Research

Sustained cART-free HIV-1 control by immunotherapeutic interventions

Leading the Way to Effective HIV Care: Guidelines for Prevention and Treatment

HIV/AIDS pandemic has resulted in 39.9 million people living with HIV-1 (PLWH) and 42.3 million deaths since 1981. In Hong Kong, despite active prevention and timely introduction of combination antiretroviral therapy (cART), the cumulative number of PLWH has increased to 11,943 in 2023, requiring an estimated annual cART expense of HK$ 750 million. The local HIV-1 prevalence rate remains high among men who have sex with men (MSM). Since the life-long expensive cART is unlikely sustainable and does not cure HIV/AIDS, our overall objective is to determine effective immunotherapies that potentiate host immunity to achieve sustained cART-free HIV-1 control, a state of viral suppression below the limit of detection for a prolonged period in PLWH. With supports from previous RGC GRF/CRF/TRS grants, our research team have made several findings, which lead to our hypothesis that an effective immunotherapy will provide a sustained cART-free HIV-1 control by potentiating host immunity. First, we found that an PD1-based vaccine elicits high frequencies of cytotoxic CD8⁺ T lymphocytes (CTLs), which are essential for eliminating virus-infected cells. Monkeys pre-vaccinated with such a vaccine have shown sustained cART-free virologic control for over 6 years against a simian AIDS virus (SHIV). Second, we engineered a potent and broadly bi-specific neutralizing antibody BiIA-SG that eliminates virus in 42% humanized mice and suppresses the virus in all monkeys in two post-exposure experiments. Third, we discovered a new Δ42PD1-TLR4 immune pathway and a Δ42PD1-specific antibody drug that reduces HIV-1-induced immune dysfunction during acute infection. We also found that Δ42PD1 regulates human CTLs for conferring immune-checkpoint blockade resistance and B cells for HIV-1-induced loss of antibody responses. Importantly, our research outputs include the establishment of Immuno Cure BioTech Ltd Hong Kong, bringing the human PD1-based vaccine ICVAX into a double-blind, placebo-controlled phase I trial among PLWH. Based on these outputs and team expertise, our study is currently supported by TRS. Using systems virology and immunology methods, we will focus on three specific themes: (I) To determine the mechanism of PD1-based vaccine-mediated 6-year cART-free virologic control in SHIV-infected rhesus monkeys; (II) To determine the impact of PD1-based vaccine on viral reservoirs among cART-treated PLWH; (III) To investigate sustained cART-free HIV-1 virologic control using analytical treatment interruption and combination immunotherapy. Our findings will enrich the knowledge on mechanisms of immune protection critical for saving the lives of PLWH, and for reducing cART toxicity or resistance as well as the financial burden of both government and PLWH.

Theme I: To determine the mechanism of PD1-based vaccine-mediated 6-year cART-free virologic control in SHIV-infected rhesus monkeys

The famous rhesus CMV (RhCMV)-vectored simian AIDS vaccine provides a proof-of-concept that vaccine-induced strong and poly-functional effector memory T cell responses can achieve viremia suppression for a prolonged period in monkey models. We previously also reported a heterologous mucosal vaccinia MVTT prime and intramuscular adenovirus Ad5 boost vaccination regimen in the SIVmac239/macaque model with significant viral suppression and survival advantages. These virus-based vaccines, however, face issues of human safety, large-scale manufacture feasibility, and host anti-vector immunity. It is, therefore, important to discover new types of vaccines to induce potent polyfunctional effector memory CD8+ T cells for durable cART-free virologic control. In 2013, our research team first discovered a novel dendritic cell-directed antigen delivery strategy using PD1-based vaccine for inducing high frequencies of HIV-1 Gag-specific, broadly reactive, poly-functional, long-lived CD8⁺ cytotoxic T lymphocytes (CTLs) through antigen cross-presentation in mice. Subsequently, we demonstrated that the PD1-based vaccine induced potent HIV-1 Gag-specific CD8⁺ T cells even when CD4⁺ T helper cells were depleted in immunocompetent mice, indicating its critical mode of antigen cross-presentation. We further tested a rhesus PD1 (rhPD1)-based DNA vaccine in rhesus monkeys against the pathogenic SHIV_SF162P3CN challenge. This strategy resulted in long-term sustained cART-free viremia control, as well as induced higher levels of durable SIV Gag-specific polyfunctional effector memory CD8⁺ T cells, in SHIV-infected rhesus monkeys. Based on these experimental findings, we will further determine the mechanisms of PD1-based vaccine-mediated sustained cART-free virologic control in SHIV-infected rhesus monkeys, including the protective role of CD8⁺ T cells and the atlas of viral latency.

Theme II: To determine the impact of PD1-based vaccine on viral reservoir among cART-treated PLWH

In addition to rhPD1-based DNA vaccine, our team have also made a human PD1-based (huPD1) vaccine, namely ICVAX, using antigen derived from HIV-1 strains for clinical development. To cover HIV-1 genetic diversity , we conducted sequence analysis of 539 Chinese HIV-1 strains and synthesized two gene-optimized mosaic antigens (mosaic-1 and mosaic-2). Since the whole Gag protein forms virus-like particle (VLP) that may occlude the antigenic epitopes and alter huPD1-based antigen cross presentation, we focused on the Gag p41 antigen that consists of p17 matrix and p24 capsid polypeptides. Thus, ICVAX was made by fusion of human soluble PD1 with mosaic-1 and mosaic-2 Gag p41 antigens with broad cross reactivity with T cells derived from PLWH in China. For clinical studies, we have collaborated with HIV/AIDS immunologist Prof. Xia JIN, the CEO of Immuno Cure BioTech Limited. The company has licensed the exclusive use of the HKU patent of the PD1-based vaccine technology. In this collaboration, we have successfully generated the GMP-grade ICVAX, completed FDA-required animal safety studies, and conducted Phase I clinical trial under IND (Investigational New Drug) approval from Chinese National Medical Products Administration (NMPA) in China. Like monkey experiments, the approved ICVAX vaccination is through intramuscular injection with electroporation (EP). During EP, short electric pulses are applied at the injection site to facilitate the transfer of our ICVAX vaccine from the extracellular spaces into the cell nucleus. In vivo EP enhances the expression of transgenes encoded in DNA vaccines at the injection site by 2-3 log₁₀.  In this theme, we will conduct an in-depth study of the anti-viral T cell responses elicited by ICVAX/EP in cART-treated PLWH to elucidate how the vaccination strategy impacts HIV reservoirs in PLWH.

Theme III: To investigate sustained cART-free HIV-1 control using analytical treatment interruption (ATI) and combination immunotherapy

ATI is a necessary approach in HIV-1 cure-related clinical trials to test the efficacy of an investigational immunotherapy towards viral reservoir elimination or cART-free viral control after cART is stopped. For this theme, we will further investigate the immunogenicity and efficacy of ICVAX/EP for cART-free HIV-1 control in PLWH. A multi-centre Phase II randomized-controlled trial with ATI will be planned in mainland and Hong Kong. The primary objective of this Phase II trial is immunogenicity evaluation, and the secondary one is to determine basic efficacy and virological parameters post vaccination. Detailed immunological investigations will be performed in this proposed study, from which potential mechanism of action of the ICVAX/EP vaccine may be elucidated and used as evidence to support the future phase III clinical trial.