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| 2. |
- Abi-Rached, Laurent, et al.
(författare)
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The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans
- 2011
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 334:6052, s. 89-94
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Tidskriftsartikel (refereegranskat)abstract
- Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.
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| 3. |
- Bradley, Frideborg, et al.
(författare)
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Multi-omics analysis of the cervical epithelial integrity of women using depot medroxyprogesterone acetate
- 2022
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 18:5
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Tidskriftsartikel (refereegranskat)abstract
- Depot medroxyprogesterone acetate (DMPA) is an injectable hormonal contraceptive used by millions of women worldwide. However, experimental studies have associated DMPA use with genital epithelial barrier disruption and mucosal influx of human immunodeficiency virus (HIV) target cells. We explored the underlying molecular mechanisms of these findings. Ectocervical biopsies and cervicovaginal lavage (CVL) specimens were collected from HIV-seronegative Kenyan sex workers using DMPA (n = 32) or regularly cycling controls (n = 64). Tissue samples were assessed by RNA-sequencing and quantitative imaging analysis, whereas protein levels were measured in CVL samples. The results suggested a DMPA-associated upregulation of genes involved in immune regulation, including genes associated with cytokine-mediated signaling and neutrophil-mediated immunity. A transcription factor analysis further revealed DMPA-associated upregulation of RELA and NFKB1 which are involved in several immune activation pathways. Several genes significantly downregulated in the DMPA versus the control group were involved in epithelial structure and function, including genes encoding keratins, small proline-rich proteins, and cell-cell adhesion proteins. Pathway analyses indicated DMPA use was associated with immune activation and suppression of epithelium development, including keratinization and cornification processes. The cervicovaginal microbiome composition (Lactobacillus dominant and non-Lactobacillus dominant) had no overall interactional impact on the DMPA associated tissue gene expression. Imaging analysis verified that DMPA use was associated with an impaired epithelial layer as illustrated by staining for the selected epithelial junction proteins E-cadherin, desmoglein-1 and claudin-1. Additional staining for CD4(+) cells revealed a more superficial location of these cells in the ectocervical epithelium of DMPA users versus controls. Altered protein levels of SERPINB1 and ITIH2 were further observed in the DMPA group. Identification of specific impaired epithelial barrier structures at the gene expression level, which were verified at the functional level by tissue imaging analysis, illustrates mechanisms by which DMPA adversely may affect the integrity of the genital mucosa. Author summarySexual transmission accounts for the majority of all new HIV infections in women, and alterations to the mucosal environment of the female genital tract have been associated with an increase in the risk of acquiring HIV. Observational epidemiological studies have implied that the use of the injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with increased HIV-acquisition. However, a prospective clinical study has not confirmed this association and the controversial findings are currently evaluated in the context of international reproductive health policies. Several studies using various model systems indicate that DMPA affects the integrity of the genital epithelial barrier as well as the mucosal immune system, but the exact mechanisms remain largely unknown. To characterize the effect of DMPA on the genital mucosal environment, we used a multi-omics approach to assess paired genital secretions and cervical tissue samples from long-term regular DMPA users living in Kenya. This unique cohort represents a population at risk of HIV infection in which DMPA is one of the most commonly used hormonal contraceptives. We identified impaired cervical epithelial barrier structures, including DMPA-associated reduction in the expression of cell-cell adhesion molecules, keratins, small proline-rich proteins and a thinner upper epithelial layer with more superficially located CD4(+) cells. Gene set enrichment pathway analyses indicated DMPA use was associated with immune activation and suppression of epithelium development including keratinization and cornification pathways. Protein analysis identified altered levels of selected anti-proteases. Our findings illustrate mechanisms by which DMPA adversely may affect the integrity of the genital mucosa.
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| 4. |
- Edfeldt, Gabriella, et al.
(författare)
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Distinct cervical tissue-adherent and luminal microbiome communities correlate with mucosal host gene expression and protein levels in Kenyan sex workers
- 2023
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Ingår i: Microbiome. - : Springer Nature. - 2049-2618. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The majority of studies characterizing female genital tract microbiota have focused on luminal organisms, while the presence and impact of tissue-adherent ectocervical microbiota remain incompletely understood. Studies of luminal and tissue-associated bacteria in the gastrointestinal tract suggest that these communities may have distinct roles in health and disease. Here, we performed a multi-omics characterization of paired luminal and tissue samples collected from a cohort of Kenyan female sex workers.Results We identified a tissue-adherent bacterial microbiome, with a higher alpha diversity than the luminal microbiome, in which dominant genera overall included Gardnerella and Lactobacillus, followed by Prevotella, Atopobium, and Sneathia. About half of the L. iners-dominated luminal samples had a corresponding Gardnerella-dominated tissue microbiome. Broadly, the tissue-adherent microbiome was associated with fewer differentially expressed host genes than the luminal microbiome. Gene set enrichment analysis revealed that L. crispatus-dominated tissue-adherent communities were associated with protein translation and antimicrobial activity, whereas a highly diverse microbial community was associated with epithelial remodeling and pro-inflammatory pathways. Tissue-adherent communities dominated by L. iners and Gardnerella were associated with lower host transcriptional activity. Tissue-adherent microbiomes dominated by Lactobacillus and Gardnerella correlated with host protein profiles associated with epithelial barrier stability, although with a more pro-inflammatory profile for the Gardnerella-dominated microbiome group. Tissue samples with a highly diverse composition had a protein profile representing cell proliferation and pro-inflammatory activity.Conclusion We identified ectocervical tissue-adherent bacterial communities in all study participants of a female sex worker cohort. These communities were distinct from cervicovaginal luminal microbiota in a significant proportion of individuals. We further revealed that bacterial communities at both sites correlated with distinct host gene expression and protein levels. The tissue-adherent bacterial community could possibly act as a reservoir that seed the lumen with less optimal, non-Lactobacillus, bacteria.
