Bharadwaj Vemparala (1), Caroline Passaes (2, 3), Delphine Desjardins (4), Anaïs Chapel (2, 3), Valérie Monceaux (2, 3), Julien Lemaitre (4), Adeline Mélard (5), Federico Perdomo-Celis (3), Cyril Planchais (6), Maël Gourvès (2), Nastasia Dimant (4), Annie David (3), Nathalie Dereuddre-Bosquet (4), Aurélie Barrail-Tran (4, 7), Hélène Gouget (4), Céline Guillaume (4), Francis Relouzat (4), Olivier Lambotte (4, 8), Michaela Müller-Trutwin (3), Hugo Mouquet (6), Christine Rouzioux (9), Véronique Avettand-Fenoël (5, 10), Roger Le Grand (4), Asier Sáez-Cirión (2, 3), Narendra M Dixit (1, 11), Jérémie Guedj (12)
(1) Department of Chemical Engineering, Indian Institute of Science, Bengaluru, India, (2) Institut Pasteur, Université Paris Cité, Viral Reservoirs and Immune Control Unit, Paris, France, (3) Institut Pasteur, Université Paris Cité, HIV Inflammation and Persistence Unit, Paris, France, (4), Université Paris-Saclay, CEA, INSERM, UMR1184, Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT Department), Fontenay-aux-Roses/Le Kremlin-Bicêtre, France, (5) Université Paris Cité; INSERM, U1016; CNRS, UMR8104 Paris, France, (6) Institut Pasteur, Université Paris Cité, INSERM U1222, Humoral Immunology Unit, Paris, France, (7) Université Paris-Saclay, AP-HP, Hôpital Bicêtre, Service de Pharmacie, Le Kremlin Bicêtre, France, (8) Université Paris-Saclay, AP-HP. Hôpital Bicêtre, Clinical Immunology Department, 94270 Le Kremlin Bicêtre, France, (9) Université Paris Cité/APHP Hôpital Necker - Enfants Malades, Paris, France, (10) APHP Hôpital Cochin, Service de Virologie, Paris, France, (11) Department of Bioengineering, Indian Institute of Science, Bengaluru, India, (12) Université Paris Cité, IAME, INSERM, F-75018 Paris, France.
Objectives:
The current standard of care for HIV infection involves antiretroviral therapy (ART) [1]. ART is not curative and treatment interruption results in rebound of virus levels, necessitating lifelong ART for sustained inhibition of disease progression [2]. However, a small fraction of people living with HIV (PLWH) under ART, termed post-treatment controllers (PTCs), elicit long term virus control after treatment interruption [3]. Studies on PTCs are driving efforts to develop novel therapeutics aimed at eliciting such long-term control in PLWH. Both human and primate studies have shown that early ART initiation is associated with a higher chance of post-treatment control [4, 5]. However, the underpinning mechanisms are unclear.
Methods:
We developed a novel within-host mathematical model for analyzing the influence of ART initiation time on virus and immune response dynamics, and the occurrence of post treatment control. Our hypothesis is the following. Upon HIV infection, virus-specific CD8 T cells accumulate ‘antigenic experience’ through repeated exposure to antigen. Antigenic experience governs the differentiation and survival rates of memory CD8 T cells, required for antiviral responses post ART interruption. Following evidence from immunology [6], we let the proliferative potential of memory CD8 T cells be inversely dependent on their antigenic experience. Thus, early ART treatment is expected to preserve the memory CD8 T cell pool, enabling better response to rebounding virus post ART interruption. We constructed coupled ODEs to describe the time course of viral load, latent reservoir and CD8 T cell responses before, during and after ART. We fit the model to longitudinal data from a recent SIV-primate study of 23 macaques [5].
Results:
- The model predicted decreasing set-point viral load post ART interruption with earlier time of treatment initiation. Early ART was thus predicted to confer a higher chance of post-treatment control despite progressive infection prior to ART initiation.
- Our model predicted that upon early ART initiation, proliferative potential of memory CD8 T cells was preserved, allowing for robust recall responses post ART interruption. Late ART initiation, on the other hand, resulted in impaired responses post ART interruption, reigniting disease progression.
- Fitting our model to longitudinal data from the SIV-primate study allowed estimation of how late ART could be initiated while preserving memory CD8 T cell responses necessary for eliciting post-treatment control with high probability.
Conclusions:
The existence of a PTC phenotype, although rare, indicates the possibility of therapeutically triggering long-term control in PLWH. Our model, to our knowledge, is the first to provide a mechanistic explanation of the influence of ART initiation time on the emergence of post treatment control. The framework would enable the development of quantifiable targets for therapies under development for eliciting post-treatment control.
References:
[1] Bekker L-G, Beyrer C, Mgodi N, et al. HIV infection. Nat Rev Dis Primers 2023; 9: 1–21.
[2] Siliciano JD, Siliciano RF. HIV cure: The daunting scale of the problem. Science 2024; 383: 703–705.
[3] Goulder P, Deeks SG. HIV control: Is getting there the same as staying there? PLoS Pathog 2018; 14: e1007222.
[4] Sáez-Cirión A, Bacchus C, Hocqueloux L, et al. Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 2013; 9: e1003211.
[5] Passaes C, Desjardins D, Chapel A, et al. Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8+ T-cells. Nat Commun 2024; 15: 178.
[6] Muroyama Y, Wherry EJ. Memory T-Cell Heterogeneity and Terminology. Cold Spring Harb Perspect Biol 2021; a037929.
Reference: PAGE 32 (2024) Abstr 11145 [www.page-meeting.org/?abstract=11145]
Poster: Drug/Disease Modelling - Infection