Soluble Toll-like receptor 2 is significantly elevated in HIV-1 infected breast milk and inhibits HIV-1 induced cellular activation, inflammation and infection

Henrick, Bethany M.; Yao, Xiao‐Dan; Drannik, Anna G.; Abimiku, Alash’le; Rosenthal, Kenneth L.

doi:10.1097/qad.0000000000000381

Cited by 18 publications

(42 citation statements)

References 39 publications

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“…Given that multiple viruses induce immune activation via TLR2 as a means to facilitate entry ( 36 , 38 , 39 ), as well as our recent paper which showed that soluble TLR2 (sTLR2) directly interacted with HIV-1 structural proteins ( 45 ), we explored whether cellular expression of TLR2 increased cell-free HIV-1 integration and viral-induced inflammation.…”

Section: Resultsmentioning

confidence: 99%

“…However, we previously demonstrated that following cART and subsequent decrease in viral load, TLR expression in previously untreated HIV-infected individuals normalized, thus suggesting that HIV itself may be involved in increased activation ( 12 ). Additionally, we recently showed that soluble TLR2 (sTLR2), which is found in human milk, other mucosal fluids, and systemically, inhibited HIV infection in vitro ( 44 ), through a direct interaction with HIV-1 structural proteins, and inhibited virally induced NFκB activation and inflammation ( 45 ). These findings led us to ask a rather simple but important question, namely, do HIV-1 structural proteins act as PAMPs for TLR2 and its heterodimers?…”

Section: Discussionmentioning

confidence: 99%

“…Specifically regarding HIV, Thibault et al ( 40 ) described that detection of pathogen-derived products through TLR2 induced an effector phenotype in naïve and memory CD4+ T cells and increased HIV replication ( 40 ). Conversely, the extracellular portion of TLR2, which is found systemically and in mucosal fluids, significantly inhibits pro-inflammatory cytokine production ( 41 – 43 ) and directly inhibits cell-free HIV-1 infection in vitro ( 44 , 45 ). Moreover, we previously demonstrated that soluble TLR2 (sTLR2) directly interacts with HIV-1 p17, p24, and gp41 and inhibits viral protein-induced NFκB activation and inflammation ( 45 ).…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, the extracellular portion of TLR2, which is found systemically and in mucosal fluids, significantly inhibits pro-inflammatory cytokine production ( 41 – 43 ) and directly inhibits cell-free HIV-1 infection in vitro ( 44 , 45 ). Moreover, we previously demonstrated that soluble TLR2 (sTLR2) directly interacts with HIV-1 p17, p24, and gp41 and inhibits viral protein-induced NFκB activation and inflammation ( 45 ). These findings led us to further hypothesize that structural proteins of HIV-1 may serve as PAMPs for cellular TLR2 heterodimers.…”

Section: Introductionmentioning

confidence: 99%

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HIV-1 Structural Proteins Serve as PAMPs for TLR2 Heterodimers Significantly Increasing Infection and Innate Immune Activation

2015

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Immune activation is critical to HIV infection and pathogenesis; however, our understanding of HIV innate immune activation remains incomplete. Recently we demonstrated that soluble TLR2 (sTLR2) physically inhibited HIV-induced NFκB activation and inflammation, as well as HIV-1 infection. In light of these findings, we hypothesized that HIV-1 structural proteins may serve as pathogen-associated molecular patterns (PAMPs) for cellular TLR2 heterodimers. These studies made use of primary human T cells and TZMbl cells stably transformed to express TLR2 (TZMbl-2). Our results demonstrated that cells expressing TLR2 showed significantly increased proviral DNA compared to cells lacking TLR2, and mechanistically this may be due to a TLR2-mediated increased CCR5 expression. Importantly, we show that HIV-1 structural proteins, p17, p24, and gp41, act as viral PAMPs signaling through TLR2 and its heterodimers leading to significantly increased immune activation via the NFκB signaling pathway. Using co-immunoprecipitation and a dot blot method, we demonstrated direct protein interactions between these viral PAMPs and TLR2, while only p17 and gp41 bound to TLR1. Specifically, TLR2/1 heterodimer recognized p17 and gp41, while p24 lead to immune activation through TLR2/6. These results were confirmed using TLR2/1 siRNA knock down assays which ablated p17 and gp41-induced cellular activation and through studies of HEK293 cells expressing selected TLRs. Interestingly, our results show in the absence of TLR6, p24 bound to TLR2 and blocked p17 and gp41-induced activation, thus providing a novel mechanism by which HIV-1 can manipulate innate sensing. Taken together, our results identified, for the first time, novel HIV-1 PAMPs that play a role in TLR2-mediated cellular activation and increased proviral DNA. These findings have important implications for our fundamental understanding of HIV-1 immune activation and pathogenesis, as well as HIV-1 vaccine development.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HIV-1 Structural Proteins Serve as PAMPs for TLR2 Heterodimers Significantly Increasing Infection and Innate Immune Activation

