Genetic and epigenetic regulation of natural resistance to HIV-1 infection: new approaches to unveil the HESN secret

Fenizia, Claudio; Saulle, Irma; Clerici, Mario; Biasin, Mara

doi:10.1080/1744666x.2020.1732820

Cited by 10 publications

(8 citation statements)

References 176 publications

(195 reference statements)

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“…It is also important to underline that following long-term antiretroviral therapy HIV-patients display an altered lipid profile which can result in dyslipidemia [44], and that disease progression was shown to be delayed in HIV-infected patients showing increased cholesterol metabolism and reduced cholesterol synthesis [45][46][47]. being mediated by the upregulation of several ISGs [3,4,21] among which, CH25H is suggested to play a pivotal role. The expression of this enzyme, which catalyzes the formation of 25HC from cholesterol [48] was, indeed, significantly augmented in both uninfected and in vitro HIV-1-infected PBMCs and MDMs from HESN and is likely to be at least in part responsible for the 25HC-dependent upregulation of LXR and downregulation of SREBP1 [21,35], as we observed in our experimental setting.…”

Section: Discussionmentioning

confidence: 99%

“…These individuals, referred to as HIV-1-exposed seronegative (HESN) have the extraordinary capacity to remain HIV-1 uninfected despite frequent risk behaviors, including injection drug use with needle sharing or sexual intercourse with infected partners [1,2]. Natural protection to HIV-1 infection has been associated with a wide range of genetic and immunological factors [3][4][5]. In particular, several publications reported a strong correlation between HIV-1 infection, resistance and the presence of an immune activation status [4,6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Among the different immunological factors thus far correlated with the HESN phenotype, Type-I Interferons seem to play a crucial role in controlling HIV-1 infection [3,4,[16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Sterol metabolism modulates susceptibility to HIV-1 Infection

Saulle

Ibba²,

Vittori³

et al. 2020

Aids

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Background 25-hydroxylase (CH25H) is an Interferon stimulated gene (ISG), which catalyzes the synthesis of 25-Hydroxycholesterol (25HC). 25HC intervenes in metabolic and infectious processes as controls cholesterol homeostasis and influences viral entry into host cells. We verified whether natural resistance to HIV-1 infection in HIV-1-exposed seronegative (HESN) individuals is at least partially mediated by particularities in sterol biosynthesis. Methods Peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) isolated from 15 sexually-exposed HESN and 15 healthy controls (HC) were in vitro HIV-1infected and analyzed for: 1) percentage of IFN-producing plasmacytoid Dendritic Cells (pDCs); 2) Cholesterol signaling and inflammatory response RNA expression; 3) resistance to HIV-1 infection. MDMs from 5 HC were in vitro HIV-1-infected in the absence/presence of exogenously added 25HC. Results IFN-producing pDCs were augmented in HESN compared to HCs both in unstimulated and in in vitro HIV-1-infected PBMCs (p<0.001). An increased expression of CH25H and of a number of genes involved in cholesterol metabolism (ABCA1, ABCG1, CYP7B1, LXR, OSBP, PPARSCARB1) was observed as well; this, was associated with a reduced susceptibility to in vitro HIV-1-infection of PBMCs and MDMs (p<0.01). Notably, addition of 25HC to MDMs resulted in increased cholesterol efflux and augmented resistance to in vitro HIV-1-infection. Conclusions Results herein show that in HESN sterol metabolism might be particularly efficient. This could be related to the activation of the IFN pathway and results into a reduced susceptibility to in vitro HIV-1 infection. These results suggest a possible basis for therapeutic interventions to modulate HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sterol metabolism modulates susceptibility to HIV-1 Infection

Saulle

Ibba²,

Vittori³

et al. 2020

Aids

Self Cite

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“…Such high-risk subjects are referred to as HIV-exposed seronegative (HESN) individuals and include sex workers, HIV-status discordant couples, intravenous drug users, and children born to untreated HIV-infected mothers. Relative resistance to HIV infection is likely multi-factorial and several studies have identified innate immune and anti-inflammatory factors, HIV-specific T-and B-cell responses, increased regulatory T-and B-cell activity as well as genetic and epigenetic correlates to this phenotype [2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

et al. 2021

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Immunological correlates of natural resistance to HIV have been identified in HIV-exposed seronegative (HESN) individuals and include a low-inflammatory genital mucosal status. The cervicovaginal epithelium has not been studied for such correlates despite constituting an important barrier against sexual HIV transmission. To fill this gap in knowledge, we collected samples of blood, cervical mononuclear cells, cervicovaginal lavage, and ectocervical tissue from Kenyan HESN sex workers (n = 29) and controls (n = 33). The samples were analyzed by flow cytometry, protein profiling, 16S rRNA gene sequencing, in situ image analysis, and tissue-based RNA sequencing. A significantly higher relative proportion of regulatory T cells in blood (B7+CD25hiFoxP3+CD127loCD4+ and B7+Helios+FoxP3+CD4+), and a significantly lower proportion of activated cervical T cells (CCR5+CD69+CD4+ and CCR5+CD69+CD8+), were found in the HESN group compared with the controls. In contrast, there were no statistically significant differences between the study groups in cervicovaginal protein and microbiome compositions, ectocervical epithelial thickness, E-cadherin expression, HIV receptor expression, and tissue RNA transcriptional profiles. The identification of an intact ectocervical microenvironment in HESN individuals add new data to current knowledge about natural resistance to sexual transmission of HIV.

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“…Whether these reflect an unknown resistance to infection in selected population subsets is currently unknown. Recruited caregivers may have personal factors that do not allow SARS-CoV-2 infection as demonstrated in HIV infection where genetic and epigenetic factors are involved in natural resistance to infection ( 14 ). Further investigations are needed to evaluate these factors.…”

Section: Discussionmentioning

confidence: 99%

No Spread of SARS-CoV-2 From Infected Symptomatic Children to Parents: A Prospective Cohort Study in a Controlled Hospital Setting

et al. 2021

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Introduction: The transmission rates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from children to adults are unclear due to a lack of controlled conditions.Materials and Methods: We investigated the occurrence of SARS-CoV-2 transmission among 12 discordant child-parent pairs in our ward. In each hospital isolation room, caregivers and children lived in close contact during the entire hospitalization period.Results: A total of 136 swab-positive children (mean age, 3.6 ± 4.9 median age, 1; IQR 0–6.2, range 0.1–17) attended by their caregivers were hospitalized. Of those, 12/136 (8.8%, mean age, 6.1 ± 5.3 median age, 4.5) were attended by caregivers who were swab and serology negative at admission despite previous close contact with positive children at home. Three children were completely dependent on their mothers, one of whom was being breastfed. The mean duration of overall exposure to the index case was 20.5 ± 8.2 days.Conclusion: None of the infected children transmitted SARS-CoV-2 infection to their caregivers, raising the hypothesis of a cluster of resistant mothers or of limited transmission from children to adults despite prolonged exposure and close contact. These data might provide reassurance regarding school openings and offer the chance of investigating SARS-CoV-2 variants in the future under the same quasi-experimental conditions.

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Genetic and epigenetic regulation of natural resistance to HIV-1 infection: new approaches to unveil the HESN secret

Cited by 10 publications

References 176 publications

Sterol metabolism modulates susceptibility to HIV-1 Infection

Sterol metabolism modulates susceptibility to HIV-1 Infection

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

No Spread of SARS-CoV-2 From Infected Symptomatic Children to Parents: A Prospective Cohort Study in a Controlled Hospital Setting

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