Researchers Identify Gene Behind HIV Vaccine Ineffectiveness

Continuing their journey to develop a vaccine for HIV, Oregon Health & Science University researchers have identified a gene that could have prevented their vaccine from working in humans.

The study, published Oct. 11 in Science Immunology, removes one more barrier to developing a vaccine for HIV, and potentially other diseases such as malaria and cancer.

Daniel Malouli, Ph.D., assistant professor in the OHSU Vaccine and Gene Therapy Institute and lead author on the study, said the research team looked at whether human cytomegalovirus, or HCMV, has additional genes that could prevent a particular immune response which would keep their vaccine from working against HIV. In previous studies, the team’s research with nonhuman primates showed that vaccines based on rhesus CMV, called RhCMV, trigger unique T cell responses not seen with any other vaccine. They found that these unique immune responses are essential for rhesus CMV-based vaccines to be effective against SIV, the pathogen most used to model HIV/AIDS in nonhuman primates.

“To develop an equivalent vaccine for clinical trials, we need our HCMV-based vaccines to induce similar T cell responses in humans,” Malouli said.

Human and rhesus CMV are similar, and in past studies, OHSU researchers at the OHSU Vaccine and Gene Therapy Institute discovered that rhesus CMV needs certain genes turned off to trigger these unique immune responses. This is the result of decades of work by the research team led by VGTI associate director Louis Picker, M.D., and professors Klaus Früh, Ph.D., and Scott Hansen, Ph.D. The group has been working on developing this vaccine platform since the early 2000s, and in 2016, their OHSU startup company, TomegaVax, was acquired by San Francisco-based Vir Biotechnology. The company is currently testing the platform in a human clinical trial for HIV, together with the National Institutes of Health and the Bill and Melinda Gates Foundation. Früh, Picker and Hansen are corresponding authors on the new publication.

Malouli did graduate work with Früh in 2007, where he researched attenuation strategies of rhesus CMV-based vaccine vectors. Later, he joined Picker’s lab as a staff scientist to study how rhesus CMV affects T cell responses and improve the design of the CMV vaccines so they can be tested in human clinical trials. He now has his own lab at OHSU’s VGTI.

For this study, the researchers inserted 41 human CMV-specific genes into rhesus CMV and observed the immune responses in the non-human primates.

“We found that rhesus CMV expressing a specific human CMV gene, UL18, only triggered standard responses because UL18 interacts with an inhibitory receptor on T cells that blocks their reprogramming,” Malouli said.

As a result of this research, Früh said the team has designed a human CMV-based vaccine for HIV that doesn't include UL18 or other genes that could potentially stop the vaccine from working in human patients.

“Our goal is to create a new kind of vaccine not just for HIV, but also for cancer and other diseases,” Früh said.

Malouli added, “This CMV vector system invented at OHSU is unique. The applicability of our vector system to other diseases is endless.”

Human clinical trials of the HIV vaccine, with the UL18 omitted, are now underway by Vir Biotechnology and the NIH, with additional support from the Bill and Melinda Gates Foundation.

Reference: Malouli D, Taher H, Mansouri M, et al. Human cytomegalovirus UL18 prevents priming of MHC-E– and MHC-II–restricted CD8⁺ T cells. Sci Immunol. 2024;9(100):eadp5216. doi: 10.1126/sciimmunol.adp5216

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