Le Wang
Walter & Eliza Hall Institute of Medical Research
Abstract
AIDS, caused by HIV, remains a significant global health challenge affecting approximately 40 million individuals worldwide. While Antiretroviral Therapy (ART) effectively controls HIV, the virus persists latent in patients and can’t be eliminated, posing ongoing health and economic burdens. My PhD project focuses on developing and accessing novel HIV cure strategies.
We hypothesise the imbalance between cell death and survival signalling is the primary reason of HIV persistence despite ART treatment. This hypothesis is supported by emerging research that discovers the pro-survival feature of the HIV reservoir (cells that are latently infected with HIV). As a result, targeting apoptosis pathway is promising to diminish HIV reservoir, and eventually may shed light on an HIV cure.
To study chronic and latent HIV infection in vivo, we generated a humanised immune system mouse (HIS mouse) model by transplanting human CD34+ hemopoietic stem cells into immunodeficient NSG mice. After confirming reconstitution of human immune system by flow cytometry, HIS mice are transferred to WEHI Physical Containment Level 3 (PC3) laboratory and infected with HIV. Mice are then treated with ART to suppress HIV until their plasma viral load is undetectable by qRT-PCR. Subsequently, pro-apoptotic treatment is administered for weeks.
The treatment efficacy is evaluated by Analytical Treatment Interruption (ATI) to measure HIV rebound dynamics, as the most clinical-relevant marker of HIV reservoir size. Using this sophisticated model and the 36-week-length experiment design, we have previously shown that interfering with intrinsic apoptosis pathway is effective to diminish HIV reservoir in vivo.
In my project, I generated batches of HIS mice, infected them with HIV and suppressed their HIV viremia as described above. By using Xevinapant (a SMAC Mimetic that induces extrinsic apoptosis) to treat latent HIV infected HIS mice for 4 weeks, I am able to show a delay of HIV rebound in HIS mice. After extending treatment duration from 4 weeks to 6 weeks, a more significant rebound delay is obtained. This suggests that inducing extrinsic apoptosis can be a clinically feasible strategy to cure latent HIV infection. On the other hand, to study HIV reservoir quantitively, I have adapted the HIV Intact Proviral DNA assay (IPDA) from clinical samples to mouse samples, which only have a tiny sample size. By using digital PCR platform, I successfully revealed HIV reservoir characteristics in HIS mice, which I found is comparable to human data in terms of proviral DNA load.
In the future, I plan to further investigate the effect of Xevinapant on HIV reservoir by IPDA on the digital PCR platform. I will also test combination therapy of Xevinapant and other drugs that induces intrinsic apoptosis and assess possible synergy effect. I also plan to combine pro-apoptotic treatment with latency-reversing agents as an enhanced “Kick and Kill” strategy towards an HIV cure.
Awards
1st Place
The Grand Prize recipient from each participating country wins a trip to Promega headquarters in Madison, WI USA to meet our R&D team, present their project and network with fellow award recipients.
Public votes are cast between 15 October - 15 November 2024 for each nominee. The candidate with the most votes wins.
Runner Up Awards
Four remaining Finalists will each receive a limited edition Promega Lab Set with LEGO® Elements and a Duffel Bag
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