The research team of the AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU) announced a breakthrough discovery on a novel Δ42PD1-TLR4 immune pathway that likely accounts for acute gut inflammation in HIV-1 patients earlier this month. More importantly, the team generated an antibody against this inflammatory pathway and tested it in a humanised mice model to successfully block HIV-1-induced inflammation in small intestines.

Their study not only solves the mystery of an inflammatory mechanism during acute HIV-1 infection, but also anticipates to develop the antibody as a new immunotherapy to fight against AIDS and other inflammation-related diseases. The new findings of this research are recently published in the international prestigious journal, Nature Microbiology.

New preventive strategies against HIV-1 pathogenesis are needed

AIDS is primarily caused by a virus called Human Immunodeficiency Virus Type One (HIV-1). The virus mainly destroys the white blood cells called CD4 T lymphocytes and weakens the body’s immune system. As a result, the body cannot fight off opportunistic infections and cancers, and therefore progress to AIDS.

The initial and massive depletion of CD4 T cells occurs in the intestines within 2-3 weeks after HIV-1 infection, largely due to inflammation-associated immune activation in close proximity with the primary site of infection in the vagina or colon, together with inflammation of the gut. The consequences are the breakdown of the gut barrier and allowing microbes to breach into the inner layers of the intestines. However, the mechanism underlying the initiate intestinal inflammation is not fully defined. An effective vaccine for human use still requires much effort, it is therefore important to identify new preventive strategies against HIV-1 pathogenesis.

New pathway may be important for other inflammatory diseases not limited to HIV-1

The team has been working on the study since 2013 when they discovered the new molecule named as Δ42PD1. Their research, published in Molecular Therapy, showed that Δ42PD1 is primarily found on the gut-homing γδ subset of T cells that is highly induced following acute HIV-1 infection in patients and correlated with inflammatory cytokines.

HKU discovered that gut inflammation can be prevented by blocking Δ42PD1-TLR4 pathway. Photo credit: Li Ka Shing Faculty of Medicine, The University of Hong Kong
HKU discovered that gut inflammation can be prevented by blocking Δ42PD1-TLR4 pathway. Photo credit: Li Ka Shing Faculty of Medicine, The University of Hong Kong

Using a humanised mouse model, the team found that Δ42PD1+γδ-T cells could migrate to the small intestines and cause inflammation through TLR4. Their research did not stop here, the team generated an antibody that not only blocks the function of the Δ42PD1/TLR4 pathway but also reduces HIV-1 manifestations in the gut when injected at least 2 hours before the arrival of the Δ42PD1+γδ-T cells in the gut. As a result, inflammation is markedly reduced in the small intestines where the epithelial layer remains intact, thus protecting against microbial translocation. The research team hopes to further extend their research to other mucosa-associated inflammatory diseases, such as, influenza infection, colitis and cancer, etc.

“By discovering a new pathway that could promote HIV-1 pathogenesis in the gut, we understood better what is happening in acute HIV-1. Having also found a way to block it, we can provide new measures in relieving the initial pathological inflammatory response and clinical burden in chronic HIV-1 patients,” says Dr Allen Cheung Ka Loon, Postdoctoral Fellow of the AIDS Institute at HKU. 

Professor Chen Zhiwei, Director of the AIDS Institute and Professor of Department of Microbiology, adds, “The HKU research team, for the first time, discovers a new immune pathway that accounts for gut-associated inflammation. Our findings also demonstrated that by blocking this pathway it is possible to prevent HIV-1-induced mucosal damages. We believe this pathway is important for other inflammatory diseases not limited to HIV-1, and hope to develop the antibody as a new immunotherapy to benefit patients quickly.”

In Hong Kong, about 80% of HIV positive people were infected through unprotected sexual contacts. As of March 2017, there are 8,612 cumulative reported HIV cases in Hong Kong, where the incidence rate does not seem to be slowing down. Of these, more than 80% are men transmitted mainly through homosexual contact. MIMS

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