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. 2020 Sep 12;71(6):1438-1446.
doi: 10.1093/cid/ciz1001.

Cytomegalovirus Seropositivity Is Associated With Increased Microbial Translocation in People Living With Human Immunodeficiency Virus and Uninfected Controls

Rayoun Ramendra  1   2   3 , Stéphane Isnard  1   2 , John Lin  1   2 , Brandon Fombuena  1   2   3 , Jing Ouyang  1   2   4 , Vikram Mehraj  1   2   5 , Yonglong Zhang  6 , Malcolm Finkelman  6 , Cecilia Costiniuk  1   2 , Bertrand Lebouché  1   2   7 , Carl Chartrand-Lefebvre  5 , Madeleine Durand  5 , Cécile Tremblay  3   5 , Petronela Ancuta  3   5 , Guy Boivin  8 , Jean-Pierre Routy  1   2   9
Affiliations

Cytomegalovirus Seropositivity Is Associated With Increased Microbial Translocation in People Living With Human Immunodeficiency Virus and Uninfected Controls

Rayoun Ramendra et al. Clin Infect Dis. .

Abstract

Background: Cytomegalovirus (CMV) seropositivity and anti-CMV immunoglobulin G (IgG) levels are associated with adverse health outcomes in elderly populations. Among people living with human immunodeficiency virus (PLWH), CMV seropositivity has been associated with persistent CD8 T-cell elevation and increased risk of developing non-AIDS comorbidities despite long-term antiretroviral therapy (ART). Herein, we investigated whether CMV seropositivity and elevation of anti-CMV IgG levels were associated with increased epithelial gut damage, microbial translocation, and systemic inflammation.

Methods: A total of 150 PLWH (79 ART-naive and 71 ART-treated) were compared to 26 without human immunodeficiency virus (HIV) infection (uninfected controls). Plasma markers of HIV disease progression, epithelial gut damage, microbial translocation, nonspecific B-cell activation, anti-CMV and anti-Epstein-Barr virus (EBV) IgG levels, and proinflammatory cytokines were measured.

Results: CMV seropositivity and elevated anti-CMV IgG levels were associated with markers of epithelial gut damage, microbial translocation, and inflammation in PLWH and participants without HIV infection. In contrast, total nonspecific IgG, immunoglobulin M, immunoglobulin A, and anti-EBV IgG levels were not associated with these markers. CMV seropositivity was associated with markers of epithelial gut damage, microbial translocation, and inflammation independent of sociodemographic and behavioral characteristics of the study population.

Conclusions: CMV-seropositive people with and without HIV had increased epithelial gut damage, microbial translocation, and inflammation. Furthermore, anti-CMV IgG levels were independently associated with increased epithelial gut damage and microbial translocation. CMV coinfection may partially explain persistent gut damage, microbial translocation, and inflammation in ART-treated PLWH.

Keywords: HIV; cytomegalovirus; epithelial gut damage; inflammation; microbial translocation.

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Figures

Figure 1.
Figure 1.
Plasma levels of markers of epithelial gut damage and microbial translocation are elevated in antiretroviral therapy (ART)–naive and ART-treated cytomegalovirus (CMV)–seropositive people living with human immunodeficiency virus (PLWH). A, CMV-seropositive ART-naive and ART-treated PLWH as well as participants without human immunodeficiency virus (HIV) infection have higher plasma levels of intestinal fatty acid binding protein (I-FABP) compared with their CMV-uninfected counterparts. B, CMV-seropositive ART-naive and ART-treated PLWH have higher plasma levels of lipopolysaccharide (LPS) compared with their CMV-seronegative counterparts. C, CMV-seropositive ART-naive and ART-treated PLWH have higher plasma levels of (1→3)-β-d-glucan (BDG) compared with their CMV-seronegative counterparts. Horizontal lines represent first quartile, median, and third quartile, respectively. P values show Kruskal-Wallis tests with Dunn post hoc test between different groups. Light blue: ART-naive PLWH; dark blue: ART-treated PLWH; purple: participants without HIV infection.
Figure 2.
Figure 2.
Anti-cytomegalovirus (CMV) immunoglobulin G (IgG) levels are associated with plasma levels of intestinal fatty acid binding protein (I-FABP), a marker of gut damage, and the microbial products lipopolysaccharide (LPS) and (1→3)-β-d-glucan (BDG) among CMV-coinfected people living with human immunodeficiency virus (PLWH). A, Anti-CMV IgG levels are associated with plasma levels of I-FABP (n= 119). B, Plasma levels of anti-CMV IgG are associated with plasma levels of LPS (n= 119). C, Anti-CMV IgG levels are associated with plasma levels of BDG (n= 119). P values show nonparametric Spearman correlations. Light blue: ART-naive PLWH; dark blue: ART-treated PLWH.
Figure 3.
Figure 3.
Plasma levels of marker of inflammation CXCL13 and the proinflammatory cytokines interleukin (IL) 6 and IL-8 are elevated in cytomegalovirus (CMV)–coinfected people living with human immunodeficiency virus (HIV), ie, PLWH. A, CMV-seropositive antiretroviral therapy (ART)–naive and ART-treated PLWH have higher plasma levels of CXCL13 compared with their CMV-seronegative counterparts. B, Plasma levels of anti-CMV immunoglobulin G (IgG) are associated with plasma levels of CXCL13 in CMV-infected PLWH (n= 119). C, CMV-seropositive ART-naive and ART-treated PLWH have higher plasma levels of IL-6 compared with their CMV-seronegative counterparts. D, Plasma levels of anti-CMV IgG are associated with plasma levels of IL-6 in CMV-infected PLWH (n= 119). E, CMV-seropositive ART-naive and ART-treated PLWH have higher plasma levels of IL-8 compared with their CMV-seronegative counterparts. F, Plasma levels of anti-CMV IgG are associated with plasma levels of IL-8 in CMV-infected PLWH (n= 119). Horizontal lines represent first quartile, median, and third quartile, respectively. P values show Kruskal-Wallis tests with Dunn post hoc test between different groups. Associations with anti-CMV IgG levels show nonparametric Spearman correlations. Light blue: ART-naive PLWH; dark blue: ART-treated PLWH; purple: people without HIV infection.
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