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Persistent accumulation of gut macrophages with impaired phagocytic function correlates with SIV disease progression
Zachary D Swan1,2, Anthea L Bouwer1,2, Elizabeth R Wonderlich1,2
1Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA.
Abstract:
The contribution of macrophages in the gastrointestinal tract to disease control or progression in HIV infection remains unclear. To address this question, we analyzed CD163+ macrophages in ileum and mesenteric lymph nodes (LN) from SIV-infected rhesus macaques with dichotomous expression of controlling MHC class I alleles predicted to be SIV controllers or progressors. Infection induced accumulation of macrophages into gut mucosa in the acute phase that persisted in progressors but was resolved in controllers. In contrast, macrophage recruitment to mesenteric LNs occurred only transiently in acute infection irrespective of disease outcome. Persistent gut macrophage accumulation was associated with CD163 expression on α4β7+ CD16+ blood monocytes and correlated with epithelial damage. Macrophages isolated from intestine of progressors had reduced phagocytic function relative to controllers and uninfected macaques, and the proportion of phagocytic macrophages negatively correlated with mucosal epithelial breach, lamina propria Escherichia coli density, and plasma virus burden. Macrophages in intestine produced low levels of cytokines regardless of disease course, while mesenteric LN macrophages from progressors became increasingly responsive as infection advanced. These data indicate that noninflammatory CD163+ macrophages accumulate in gut mucosa in progressive SIV infection in response to intestinal damage but fail to adequately phagocytose debris, potentially perpetuating their recruitment.
Insights
In HIV infection, macrophages accumulate in the gut during progressive disease, failing to clear debris and worsening intestinal damage. This macrophage accumulation is linked to disease progression and gut barrier dysfunction.
Area of Science:
- Immunology
- Gastroenterology
- Virology
Background:
- The role of macrophages in the gastrointestinal tract during HIV infection is not fully understood.
- Understanding macrophage behavior is crucial for controlling HIV disease progression.
Purpose of the Study:
- To investigate the contribution of CD163+ macrophages in the gut to disease control versus progression in SIV infection.
- To analyze macrophage accumulation, function, and cytokine production in the ileum and mesenteric lymph nodes (LN) of SIV-infected rhesus macaques.
Main Methods:
- Analysis of CD163+ macrophages in ileum and mesenteric LNs from SIV-infected rhesus macaques with known SIV controller or progressor MHC class I alleles.
- Assessment of macrophage recruitment, CD163 expression on blood monocytes, phagocytic function, cytokine production, and correlation with disease parameters like epithelial damage and viral load.
Main Results:
- Persistent macrophage accumulation in the gut mucosa was observed in progressors but resolved in controllers.
- Persistent gut macrophages expressed CD163 on alpha4beta7+ CD16+ blood monocytes and correlated with epithelial damage.
- Macrophages from progressors exhibited reduced phagocytic function, correlating with increased gut permeability, bacterial translocation, and viral load.
Conclusions:
- Noninflammatory CD163+ macrophages accumulate in the gut mucosa during progressive SIV infection, driven by intestinal damage.
- Impaired phagocytic function of these macrophages may perpetuate their recruitment and contribute to disease progression.
- Distinct macrophage responses in the gut mucosa versus mesenteric LNs highlight compartmentalized immune roles in HIV infection.
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