African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

Raehtz, Kevin; Barrenäs, Fredrik; Xu, Cuiling; Busman‐Sahay, Kathleen; Valentine, Audrey; Law, G. Lynn; Ma, Dongzhu; Policicchio, Benjamin B.; Wijewardana, Viskam; Brocca-Cofano, Egidio; Trichel, Anita; Gale, Michael; Keele, Brandon F.; Estes, Jacob D.; Apetrei, Cristian; Pandrea, Ivona

doi:10.1371/journal.ppat.1008333

Cited by 27 publications

(41 citation statements)

References 150 publications

(314 reference statements)

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“…Moreover, when gut epithelial integrity is preserved, there was no evidence of increased microbial translocation in a study of early SIV infection in natural hosts’ infection. 20 This study and our results both suggest that a gut epithelial damage enhances the persistence of HIV reservoirs and increases inflammation-associated comorbidities.…”

Section: Discussionsupporting

confidence: 62%

Differences in HIV burden in the inflamed and non-inflamed colon from a person living with HIV and ulcerative colitis

Peng

Isnard

Lin

et al. 2021

Journal of Virus Eradication

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The greatest obstacle to an HIV cure is the persistence of latently infected cellular reservoirs in people living with HIV (PLWH) taking antiretroviral therapy (ART). However, no consensus exists on the direct link between local tissue inflammation and the HIV burden. Herein, we have compared the levels of local inflammation, epithelial integrity and HIV DNA between inflamed and non-inflamed colon tissue in a PLWH who underwent a colectomy due to ulcerative colitis. We have observed a 27-fold higher frequency of cells harboring HIV DNA in inflamed compared to non-inflamed colon tissue. Analysis of the expression of occludin-1 and claudin-3 confirmed our macroscopic characterization of inflamed and non-inflamed colon. Our results confirm that increased gut permeability and inflammation are associated with a higher frequency of infected cells and suggest that restoring gut barrier integrity may be used as a strategy to reduce inflammation and HIV persistence in the gut.

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Section: Discussionsupporting

confidence: 62%

Differences in HIV burden in the inflamed and non-inflamed colon from a person living with HIV and ulcerative colitis

Peng

Isnard

Lin

et al. 2021

Journal of Virus Eradication

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“…During SIVmac infection, NKG2 a/c + CD8 + T cells displayed proliferative responses that were shorter in time when compared with conventional CD8 + T cells than in SIVagm infection. In AGM, the conventional CD8 + T cells did not show significant increases in proliferation, in line with the literature ( Favre et al., 2009 )( Raehtz et al., 2020 ) ( Jacquelin et al., 2014 ), whereas NKG2 a/c + CD3 + CD8 + T cells showed a strong increase in proliferative capacity in acute infection (day 7 p.i.) ( Figure 3 A).…”

Section: Resultssupporting

confidence: 90%

Role of NKG2a/c+CD8+ T cells in pathogenic versus non-pathogenic SIV infections

et al. 2021

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Summary Some viruses have established an equilibrium with their host. African green monkeys (AGM) display persistent high viral replication in the blood and intestine during Simian immunodeficiency virus (SIV) infection but resolve systemic inflammation after acute infection and lack intestinal immune or tissue damage during chronic infection. We show that NKG2 a/c + CD8 + T cells increase in the blood and intestine of AGM in response to SIVagm infection in contrast to SIVmac infection in macaques, the latter modeling HIV infection. NKG2 a/c + CD8 + T cells were not expanded in lymph nodes, and CXCR5 + NKG2 a/c + CD8 + T cell frequencies further decreased after SIV infection. Genome-wide transcriptome analysis of NKG2 a/c + CD8 + T cells from AGM revealed the expression of NK cell receptors, and of molecules with cytotoxic effector, gut homing, and immunoregulatory and gut barrier function, including CD73. NKG2 a/c + CD8 + T cells correlated negatively with IL-23 in the intestine during SIVmac infection. The data suggest a potential regulatory role of NKG2 a/c + CD8 + T cells in intestinal inflammation during SIV/HIV infections.

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“…This could thus contribute to the lack of chronic inflammation and intact tissue structures (such as integrity of follicular dendritic cell network and lack of fibrosis in LN of AGM in contrast to MAC) [10,68,69]. It is in agreement with observations that AGMs are able to actively maintain integrity of the gut mucosal barrier throughout SIV infection [69][70][71]. The lack of tissue damage could help AGM to avoid disease progression as dextran sulfate sodium-induced colitis, and tissue damage during SIVagm infection was demonstrated to lead to increased viral load, microbial translocation and inflammation [72].…”

Section: Discussionsupporting

confidence: 84%

DNA methylation changes in metabolic and immune-regulatory pathways in blood and lymph node CD4 + T cells in response to SIV infections

et al. 2020

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The molecular mechanisms underlying HIV-induced inflammation, which persists even during effective long-term treatment, remain incompletely defined. Here, we studied pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections in macaques and African green monkeys, respectively. We longitudinally analyzed genome-wide DNA methylation changes in CD4 + T cells from lymph node and blood, using arrays. DNA methylation changes after SIV infection were more pronounced in lymph nodes than blood and already detected in primary infection. Differentially methylated genes in pathogenic SIV infection were enriched for Th1-signaling (e.g., RUNX3, STAT4, NFKB1) and metabolic pathways (e.g., PRKCZ). In contrast, nonpathogenic SIVagm infection induced DNA methylation in genes coding for regulatory proteins such as LAG-3, arginase-2, interleukin-21 and interleukin-31. Between 15 and 18% of genes with DNA methylation changes were differentially expressed in CD4 + T cells in vivo. Selected identified sites were validated using bisulfite pyrosequencing in an independent cohort of uninfected, viremic and SIV controller macaques. Altered DNA methylation was confirmed in blood and lymph node CD4 + T cells in viremic macaques but was notably absent from SIV controller macaques. Our study identified key genes differentially methylated already in primary infection and in tissues that could contribute to the persisting metabolic disorders and inflammation in HIV-infected individuals despite effective treatment.

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African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

Cited by 27 publications

References 150 publications

Differences in HIV burden in the inflamed and non-inflamed colon from a person living with HIV and ulcerative colitis

Differences in HIV burden in the inflamed and non-inflamed colon from a person living with HIV and ulcerative colitis

Role of NKG2a/c+CD8+ T cells in pathogenic versus non-pathogenic SIV infections

DNA methylation changes in metabolic and immune-regulatory pathways in blood and lymph node CD4 + T cells in response to SIV infections

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