Early HIV-1 Infection Is Associated With Reduced Frequencies of Cervical Th17 Cells

McKinnon, Lyle R.; Nyanga, Billy; Kim, Connie J.; Izulla, Preston; Kwatampora, Jessie; Kimani, Makobu; Shahabi, Kamnoosh; Mugo, Nelly; Smith, Jennifer S.; Anzala, Aggrey O.; Kimani, Joshua; Kaul, Rupert

doi:10.1097/qai.0000000000000389

Cited by 48 publications

(37 citation statements)

References 21 publications

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“…HIV/SIV efficiently replicate in Th17 as demonstrated by studies by our group and others [40-48]. More specifically, mucosal Th17 cells represent major targets of HIV/SIV infection [49, 50] and subsequent rapid depletion [51-57]. Consistent with this paradigm, a very recent study identified CCR6 + RORgt + Th17 as the first cells to be infected upon vaginal SIV challenge [58].…”

Section: Introductionmentioning

confidence: 78%

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

Gosselin

Salinas

Planas

et al. 2017

Aids

130

181

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Objectives To investigate the contribution of colon and blood CD4+ T-cell subsets expressing the chemokine receptor CCR6 to HIV persistence during ART. Design Matched sigmoid biopsies and blood samples (n=13) as well as leukapheresis (n=20) were collected from chronically HIV-infected individuals receiving ART. Subsets of CD4+ T-cells with distinct differentiation/polarization profiles were identified using surface markers as follows: memory (TM, CD45RA-), central memory (TCM; CD45RA−CCR7+), effector (TEM/TM; CD45RA−CCR7−), Th17 (CCR6+CCR4+), Th1Th17 (CCR6+CXCR3+), Th1 (CCR6−CXCR3+), and Th2 (CCR6−CCR4+). Methods We used polychromatic flow cytometry for cell sorting, nested real-time PCR for HIV-DNA quantification, ELISA and flow cytometry for HIV-p24 quantification. HIV reactivation was induced by TCR-triggering in the presence/absence of all-trans retinoic acid. Results Compared to blood, the frequency of CCR6+ TM was higher in the colon. In both colon and blood compartments, CCR6+ TM were significantly enriched in HIV-DNA when compared to their CCR6− counterparts (n=13). In blood, integrated HIV-DNA levels were significantly enriched in CCR6+ versus CCR6− TCM of 4/5 individuals and CCR6+ versus CCR6− TEM of 3/5 individuals. Among blood TCM, Th17 and Th1Th17 contributed the most to the pool of cells harboring integrated HIV-DNA despite their reduced frequency compared to Th2 which were infected the least. HIV reactivation was induced by TCR triggering and/or retinoic acid exposure at higher levels in CCR6+ versus CCR6− TM, TCM, and TEM. Conclusions CCR6 is a marker for colon and blood CD4+ T-cells enriched for replication-competent HIV-DNA. Novel eradication strategies should target HIV persistence in CCR6+CD4+ T-cells from various anatomic sites.

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Section: Introductionmentioning

confidence: 78%

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

Gosselin

Salinas

Planas

et al. 2017

Aids

130

181

View full text Add to dashboard Cite

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“…10,51 Another group has also recently shown these to be optimal HIV target cells. 52 Furthermore, MIP-3a is increased in the cervix during early HIV infection, 53 and blockade of chemokines including MIP-3a by antiinflammatory glycerol monolaurate prevented nonhuman primates from acquiring Simian immunodeficiency virus infection. 11 However, it is worth noting that as we did not ascertain the cellular source of these protein factors, future experiments will be needed confirm that they originated from neutrophils vs. other immune cells of the mucosa.…”

Section: Discussionmentioning

confidence: 99%

Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells

et al. 2016

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Elevated inflammatory cytokines (EMCs) at mucosal surfaces have been associated with HIV susceptibility, but the underlying mechanisms remain unclear. We characterized the soluble mucosal proteome associated with elevated cytokine expression in the female reproductive tract. A scoring system was devised based on the elevation (upper quartile) of at least three of seven inflammatory cytokines in cervicovaginal lavage. Using this score, HIV-uninfected Kenyan women were classified as either having EMC (n=28) or not (n=68). Of 455 proteins quantified in proteomic analyses, 53 were associated with EMC (5% false discovery rate threshold). EMCs were associated with proteases, cell motility, and actin cytoskeletal pathways, whereas protease inhibitor, epidermal cell differentiation, and cornified envelope pathways were decreased. Multivariate analysis identified an optimal signature of 16 proteins that distinguished the EMC group with 88% accuracy. Three proteins in this signature were neutrophil-associated proteases that correlated with many cytokines, especially GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-1β (interleukin-1β), MIP-3α (macrophage inflammatory protein-3α), IL-17, and IL-8. Gene set enrichment analyses implicated activated immune cells; we verified experimentally that EMC women had an increased frequency of endocervical CD4(+) T cells. These data reveal strong linkages between mucosal cytokines, barrier function, proteases, and immune cell movement, and propose these as potential mechanisms that increase risk of HIV acquisition.

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“…Although the complete understanding and the etiology of epithelial disruption during HIV infection remains unclear, it is known that these tight junctions are breached during HIV infection [6], which has been linked to many immunological influences [9**]. For example, homeostatic T cell subsets are lost very early in infection, including Th17 cells, which are crucial in responding to bacterial antigens [10*,11*]. Indeed, Th17 cells in HIV infection are thought to aid in maintainence of the epithelial barrier by amplifying signals of microbial translocation [12].…”

Section: Introductionmentioning

confidence: 99%

Microbial translocation and microbiome dysbiosis in HIV-associated immune activation

Zevin

McKinnon

Burgener

et al. 2016

Current Opinion in HIV and AIDS

218

149

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Purpose of Review To describe the mechanisms and consequences of both microbial translocation and microbial dysbiosis in HIV infection. Recent Findings Microbes in HIV are likely playing a large role in contributing to HIV pathogenesis, morbidities and mortality. Two major disruptions to microbial systems in HIV infection include microbial translocation and microbiome dysbiosis. Microbial translocation occurs when the bacteria (or bacterial products) that should be in the lumen of the intestine translocate across the tight epithelial barrier into systemic circulation, where they contribute to inflammation and pathogenesis. This is associated with poorer health outcomes in HIV infected individuals. In addition, microbial populations in the GI tract are also altered after HIV infection, resulting in microbiome dysbiosis, which further exacerbates microbial translocation, epithelial barrier disruption, inflammation, and mucosal immune functioning. Summary Altered microbial regulation in HIV infection can lead to poor health outcomes, and understanding the mechanisms underlying microbial dysbiosis and translocation may result in novel pathways for therapeutic interventions.

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Early HIV-1 Infection Is Associated With Reduced Frequencies of Cervical Th17 Cells

Cited by 48 publications

References 21 publications

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells

Microbial translocation and microbiome dysbiosis in HIV-associated immune activation

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