T-cell activation and B-cell interaction signatures in rectal tissues are associated with HIV replication in ex-vivo model of infection

Smith, S Abigail; Murray, Phillip M.; Amancha, Praveen Kumar; Ackerley, Cassie Grimsley; Tharp, Gregory K.; Bosinger, Steven E.; Amara, Rama Rao; Kelley, Colleen F.

doi:10.1097/qad.0000000000003356

Cited by 3 publications

(4 citation statements)

References 38 publications

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“…Prior work [65,66] has also shown that asymptomatic rectal STI is associated with HIV seroconversion even in the setting of routine screening and treatment, which suggests that ongoing mucosal inflammation associated with asymptomatic STI could increase susceptibility to HIV. In our prior studies utilizing the explant challenge model to approximate HIV acquisition and early replication, we found increased p24 production was associated with differences in rectal mucosal cellular composition and the transcriptome [67]. Given the lack of immunologic effects of asymptomatic bacterial STI on either the cellular composition or the transcriptome in YMSM without HIV, the lack of differences in p24 production is not surprising and suggests that prior epidemiologic associations between asymptomatic STI and HIV acquisition may be confounded by behavioral factors.…”

Section: Plos Pathogensmentioning

confidence: 78%

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HIV, asymptomatic STI, and the rectal mucosal immune environment among young men who have sex with men

Doren

Smith

et al. 2023

PLoS Pathog

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Young men who have sex with men (YMSM) are disproportionately affected by HIV and bacterial sexually transmitted infections (STI) including gonorrhea, chlamydia, and syphilis; yet research into the immunologic effects of these infections is typically pursued in siloes. Here, we employed a syndemic approach to understand potential interactions of these infections on the rectal mucosal immune environment among YMSM. We enrolled YMSM aged 18–29 years with and without HIV and/or asymptomatic bacterial STI and collected blood, rectal secretions, and rectal tissue biopsies. YMSM with HIV were on suppressive antiretroviral therapy (ART) with preserved blood CD4 cell counts. We defined 7 innate and 19 adaptive immune cell subsets by flow cytometry, the rectal mucosal transcriptome by RNAseq, and the rectal mucosal microbiome by 16S rRNA sequencing and examined the effects of HIV and STI and their interactions. We measured tissue HIV RNA viral loads among YMSM with HIV and HIV replication in rectal explant challenge experiments among YMSM without HIV. HIV, but not asymptomatic STI, was associated with profound alterations in the cellular composition of the rectal mucosa. We did not detect a difference in the microbiome composition associated with HIV, but asymptomatic bacterial STI was associated with a higher probability of presence of potentially pathogenic taxa. When examining the rectal mucosal transcriptome, there was evidence of statistical interaction; asymptomatic bacterial STI was associated with upregulation of numerous inflammatory genes and enrichment for immune response pathways among YMSM with HIV, but not YMSM without HIV. Asymptomatic bacterial STI was not associated with differences in tissue HIV RNA viral loads or in HIV replication in explant challenge experiments. Our results suggest that asymptomatic bacterial STI may contribute to inflammation particularly among YMSM with HIV, and that future research should examine potential harms and interventions to reduce the health impact of these syndemic infections.

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Section: Plos Pathogensmentioning

confidence: 78%

“…Events were acquired on the LSR-Fortessa platform and analyzed with Flowjo software (Treestar Inc. CA). We used the gating strategies previously reported by our group for these analyses [60,67] and depicted in S3-S5 Figs.…”

Section: Blood and Rectal Mucosal Mononuclear Cell Phenotypingmentioning

confidence: 99%

HIV, asymptomatic STI, and the rectal mucosal immune environment among young men who have sex with men

