Synergistic Pathogen Expansion: Unveiling Mechanisms of Increased Disease Severity in Mtb-HIV Coinfection Using an Agent-Based Model

Authors: Alexis Hoerter¹, Alexa Petrucciani¹, Israel Guerrero², Charles Renshaw², Maria Montoya², Eusondia Arnett², Larry S. Schlesinger² and Elsje Pienaar^1,3

Affiliations:

¹Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA

²Texas Biomedical Research Institute, San Antonio, TX, USA

³Regenstrief Center for Healthcare Engineering, Purdue University, West Lafayette, IN, USA

Abstract:

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), and human immunodeficiency virus-1 (HIV) are major public health concerns, individually and in combination. Individuals with HIV are 15-21 times more likely to develop active TB, and TB is the leading cause of death in HIV+ individuals. Understanding how Mtb and HIV work together to overcome the host immune responses is crucial to developing treatment strategies geared towards treating coinfection rather than each singular infection. To this, we have developed an agent-based model (ABM) as a mechanistic computational tool to simulate the immune response to Mtb and HIV, separately and during coinfection. Our computational model mimics Mtb-HIV coinfection through interactions between virtual macrophages, Mtb-and HIV-specific CD4+ and CD8+ T cells, Mtb and HIV. Parameters were kept the same for TB- and HIV-only infections. For coinfection, we divided 22 parameters into 6 groups and scaled them between 0-2 times the value in the single infection scenarios. These parameters represent observations seen in literature across different experiment types as potential causes for amplified HIV and Mtb growth in coinfection including differences in viral replication rates, probabilities of HIV infection, cell cytokine secretion rates, proliferation potential of T cells, macrophage phagocytosis probabilities, and T cell activation probabilities. The ABM is calibrated to in vitro experimental ratios of coinfection HIV growth and Mtb growth at Day 5 compared to their respective single infection. Our preliminary results suggest that HIV-induced cellular dysfunction of cytokine secretion and T-cell proliferation potential may be increasing pathogenicity in coinfection. This ABM marks one of the first steps to incorporate multiple observations from different systems into one platform. By identifying mechanisms by which Mtb and HIV compound disease severity, we highlight the potential of computational approaches in understanding and guiding the future development of targeted coinfection treatment.

Synergistic Pathogen Expansion: Unveiling Mechanisms of Increased Disease Severity in Mtb-HIV Coinfection Using an Agent-Based Model

Synergistic Pathogen Expansion: Unveiling Mechanisms of Increased Disease Severity in Mtb-HIV Coinfection Using an Agent-Based Model

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