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Comparable V?2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals.

ABSTRACT: Crosstalk between innate and adaptive pathways is a critical component to developing an effective, lasting immune response. Among natural effector cells, innate-like ?? T cells promote immunity by facilitating communication between the two compartments and exerting cytotoxic effector functions. Dysregulation of ?? T cell populations is a byproduct of primary Humanimmunodeficiency virus (HIV) infection. This is most pronounced in the depletion and loss of function within cells expressing a V?9V?2 TCR (V?2 cells). Whether or not prolonged viral suppression mediated by antiretroviral therapy (ART) can reverse these effects has yet to be determined. In this study, we present evidence of similar V?2 cell functional responses within a cohort of people living with HIV (PLWH) that has been stably suppressed for >1 year and uninfected donors. Through the use of aminobisphosphonate drugs, we were able to generate a comprehensive comparison between ex vivo and expanded V?2 cells within each group. Both groups had largely similar compositions of memory and effector phenotypes, post-expansion TCR repertoire diversity, and cytotoxic capabilities. Our findings support the notion that ART promotes the recovery of V?2 polyfunctionality and provides insight for strategies aiming to reconstitute the full immune response after infection with HIV.

SUBMITTER: Clohosey ML

PROVIDER: S-EPMC7760715 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Comparable Vδ2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals.

Clohosey Matthew L ML Mann Brendan T BT Ryan Paul L PL Apanasovich Tatiyana V TV Maggirwar Sanjay B SB Pennington Daniel J DJ Soriano-Sarabia Natalia N

Cells 20201201 12

Crosstalk between innate and adaptive pathways is a critical component to developing an effective, lasting immune response. Among natural effector cells, innate-like γδ T cells promote immunity by facilitating communication between the two compartments and exerting cytotoxic effector functions. Dysregulation of γδ T cell populations is a byproduct of primary Humanimmunodeficiency virus (HIV) infection. This is most pronounced in the depletion and loss of function within cells expressing a Vγ9Vδ2 ...[more]

PMID: 33271808

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Project description:BACKGROUNDPeople living with HIV (PLHIV) receiving antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to development of cardiovascular diseases (CVDs). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy control participants (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV.METHODSProximity extension assay technology was used to measure 1,472 plasma proteins. Markers of systemic inflammation (C-reactive protein, D-dimer, IL-6, soluble CD14, and soluble CD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for development of CVD during a 5-year follow-up.RESULTSPLHIV receiving ART had systemic dysregulation of protein concentrations, compared with HCs. Most of the DEPs originated from the intestine and lymphoid tissues and were enriched in immune- and lipid metabolism-related pathways. DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD during 5-year follow-up.CONCLUSIONOur findings suggest a systemic dysregulation of protein concentrations in PLHIV; some proteins were associated with CVD development. Most DEPs originated from the gut and were related to specific gut bacterial species.TRIAL REGISTRATIONClinicalTrials.gov NCT03994835.FUNDINGAIDS-fonds (P-29001), ViiV healthcare grant (A18-1052), Spinoza Prize (NWO SPI94-212), European Research Council (ERC) Advanced grant (grant 833247), and Indonesia Endowment Fund for Education.

Project description:ObjectiveInflammation may contribute to brain white matter health in people living with HIV who report cognitive symptoms despite adherence to combination antiretroviral therapy and viral suppression. We explored relationships between diffusion tensor imaging (DTI) metrics of white matter, plasma biomarkers of immune activation, and cognitive function in the HIV-infected population.DesignRetrospective study of older adults living with HIV who are combination antiretroviral therapy adherent, virally suppressed, and self-report cognitive symptoms.MethodsMRI, blood draws, and standardized neuropsychological test scores were collected from HIV-infected individuals. DTI metrics (fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity) and plasma biomarkers (soluble CD163, soluble CD14, neopterin, IFN γ-induced protein 10, monocyte chemoattractant protein 1) were quantified. Statistical analysis explored associations between biomarker levels or neuropsychological test scores and DTI metrics using region of interest analyses and a voxelwise approach.ResultsA total of 43 participants with median (interquartile range) age of 64 (62-66 years), CD4 cell count of 600 (400-760 cell/μl) who were all virally suppressed (<100 copies/ml) were selected. Higher levels of monocyte chemoattractant protein 1 associated with lower fractional anisotropy and higher mean diffusivity (P < 0.05) across white matter tracts including corpus callosum, corona radiata, and superior longitudinal fasciculus. Higher neopterin associated with higher mean diffusivity in the genu of corpus callosum, and higher soluble CD14 associated with lower fractional anisotropy in the bilateral superior corona radiata (P < 0.05). Worse global performance and speed domain scores associated with higher mean diffusivity and lower fractional anisotropy, and worse executive domain scores associated with lower fractional anisotropy (P < 0.05).ConclusionElevated inflammatory plasma biomarkers link to white matter abnormalities among virally suppressed individuals. DTI abnormalities associate to cognitive performance. We conclude that inflammatory processes impact clinically relevant brain health indices despite viral suppression.

