Background/Purpose: Human immunodeficiency virus (HIV) remains a significant life-threatening agent and burden on public health. Lesser studied and understood aspects of HIV include HIV-associated inflammatory arthritis. By utilizing humanized mice with human cytokine knock-ins that better support a human immune system than other models, we studied HIV-associated arthritis and enthesitis to understand their development and progression.

Methods: MISTRG-IL15 mice (human M-CSF/GM-CSF, IL-3, SIRPα, TPO, RAG2 -/-, IL2rg-/-, and IL-15 knocked into the respective endogenous mouse loci) were reconstituted with CD34+ hematopoietic stem cells obtained from human fetal cord blood. After checking for engraftment after 6-8 weeks, we infected reconstituted mice with HIV. Synovial tissues were obtained from the knee joints of the hind limbs at different time points and processed into single cell suspensions. Intercellular staining was performed on cells incubated with PMA/Ionomycin for 4 hours and then permeabilized and fixed for flow cytometry. NK cells were defined as CD3-CD56+. Histochemistry was also performed on hind paws that were fixed in 4% paraformaldehyde. Samples were then sectioned and stained with H&E for histologic analysis. Different chemokine receptor-tropic HIV viruses were also utilized to determine importance of specific infected cells on development of inflammation.

Results: Humanized MISTRG-IL15 mice developed inflammatory arthritis as well as enthesitis after HIV infection. Significant increases in total inflammatory cells and NK cells were seen in the synovial tissue throughout the course of infection. GM-CSF producing NK cells also increased throughout the course of HIV infection. Late in the course of infection, IFNγ- and granzyme B-producing NK cells increased, along with a pro-inflammatory environment in the synovial tissue. Histologic analysis showed increased cellular infiltrate in the synovium and tendons of mice infected by HIV infection with erosive changes that worsened during course of infection. Antiretroviral therapy (ART) eliminated cellular infiltration while cessation of therapy resulted in return of cellular infiltration in synovial tissue. Use of a chemokine receptor-tropic HIV virus that does not infect macrophages (X4-tropic) showed reduced pro-inflammatory cytokine production by NK cells, strongly suggesting HIV-infected macrophages induced the NK cell changes.

Conclusion: We have developed a unique humanized mouse model of HIV infection which allows opportunities to study HIV-associated arthritis and enthesitis in depth. In addition to providing a model to study arthritis induced by other human pathogens, findings from such studies will provide mechanistic understanding of inflammatory arthritis and enthesitis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-arthritis-in-hiv-infected-humanized-mice/