Doren

Smith

et al. 2023

PLoS Pathog

Self Cite

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show abstract

“…Prior work [47, 48] has shown that asymptomatic rectal STI is associated with HIV seroconversion even in the setting of routine screening and treatment, which suggests that ongoing mucosal inflammation associated with asymptomatic STI could increase susceptibility to HIV. In our prior studies utilizing the explant challenge model to approximate HIV acquisition and early replication, we found increased p24 production was associated with differences in rectal mucosal cellular composition and the transcriptome[49]. Given the lack of immunologic effects of asymptomatic bacterial STI on either the cellular composition or the transcriptome in YMSM without HIV, the lack of differences in p24 production is not surprising and suggests that prior epidemiologic associations between asymptomatic STI and HIV acquisition may be confounded by behavioral factors.…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

HIV, asymptomatic STI, and the rectal mucosal immune environment among young men who have sex with men

Doren

Smith

et al. 2023

Preprint

Self Cite

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Young men who have sex with men (YMSM) are disproportionately affected by HIV and bacterial sexually transmitted infections (STI) including gonorrhea, chlamydia, and syphilis; yet research into the immunologic effects of these infections is typically pursued in siloes. Here, we employed a syndemic approach to understand potential interactions of these infections on the rectal mucosal immune environment among YMSM. We enrolled YMSM aged 18-29 years with and without HIV and/or asymptomatic bacterial STI and collected blood, rectal secretions, and rectal tissue biopsies. YMSM with HIV were on suppressive antiretroviral therapy (ART) with preserved blood CD4 cell counts. We defined 7 innate and 19 adaptive immune cell subsets by flow cytometry, the rectal mucosal transcriptome by RNAseq, and the rectal mucosal microbiome by 16s rRNA sequencing and examined the effects of HIV and STI and their interactions. We measured tissue HIV RNA viral loads among YMSM with HIV and HIV replication in rectal explant challenge experiments among YMSM without HIV. HIV, but not asymptomatic STI, was associated with profound alterations in the cellular composition of the rectal mucosa. We did not detect a difference in the microbiome composition associated with HIV, but asymptomatic bacterial STI was associated with a higher probability of presence of pathogenic taxa. When examining the rectal mucosal transcriptome, there was evidence of statistical interaction; asymptomatic bacterial STI was associated with upregulation of numerous inflammatory genes and enrichment for immune response pathways among YMSM with HIV, but not YMSM without HIV. Asymptomatic bacterial STI was not associated with differences in tissue HIV RNA viral loads or in HIV replication in explant challenge experiments. Our results suggest that asymptomatic bacterial STI may contribute to inflammation particularly among YMSM with HIV, and that future research should examine potential harms and interventions to reduce the health impact of these syndemic infections.

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Integrated analysis of rectal mucosal microbiome and transcriptome reveals a distinct microenvironment among young MSM

Ackerley,

Smith,

Murray

et al. 2024

JCI Insight

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Crosstalk between the microbiome and gut mucosa–resident immune cells plays a pivotal role in modulating immune responses to pathogens, including responses to HIV infection. However, how these interactions may differ between young men who have sex with men (YMSM) disproportionately impacted by HIV, as compared with older adult MSM (AMSM), is not well understood. A broad analysis of associations between the microbiome and rectal transcriptome revealed 10 microbial families/genera correlated with immunologic gene pathways. Specifically, the rectal transcriptome of YMSM was characterized by upregulation of T cell activation/differentiation pathways and signaling from multiple cytokine families compared with AMSM. The microbiome of YMSM was enriched with pathogenic genera, including Peptostreptococcus , shown to be positively correlated with type I IFN pathways important for antiviral immunity. These findings demonstrate that YMSM have a unique immune phenotype and rectal microenvironment and support further evaluation of biological factors that influence rectal HIV transmission.

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T-cell activation and B-cell interaction signatures in rectal tissues are associated with HIV replication in ex-vivo model of infection

Cited by 3 publications

References 38 publications

HIV, asymptomatic STI, and the rectal mucosal immune environment among young men who have sex with men

HIV, asymptomatic STI, and the rectal mucosal immune environment among young men who have sex with men

HIV, asymptomatic STI, and the rectal mucosal immune environment among young men who have sex with men

Integrated analysis of rectal mucosal microbiome and transcriptome reveals a distinct microenvironment among young MSM

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