Chloé Bracis (1,2), Fabián Cardozo-Ojeda (2), Joshua T. Schiffer (2,3)
(1) Université Grenoble Alpes, France, (2) Fred Hutchinson Cancer Center, USA, (3) University of Washington, USA
Introduction: The human immunodeficiency virus (HIV) is a retrovirus infecting primarily CD4 T cells. Antiretroviral therapy (ART) suppresses plasma HIV viral load below the detection limit. Although successful in controlling virus replication, ART is not a cure for HIV and must be taken for life [1]. One gene-based approach for HIV cure is Adeno-associated virus (AAV) vectors encoding the antibody-like peptide eCD4Ig [2]. This potent entry inhibitor neutralizes a greater breadth of HIV isolates in-vitro than all anti-HIV broadly neutralizing antibodies discovered to date [3]. Studies in non-human primates demonstrate that injection of AAV vectors encoding eCD4Ig may allow production of eCD4Ig at levels protective from challenge with simian immune deficiency virus (SIV) and simian-HIV (SHIV) [4-6]. Ongoing pilot studies examine if AAV-delivered eCD4Ig can induce ART-free virus control in SHIV-infected primates after ART interruption. However, the number of animals, cost, and time to perform these experiments make it difficult to find the optimal conditions for ART-free virus control.
Objectives:
- 1) Develop models which recapitulate the complex observed dynamics of AAV viral loads, eCD4Ig levels and downstream effects on HIV viral load.
- 2) Use the model to explore conditions for ART-free virus remission.
Methods: We apply ordinary differential equation models to characterize AAV-vector delivery and eCD4Ig production dynamics and their effect on plasma SHIV dynamics using data from a pilot study of ten SHIV-AD8-infected rhesus macaques that we fit using nonlinear mixed effect models. We adapt standard within-host models of virus dynamics to fit viral load data during acute infection, ART, and ART interruption. Since AAV does not replicate within infected, we use a single round of initial infection to model all subsequent dynamics. We explore two possible eCD4Ig mechanisms: entry inhibition (implemented by reducing the infection rate) or enhancement of infected cell killing via antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) (implemented by increasing the infected cell death rate), where both mechanisms operate in a concentration dependent manner.
Results: We found both eCD4Ig mechanisms, entry inhibition and enhancement of infected cell killing, to be plausible in vivo. Model simulations predicted that with either mechanism, eCD4Ig thresholds required for ART-free virus control are partially dependent on the effectiveness of pre-therapy innate and adaptive anti-SHIV immune responses. However, increasing eCD4Ig levels by increasing AAV dose can lead to viral containment regardless of underlying immunity and appears to overcome the effects of anti-drug antibodies. To well capture SHIV viral dynamics, it was necessary to include several elements: an effector cell compartment, an increase in effector cells to account for a lower peak viral load post-ATI compared to initial infection, a density-dependent parameter for infected cell clearance (suggesting an important early innate response during pre-ART and post-ATI), proliferation of susceptible cells with logistic growth rather than constant growth to avoid complete depletion of the susceptible cells, and a two-phase decline with a small subset of longer-lived infected cells. To capture AAV and eCD4Ig dynamics, it was necessary to include an initially-infected productive compartment, followed by a series of non-productive waiting compartments, before infected cells became productive again. A key parameter was the transition rate to the first non-productive waiting compartment, which needed separate parameter values for AAV1 and AAV8 as well as a density-dependant term that also different between AAV1 and AAV8. Overall, our model suggests that immediately after AAV injection, many cells initially produce eCD4Ig for a short time then become non-productive, but this rate slows down over time, accounting for the initial peak after AAV injection. Contrary to past work with intravenous dosing [6], it was not necessary to include anti-drug antibodies (ADA), suggesting that ADA are less likely to eliminate eCD4Ig when it is above a certain concentration.
Conclusions: These results suggest that AAV-vector delivery of eCD4Ig therapy has promise for achieving sustained HIV remission without ART, particularly if AAV doses can be increased and HIV immune responses can be therapeutically boosted.
References:
[1] Chadwick et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999 May;5(5):512-7.
[2] Fellinger CH et al. eCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing Antibody. J Virol. 2019 Jun 28;93(14):e00443-19.
[3] Fetzer I et al. eCD4-Ig Variants That More Potently Neutralize HIV-1. J Virol. 2018 May 29;92(12):e02011-17
[4] Gardner MR et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015 Mar 5;519(7541):87-91.
[5] Gardner MR et al. AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges. Sci Transl Med. 2019 Jul 24;11(502):eaau5409.
[6] Goyal A et al. Estimation of the in vivo neutralization potency of eCD4Ig and conditions for AAV-mediated production for SHIV long-term remission. Sci Adv. 2022 Jan 14;8(2):eabj5666.
Reference: PAGE 32 (2024) Abstr 10907 [www.page-meeting.org/?abstract=10907]
Poster: Drug/Disease Modelling - Other Topics