Prof Zhiwei Chen
Chair Professor of Immunology and Immunotherapy, Department
of Microbiology
Founding Director, HKU AIDS Institute
I have been the founding director of the AIDS Institute since
2007. During the past 15 years, I have focused my research in the field of HIV/AIDS
and immunology. I not only lead the largest research consortium on HIV/AIDS funded
by Hong Kong Research Grants Council TRS program but also promote the translation
of our scientific discoveries into clinical development with two vaccines entering
phase I/II trials.
After receiving my tenured full professorship in 2014, I received three
awards from The University of Hong Kong (HKU) including the Knowledge Exchange
Excellence Award (2019), the Outstanding Researcher Award (2020-2021), and
Outstanding Research Student Supervisor Award (2020-2021). I have also received
Faculty of Medicine awards including the Knowledge Exchange Award (2018-2019) and
two Outstanding Research Output Awards (2021 and 2022). I have been ranked by
Clarivate Analytics as in the top one percent worldwide by citations and was one
of 50 most highly cited researchers at HKU in 2023.
HIV-1 is the causative agent of AIDS. To date, HIV-1 continues to
spread, leading to some 40 million people living with the virus and around the
same number of deaths worldwide by 2021. Since the life-long antiretroviral treatment
(ART) neither cures HIV/AIDS nor fully restores immune function, I sought to
discover an effective immunotherapy for making possible host immunity to
achieve a functional cure, a state of suppressed viremia below detection limit
for a prolonged period in HIV-infected patients without receiving ART.
In this effort, after winning a Research Grants Council (RGC0 General
Research Fund (GRF) grant in 2009, I was the first in the world to develop an
innovative vaccine platform. It is based on soluble PD1-mediated antigen targeting
dendritic cells for inducing enhanced host immune responses especially
cytotoxic T lymphocytes, also called CD8+ T cells, which is the
major immune surveillance force for eliminating infected or tumour cells.[1]
My discoveries have generated significant impact in the scientific
community and society at large in several areas: 1) three patents licenced by HKU;
2) high-impact publications; 3) an Outstanding Research Postgraduate Student Award;
4) a Hong Kong AIDS Foundation Forum presentation, promoting public awareness
of HIV/AIDS prevention, care and education; 5) lectures at world-renowned
institutions including the US National Institutes of Health (NIH), Institut
Pasteur, Harvard University, Rockefeller University, and The Peter Doherty
Institute; 6) a speech at HIVR4P, the international scientific meeting
dedicated exclusively to biomedical HIV prevention research; 7) HKU-exclusive
patent licensing, leading to the establishment of Immuno Cure HK Ltd; 8) recognition
as principal investigator with the RGC CRF award in 2013, the TSSSU@HKU (Technology
Startup Support Scheme for Universities at HKU) award in 2015, a university-industry
collaboration programme (UICP) grant award in 2017, and an RGC TRS (Theme-based
Research Scheme) award in 2018; and 9) the bronze medal from Inventions Geneva in
2022.
My most significant achievement as principal investigator was in
the RGC TRS-funded program “Potentiating Host Immunity for HIV-1 Functional
Cure”. My team demonstrated that CD8+ T cells induced by a PD1-based
vaccine were able to sustain viremia suppression in macaques in the absence of
ART for six years and counting.[2] The study resulted in the clinical translation of our PD1-based vaccine
platform from laboratory to two human trials. The innovative human PD1-enhanced
AIDS vaccine called ICVAX has been approved by the China Food and Drug Administration
(CFDA) for phase I clinical trials.[3] Since the trial was approved to be conducted directly among HIV-1 patients, I expect
that ICVAX-induced CD8+ T cells will benefit patients for prolonged
viremia control. This was the first anti-HIV biomedical product invented by an
HKU research team to benefit patients in the clinical-trial stages.
A related contribution was the development of a similar
PD1-enhanced DNA vaccine, ICCOV, that we based on the same technology platform.[4] With HKU-exclusive licensing and financial support from the Hong Kong
government Health and Medical Research Fund (HMRF) and the Shenzhen government,
ICCOV underwent phase-one trials at the HKU Clinical Trial Centre with demonstrated
safety and immunogenicity profiles. ICCOV is unique in inducing cross-reactive
T-cell responses to Omicron variants in humans. In addition, our team
demonstrated that the PD1-enhanced vaccine significantly increased the
therapeutic efficacy against malignant mesothelioma in mice.[5] A PD1-enhanced mesothelioma vaccine has been exclusively licensed to an industrial
partner for use on patients in Hong Kong.
