Poster Presentation 14th Lorne Infection and Immunity 2024

Promoting extrinsic apoptosis to diminish latent HIV reservoir in vivo (#152)

Le Wang 1 2 , Liana Mackiewicz 1 , Merle Dayton 1 , William Clow 1 2 , Kathryn Davidson 1 2 , Marc Pellegrini 1 3 , Marcel Doerflinger 1 2
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbonrne, Melbourne, VIC, Australia
  3. Centenary Institute, University of Sydney, Sydney, NSW, Australia

Human Immunodeficiency Virus (HIV) poses a significant global health threat. The development of combination antiretroviral therapy (ART) has led to the suppression of viremia in patients and a substantial improvement in the health condition of people living with HIV (PLWH). However, the existence of a latent HIV reservoir (cells harbor replication-competent HIV provirus) leads to HIV rebound following ART interruption. This requires patients to take life-long medication and suffer from side-effects and chronic inflammation. A functional cure for HIV is urgently needed.

Here we hypothesize that the HIV reservoir persists for a long time partly because they resist to cell death, which may serve as a therapeutic target to diminish the HIV reservoir. To study HIV infection in vivo, we injected human hemopoietic CD34+ stem cells in 48 hours-old immunodeficient (NSG) mouse pups to generate a humanized immune system mouse model (HIS mice). In this model, we used Xevinapant (Debio 1143), a SMAC-Mimetic that induces extrinsic apoptosis and has undergone multiple clinical trials as cancer treatment, to treat HIV-infected, viremia-suppressed HIS mice. During the experiment, the percentage of human immune cells, CD4 T cell, and CD8 T cell count was monitored by flow cytometry, and HIV viral load was quantified by qPCR. We evaluated our treatment’s efficacy by analytical treatment interruption (ATI), in which we interrupted all treatment including ART, and compared the time to HIV rebound between groups.

Our results indicate that this HIS mice model can successfully recapitulate essential features of HIV infection in humans. Intact proviral DNA assay (IPDA) is also successfully adapted to this mouse model. Notably, during ATI, we witnessed a delay in HIV rebound after 4 weeks of Xevinapant treatment compared to vehicle. These results suggest that targeting the extrinsic apoptosis pathway may be an effective way to purge the latent HIV reservoir and shed light on designing new strategies to cure HIV. 

Currently, we are working on using a prolonged treatment to achieve better reservoir clearance and determining Xevinapant's efficacy by IPDA.

  1. Stelzle, D., et al., Estimates of the global burden of cervical cancer associated with HIV. The Lancet Global Health, 2021. 9(2): p. e161-e169.
  2. Palella, F.J., et al., Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection. New England Journal of Medicine, 1998. 338(13): p. 853-860.
  3. Joseph K. Wong, et al., Recovery of Replication-Competent HIV Despite Prolonged Suppression of Plasma Viremia. Science, 1997.
  4. Hsue, P.Y. and D.D. Waters, HIV infection and coronary heart disease: mechanisms and management. Nature Reviews Cardiology, 2019. 16(12): p. 745-759.
  5. Hatziioannou, T. and D.T. Evans, Animal models for HIV/AIDS research. Nat Rev Microbiol, 2012. 10(12): p. 852-67.