Aging With Grace for People Living With HIV: Strategies to Overcome Leaky Gut and Cytomegalovirus Coinfection

Abstract

: The intestinal epithelial layer acts as a mechanical and functional barrier between the intraluminal microbiota and the immunologically active submucosa. A progressive loss of gut barrier function (leaky gut) leads to enhanced translocation of microbial products, which in turn contributes as endotoxins to inflammaging. Th17 T cell represents the main immune sentinels in the gut epithelium, preventing aggression from commensal and pathogenic microbes. As HIV infection deeply affects gut Th17 function and increases gut permeability, microbial translocation occurs at high level in people living with HIV (PLWH) and has been associated with the development of non-AIDS comorbidities. Although the inflammatory role of endotoxins like lipopolysaccharide produced by Gram-negative bacteria is well-established, fungal products such as β-D-glucan emerge as new contributors. In addition, PLWH are more frequently infected with cytomegalovirus (CMV) than the general population. CMV infection is a well-described accelerator of immune aging, through the induction of expansion of dysfunctional CD8 T-cells as well as through enhancement of gut microbial translocation. We critically review immune mechanisms related to bacterial and fungal translocation, with a focus on the contribution of CMV coinfection in PLWH. Improving gut barrier dysfunction, microbial composition, and reducing microbial translocation constitute emerging strategies for the prevention and treatment of HIV-associated inflammation and may be relevant for age-related inflammatory conditions.

Loss of Gut Barrier Integrity In Lupus

“…Accordingly, inoculation of mice with Porphyromonas gingivalis or Fusobacterium nucleatum , two common oral bacteria, induced gut barrier damage and aberrant inflammation ( 91 , 92 ). Beside bacteria, various viral infections, including HIV, CMV, bacteriophages and dengue virus, can also cause increased gut permeability leading to a leaky gut ( 93 – 95 ). The relationship between viral infections and leaky gut in lupus has however not been investigated.…”

Identification of CD8+ T cell subsets that normalize in early-treated people living with HIV receiving antiretroviral therapy

“…Nonetheless, a limitation of this study is the lack of data such as CD4 nadir, clinical conditions before cART initiation, or other inflammation markers that would inform on the clinical and immunological state of our cohort of individuals before cART. In this last regard, the asymptomatic reactivation of cytomegalovirus infection in PLWH has been associated with quantitative and qualitative disturbances in the pool of effector memory CD4 + and CD8 + T cells, including decreased CD4:CD8 ratios and increased frequencies of exhausted and senescent cells [ 28 ]. Furthermore, serum levels of IL-7 and IL-15 play important roles in the frequencies of both CD4 + and CD8 + T cells, as they can promote a cytotoxic and proliferative phenotype in these cells [ 29 ], and its restoration upon cART has been associated with the reconstitution of activated T cells [ 30 ].…”

The Frequency and Function of NKG2C+CD57+ Adaptive NK Cells in Cytomagalovirus Co-Infected People Living with HIV Decline with Duration of Antiretroviral Therapy

“…Prior to the availability of antiretroviral treatment (ART), CMV co-infection of People Living with HIV (PLWH) was considered to be an opportunistic infection associated with important morbidity and mortality [ 15 , 16 ]. In the era of ART availability, CMV and HIV co-infections worsen each other’s disease course by contributing to systemic inflammation, cardiovascular disease and immune senescence [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. CMV infection reshapes the NK cell repertoire by driving the expansion of a subset of NK cells expressing NKG2C and CD57 [ 22 , 23 , 24 , 25 , 26 , 27 ].…”

“…In the era of ART availability, CMV and HIV co-infections worsen each other’s disease course by contributing to systemic inflammation, cardiovascular disease and immune senescence [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. CMV infection reshapes the NK cell repertoire by driving the expansion of a subset of NK cells expressing NKG2C and CD57 [ 22 , 23 , 24 , 25 , 26 , 27 ]. NKG2C is an activating receptor belonging to the C-type lectin receptor family, which is expressed as a heterodimer with CD94 [ 28 ].…”