A second important achievement by my team and I was the discovery
of the functional isoform of the immune checkpoint programmed cell-death
protein 1 (PD-1), namely Δ42PD-1.[6] By generating two in-house Δ42PD-1-specific monoclonal antibodies, we found
that this isoform likely contributed to intestinal injury via TLR4 activation
during acute HIV-1 infection in humanized mice.[7]
[8]
A subsequent study revealed distinct Δ42PD-1+ T cell subsets,
accounting for up to 71 percent of CD8+ T cells, in hepatocellular
carcinoma (HCC) patients. Δ42PD-1+ T cells were tumour-infiltrating
and correlated positively with HCC severity through TLR4-signaling for
tumorigenesis. HCC patients treated with Nivolumab showed effective PD-1
blockade but increased frequencies of Δ42PD-1+ T cells over time. The
anti-Δ42PD-1 antibody, but not Nivolumab, inhibited tumour growth in three murine
HCC models.
Our findings not only revealed a mechanism underlying resistance
to Nivolumab treatment but also identified anti-Δ42PD-1 antibody for HCC
immunotherapy, which allowed me to contribute as co-principal investigator to
the success of another HKU-leading RGC TRS program.[9] In addition, our team has recently made a
breakthrough discovery – that Δ42PD-1 is a previously unrecognized suppressive
regulator of BCR-mediated B cell activation during HIV-1 infection.[10]
Our third most significant achievement is our contribution to SARS/COVID-19
research. With support by an NIH RO1 grant, our team determined the efficacy of a SARS vaccine, the major neutralizing
domain of SARS-CoV, vaccine cross-protection, ACE2 receptor in monkeys, first
target cells of SARS-CoV transmission, mode of viral mucosal transmission, and anti-spike
IgG-mediated lung injury.[11] [12]
[13]
[14]
[15]
[16]
[17]
After the COVID-19 outbreak, we first demonstrated
that acute SARS-CoV-2 infection impairs dendritic cell and T-cell responses.[18] This showed that the robust nasal transmission and replication of SARS-CoV-2 outcompeted systemic antibody and vaccine-induced
antibody for breakthrough infections.[19] With
collaborators, we discovered the human neutralizing
antibodies against COVID-19.[20]
[21]
[22]
[23]
[24]
[25]
[26] I
co-invented the flu-based COVID-19 nasal vaccine,
which won Gold Medal in Inventions Geneva Evaluation 2021
and
has been licensed by the China FDA for emergency use.[27] Based on this work, as co-principal
investigator, I contributed to the success of the third HKU-leading RGC TRS
program.
As a research principal
investigator, I have been responsible for garnering a total over HK$110 million
in research grants through highly competitive mechanisms such as the TRS (1), CRF
(2), GRF (9), UICP (1), ANR/RGC (1), US NIH RO1 (1), and the Bill & Melinda Gates Foundation (1). Together with funding of
HK$80
millions received for research where I have been co-principal
investigator, I have been able to sustain the HKU AIDS Institute for 15 years.
As a teacher, I have taught 75 bachelor of biomedical sciences
(BBMS), bachelor of medicine and bachelor of surgery (MBBS), Common Core
Science & Technology (CCST), and Master of Medicine and Public Health (MMPH) courses.
I have served on the BBMS Organizing Committee and Curriculum Committee, as
well as Faculty Higher Degree Committee, advised
over 60 MBBS/BBMS students, co-directed the HIV/AIDS course with Nobel Laureate
Dr
François Barre-Sinousi, co-organized three Croucher Courses on Advances in Immunology, and trained 21 PhD students to a top 5 percent or 10 percent
score.
I have also served on the editorial
boards of key journals on HIV/AIDS research, on grant committees around the
world, as a scientific committee member and speaker/chair for prestigious international
conferences, and as a contributor to an award-winning book on HIV vaccines and
the HIV Manual. I have also chaired the Hong Kong Society for Immunology
and am a board director of the Hong Kong AIDS Foundation and scientific
committee vice-chairman of the Chinese National Academic Conference on
HIV/AIDS.
[1] JCI 2013, Cancer Res 2015
[2]PLoS Path 2021
[3]JV 2022
[4]EBioMed 2022
[5]Mol Ther Onco 2020
[6]Mol Ther 2013
[7]MAbs 2015
[8]Nature Microb 2017
[9]Gut 2023
[10]IAS 2023
[11]JV 2005a
[12]JV 2005b
[13]JV 2007
[14]Virology 2008
[15]JV 2011
[16]Mucosal Immunology 2015
[17]JCI Insight 2019
[18]Immunity 2020
[19]Cell Host & Microbe 2021
[20]Nature Commun 2022
[21]Nature 2020
[22]Cell 2021
[23]Nature Commun 2021
[24]Cell Host & Microbe 2022
[25]Nature 2022
[26]Sci Trans Med 2022
[27]EBioMedicines 2022
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