2015

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“…49 The binding of sTLR2 to HIV-1 proteins in HIV-1 infected mother breast milk prevent a TLR2-dependent increase in chemokine receptor 5 expression, thus resulting in significant reduction of HIV-1 infection. 50 The concentration of erythropoietin, a factor with trophic effects on infant gut epithelia studied within a cohort of antiretroviralnaïve HIV infected Tanzanian women, suggest a protective effect against MTCT. 51 HIV gag -specific IFN-γ cellular immune responses from breastmilk of these Tanzanian were prevalent and may contribute to protection from early HIV transmission.…”

Section: Breast Milk Constituents May Provide Inside Of the Post-par-mentioning

confidence: 99%

Host molecular factors and viral genotypes in the mother-to-child HIV-1 transmission in sub-Saharan Africa

Mouafo

Dambaya

Ngoufack

et al. 2017

J Public Health Afr

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Maternal viral load and immune status, timing and route of delivery, viral subtype, and host genetics are known to influence the transmission, acquisition and disease progression of human immunodeficiency virus-1 (HIV-1) infection. This review summarizes the findings from published works on host molecular factors and virus genotypes affecting mother to child transmission (MTCT) in Africa and identifies the gaps that need to be addressed in future research. Articles in PubMed, Google and AIDSearch and relevant conference abstracts publications were searched. Accessible articles on host factors and viral genetics impacting the MTCT of HIV, done on African populations till 2015 were downloaded. Forty-six articles were found and accessed; 70% described host genes impacting the transmission. The most studied gene was the CCR5 promoter, followed by the CCR2-64I found to reduce MTCT; then SDF1-3’A shown to have no effect on MTCT and others like the DC-SIGNR, CD4, CCL3 and IP-10. The HLA class I was most studied and was generally linked to the protective effect on MTCT. Breast milk constituents were associated to protection against MTCT. However, existing studies in Sub Saharan Africa were done just in few countries and some done without control groups. Contradictory results obtained may be due to different genetic background, type of controls, different socio-cultural and economic environment and population size. More studies are thus needed to better understand the mechanism of transmission or prevention.

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Impact of maternal HIV exposure, feeding status, and microbiome on infant cellular immunity

Dzanibe

Jaspan

Zulu

et al. 2018

Journal of Leukocyte Biology

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At least one-third of infants born in sub-Saharan Africa have been exposed to the effects of maternal HIV infection and antiretroviral treatment. Intrauterine HIV exposure is associated with increased rates of morbidity and mortality in children. Although the mechanisms responsible for poor infant health with HIV-1 exposure are likely to be multifactorial, we posit that the maternal environment during gestation and in the perinatal period results in altered infant immunity and is possibly the strongest contributing factor responsible for the disproportionally high infectious events among HIV-exposed infants who remain HIV uninfected. This review provides a synthesis of studies reporting the impact of intrauterine HIV exposure, feeding practices, and microbiota on immune ontogeny in the first year of life in HIV-exposed uninfected infants.

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Soluble Toll-like receptor 2 is significantly elevated in HIV-1 infected breast milk and inhibits HIV-1 induced cellular activation, inflammation and infection

Abstract: These results indicate novel mechanisms by which sTLR2 plays a critical role in inhibiting mother-to-child HIV transmission.

Cited by 18 publications

References 39 publications

HIV-1 Structural Proteins Serve as PAMPs for TLR2 Heterodimers Significantly Increasing Infection and Innate Immune Activation

HIV-1 Structural Proteins Serve as PAMPs for TLR2 Heterodimers Significantly Increasing Infection and Innate Immune Activation

Host molecular factors and viral genotypes in the mother-to-child HIV-1 transmission in sub-Saharan Africa

Impact of maternal HIV exposure, feeding status, and microbiome on infant cellular immunity

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