3D human tissue models and microphysiological systems for HIV and related comorbidities

Abstract

Three-dimensional (3D) human tissue models/microphysiological systems (e.g., organs-on-chips, organoids, and tissue explants) model HIV and related comorbidities and have potential to address critical questions, including characterization of viral reservoirs, insufficient innate and adaptive immune responses, biomarker discovery and evaluation, medical complexity with comorbidities (e.g., tuberculosis and SARS-CoV-2), and protection and transmission during pregnancy and birth. Composed of multiple primary or stem cell-derived cell types organized in a dedicated 3D space, these systems hold unique promise for better reproducing human physiology, advancing therapeutic development, and bridging the human-animal model translational gap. Here, we discuss the promises and achievements with 3D human tissue models in HIV and comorbidity research, along with remaining barriers with respect to cell biology, virology, immunology, and regulatory issues.

Keywords: HIV/AIDS; explant; microphysiological system; organ-chip; organoid; tuberculosis.

Figure 1.. Advantages of 3D human tissue models/microphysiological systems with opportunities to advance HIV and related comorbidity science.

(A, Pathogenesis) HIV infects and forms reservoirs in tissues, in addition to the blood/peripheral blood mononuclear cells. 3D/MPS allow study of disease pathogenesis and immune interactions at the tissue level. (B, Human-relevant data) HIV is human-tropic and interindividual variability may affect disease progression and drug disposition. 3D/MPS allow for study of human-relevant research on the disease, therapeutics, cure strategies, and interindividual or subpopulation variability. (C, Interconnected tissue types) HIV and its comorbidities are multi-system diseases interacting with the immune system. Interconnected tissue types allow for better biological fidelity to study HIV disease, its complications and comorbidities, and clinical pharmacology. (D, Coinfections and comorbidities) HIV leads to an immunodeficiency and inflammation, rendering the person living with HIV susceptible to coinfections, e.g. Mycobacterium tuberculosis, and comorbidities, e.g. neurocognitive, liver, and kidney dysfunction. 3D/MPS facilitate investigation of the varying and interconnected tissue types involved in these coinfections and comorbidities. (E, Developing prophylactics and therapeutics) 3D/MPS have demonstrated use in therapeutic and prophylactic development, in some cases with better predictive accuracy than traditional preclinical models. (F, Difficult-to-access tissues) Difficult-to-access tissues, e.g. the human brain, can be infected by HIV and form reservoirs, but they cannot be easily sampled and studied. The ability to generate, e.g. via inducible pluripotent stem cells, and experiment with these tissues allows human-relevant investigations that would otherwise be challenging. Abbreviations: 3D/MPS, 3D human tissue models/microphysiological systems; HIV, human immunodeficiency virus.

Figure 2.. 3D human tissue models/microphysiological systems (3D/MPS) with potential application to scientific questions about HIV and related comorbidities.

Certain tissues or organs have relevance to specific areas of HIV and comorbidity research: (A) Sites of HIV infection, pathology, and systems immunity may be modeled using the cervix, colon, tonsil, lymph node, and brain. The cervix/vagina and rectum/colon may be applied to study HIV horizontal transmission, early immune pathogenesis, and agents for prevention. The lymphoid tissues and brain are sites of HIV reservoirs and may be used to study HIV pathogenesis, inflammatory complications, and cure strategies. (B) Sites of HIV complications and comorbidities include the lungs, heart, liver, kidneys, and colon. The lungs are the primary site of Mycobacterium tuberculosis infection and disease. HIV and its treatments may lead to complications of the heart, liver, and kidneys. (C) Sites of relevance to HIV therapeutics and clinical pharmacology include the liver, kidneys, blood, brain, and lymphoid tissues. (D) The placenta, neural tube, and brain are applicable to the study of pregnant and pediatric populations, including maternal-fetal pathogenesis, vertical HIV transmission and prevention. (E) Cellular therapies are a focus for potential HIV cure strategies. The vasculature model provides an example of a potency bioassay that may be used to assess cellular product quality, although not specific to HIV. The symbols depict various types of 3D/MPS technology, i.e. organoids, tissue-chips, human tissue explants, or bioprinting, that may be applicable to HIV-related investigations. Abbreviations: 3D/MPS, 3D human tissue models/microphysiological systems; HIV, human immunodeficiency virus.