Project description:BackgroundThe longitudinal rate and profile of cognitive decline in persons with stable, treated, and virally suppressed HIV infection is not established. To address this question, the current study quantifies the rate of cognitive decline in a cohort of virally suppressed HIV+ persons using clinically relevant definitions of decline, and determine cognitive trajectories taking into account historical and baseline HAND status.MethodsNinety-six HIV+ (clinically stable and virally undetectable) and 44 demographically comparable HIV- participants underwent standard neuropsychological testing at baseline and 18-months follow-up. We described clinically relevant cognitive trajectories based on standard definitions of historical and baseline HAND status and cognitive decline. Historical, moderate to severe HAND was formally diagnosed at the start of the cART era in 15/96 participants based on clinical neurological and neuropsychological assessment. The same standard of care has been applied to all participants at St. Vincent's Hospital Infectious Disease Department for the duration of their HIV infection (median of 20 years).ResultsRelative to HIV- controls (4.5%), 14% of HIV+ participants declined (p = .11), they also scored significantly lower on the global change score (p = .03), processing speed (p = .02), and mental flexibility/inhibition (p = .02) domains. Having HAND at baseline significantly predicted cognitive decline at follow up (p = .005). We determined seven clinically relevant cognitive trajectories taking into account whether participant has a history of HAND prior to study entry (yes/no); their results on the baseline assessment (baseline impairment: yes/no) and their results on the 18-month follow up (decline or stable) which in order of prevalence were: 1) No HAND history, no baseline impairment, 18-month follow-up stable (39%), 2) No HAND history, baseline impairment, 18-month follow-up stable (35%), 3) History of HAND; baseline impairment, 18-month follow-up stable (9%) 4) No history of HAND, baseline impairment, 18-month follow-up decline (7%), 5) History of HAND, no baseline impairment, 18-month follow-up stable (3%), 6) No HAND history, no baseline impairment, 18-month follow-up decline (3%) 7) History of HAND, baseline impairment, 18-month follow-up decline (3%). There was no relationship between cognitive decline (taking into account historical and baseline HAND) and traditional HIV disease biomarkers.ConclusionsDespite long-term viral suppression, we found mostly subclinical levels of decline in psychomotor speed and executive functioning (mental flexibility and cognitive inhibition); well-established markers of HAND progression. Moreover, 57% of our cohort is undergoing slow evolution of their disease, challenging the notion of prevalent neurocognitive stability in virally suppressed HIV infection.

Project description:ObjectiveThe aim of the study was to determine whether exclusive breastfeeding or exclusive formula feeding is more cost-effective when a Canadian mother with HIV is adherent to antiretroviral therapy and has full virologic suppression.DesignCurrent Canadian guidelines recommend that mothers with HIV practice exclusive formula feeding. This contradicts the updated World Health Organization (WHO) guidelines which recommend that mothers with HIV should breastfeed for ≥12 months while receiving support for antiretroviral therapy adherence. Due to the economic and health risks and benefits associated with each modality, there remains expert disagreement on whether the WHO recommendations should be adopted in high-income countries.MethodsA microsimulation model was developed to estimate lifetime costs and effectiveness (i.e., infant's quality-adjusted life years) of a hypothetical group of 1,000,000 initially healthy, HIV-negative infants, if the mother with HIV was on antiretroviral therapy with full virologic suppression and either exclusive breastfeeding or exclusive formula feeding. The model was developed from the economic perspective of the Ontario Ministry of Health, taking into account direct costs associated with infant feeding modality as well as related indirect costs born out of the child's lifetime health outcomes. Uncertainties related to model parameters were evaluated using one-way and probabilistic sensitivity analyses.ResultsIn comparison to exclusive formula feeding, exclusive breastfeeding was the dominant feeding modality (i.e., less costly and more effective) yielding cost-savings of $13,812 per additional quality-adjusted life year gained. Neither one-way nor probabilistic sensitivity analyses altered the conclusions.ConclusionsDespite the risk of HIV transmission, exclusive breastfeeding was more cost-effective than exclusive formula feeding. These findings merit review of current infant feeding guidelines for mothers with HIV living in high-income countries.

Dataset Information

Comparable V?2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals.

Publications

Comparable Vδ2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals.

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