
In addition to Malouli, Picker, Hansen, and Früh, OHSU’s VGTI researchers who contributed to this study include Dr. Husam Taher, Mandana Mansouri, Dr. Ravi F. Ayer, Jason Reed BS, and Courtney Papen. , BS, Dr. John B. Shell, Teresa Beechwood, BS, Thomas Martinson, BS, David Morrow, BA, Colette M. Hughes, BS, Roxanne M. Gilbride, BS, Kurt Randall, BS, Julia C. Ford BS, Karina Verika BS, Sohita Ojha, Ph.D., Jonah B. Sasha, Ph.D., Benjamin N. Bimber, Ph.D.
This study was funded by the National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI095113, R37 AI054292, U19 AI128741, and P01 AI174856 to LJP, R01 AI059457 to KF, R01 AI175459 to KF and JB Sacha, R01 AI140888 to JB Sacha and SGH, and R01 AI129703 to JB Sacha) and by the Office of the Director of the National Institutes of Health (P51OD011092 to KF, SGH, JB Sacha, and LJP).
All research involving animal subjects at OHSU must be reviewed and approved by the university’s Animal Care and Use Committee (IACUC). IACUC’s priority is to ensure the health and safety of animal research subjects. IACUC will also review procedures to ensure the health and safety of people working with animals. IACUC rigorously reviews all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
To ensure the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks, and manages relationships researchers may have with entities outside of OHSU. I am. In connection with this research, OHSU’s Picker, Hansen, and Frew have a significant financial interest in Vir Biotechnology Inc., a company that may have a commercial interest in the results of this research and technology. Picker, Hansen, Malouli, and Früh are also co-inventors on an OHSU patent licensed to Vir related to this research.
The HIV T-cell vaccine trial is being conducted by the HIV Vaccine Trials Network, with support from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Bill & Melinda Gates Foundation.
