OHSU Researchers Identify Gene Impeding HIV Vaccine Effectiveness

Key Insights

• Researchers at OHSU have identified the human CMV gene UL18 as a potential barrier to effective HIV vaccine development, hindering T cell reprogramming.
• The study, published in _Science Immunology_, demonstrated that UL18 interacts with inhibitory receptors on T cells, blocking desired immune responses.
• By excluding UL18 from human CMV-based vaccines, researchers aim to enhance vaccine efficacy against HIV and explore applications for other diseases.

Oregon Health & Science University (OHSU) researchers have pinpointed a specific gene that could be undermining the effectiveness of HIV vaccines in humans. The discovery, detailed in Science Immunology, paves the way for developing more effective vaccines against HIV and potentially other diseases, including cancer and malaria.

Identifying the UL18 Gene

The research focused on human cytomegalovirus (HCMV) and its potential to interfere with the immune response triggered by an HIV vaccine. Previous studies by the OHSU team, using rhesus CMV (RhCMV) in nonhuman primates, showed that RhCMV-based vaccines induce unique T cell responses crucial for protection against SIV, a virus similar to HIV. Daniel Malouli, Ph.D., assistant professor at OHSU's Vaccine and Gene Therapy Institute (VGTI) and lead author of the study, emphasized the need to replicate these T cell responses in humans using HCMV-based vaccines.

How UL18 Impedes Vaccine Efficacy

Researchers inserted 41 human CMV-specific genes into RhCMV and observed the immune responses in non-human primates. The study revealed that RhCMV expressing the human CMV gene UL18 triggered only standard immune responses. According to Malouli, UL18 interacts with an inhibitory receptor on T cells, effectively blocking their reprogramming and preventing the desired immune response.

Implications for Vaccine Development

Klaus Früh, Ph.D., noted that the team has designed an HCMV-based vaccine for HIV that excludes UL18 and other genes that could hinder its effectiveness. The goal is to create a novel vaccine platform applicable not only to HIV but also to cancer and other diseases. Malouli added that the CMV vector system developed at OHSU has broad applicability to various diseases.

Ongoing Clinical Trials

Human clinical trials of the HIV vaccine, modified to exclude UL18, are currently being conducted by Vir Biotechnology and the NIH, with support from the Bill and Melinda Gates Foundation. This research represents a significant step forward in the ongoing effort to develop an effective HIV vaccine, addressing a critical unmet medical need.