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| 5. |
- Edfeldt, Gabriella, et al.
(författare)
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Regular Use of Depot Medroxyprogesterone Acetate Causes Thinning of the Superficial Lining and Apical Distribution of Human Immunodeficiency Virus Target Cells in the Human Ectocervix
- 2022
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 225:7, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with an increased risk of acquiring human immunodeficiency virus (HIV). We hypothesize that DMPA use influences the ectocervical tissue architecture and HIV target cell localization.MethodsQuantitative image analysis workflows were developed to assess ectocervical tissue samples collected from DMPA users and control subjects not using hormonal contraception.ResultsCompared to controls, the DMPA group exhibited a significantly thinner apical ectocervical epithelial layer and a higher proportion of CD4+CCR5+ cells with a more superficial location. This localization corresponded to an area with a nonintact E-cadherin net structure. CD4+Langerin+ cells were also more superficially located in the DMPA group, although fewer in number compared to the controls. Natural plasma progesterone levels did not correlate with any of these parameters, whereas estradiol levels were positively correlated with E-cadherin expression and a more basal location for HIV target cells of the control group.ConclusionsDMPA users have a less robust epithelial layer and a more apical distribution of HIV target cells in the human ectocervix, which could confer a higher risk of HIV infection. Our results highlight the importance of assessing intact genital tissue samples to gain insights into HIV susceptibility factors.
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| 10. |
- Hasselrot, Tyra, et al.
(författare)
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Vaginal candida infection is associated with host molecular signatures of neutrophil activation in the adjacent ectocervical mucosa in Kenyan sex workers
- 2024
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Ingår i: American Journal of Reproductive Immunology. - 1046-7408 .- 1600-0897. ; 91:2
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Tidskriftsartikel (refereegranskat)abstract
- Problem: Overgrowth of candida species in the human vaginal mucosa causes inflammation, which could render the mucosal barrier more susceptible to HIV infection. Here, we investigated whether this condition also affects the ectocervical mucosa, a potential site of HIV entry, in women at high risk of HIV infection.Method of study: Retrospective medical data and ectocervical tissue samples were obtained from a cohort of Kenyan sex workers. Among 108 women, seven had signs of vaginal candida infection by wet smear microscopy and/or the presence of characteristic discharge. Women lacking these two criteria served as controls. Host transcriptomic profiling and quantitative in situ image analysis of epithelial barrier markers and CD4+ cell distribution were performed.Results: The candida group had 162 differentially expressed genes out of 15 435 genes as compared with the control group. Among these 162 genes, 147 were upregulated and 15 were downregulated. Gene expression pathway analysis indicated associations with an upregulated inflammatory response, defined primarily by markers of neutrophil activation. Transcription factor analysis revealed upregulation of pathways related to RELA/REL/NFKB1, JUN and STAT1 in the candida group. In situ image analysis of ectocervical tissue samples showed no differences between groups in terms of epithelial height, expression of epithelial junction proteins (E-cadherin, claudin-1, zonula occludens 1, and desmoglein-1), or epithelial CD4+ cell distribution.Conclusions: Vaginal candida infection was associated with inflammation and neutrophil infiltration, but not with severe epithelial disruption or CD4+ cell infiltration, in the ectocervical mucosa.
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| 11. |
- Nduva, George M., et al.
(författare)
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Phylogeographic Assessment Reveals Geographic Sources of HIV-1 Dissemination Among Men Who Have Sex With Men in Kenya
- 2022
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 transmission dynamics involving men who have sex with men (MSM) in Africa are not well understood. We investigated the rates of HIV-1 transmission between MSM across three regions in Kenya: Coast, Nairobi, and Nyanza. We analyzed 372 HIV-1 partial pol sequences sampled during 2006–2019 from MSM in Coast (N = 178, 47.9%), Nairobi (N = 137, 36.8%), and Nyanza (N = 57, 15.3%) provinces in Kenya. Maximum-likelihood (ML) phylogenetics and Bayesian inference were used to determine HIV-1 clusters, evolutionary dynamics, and virus migration rates between geographic regions. HIV-1 sub-subtype A1 (72.0%) was most common followed by subtype D (11.0%), unique recombinant forms (8.9%), subtype C (5.9%), CRF 21A2D (0.8%), subtype G (0.8%), CRF 16A2D (0.3%), and subtype B (0.3%). Forty-six clusters (size range 2–20 sequences) were found—half (50.0%) of which had evidence of extensive HIV-1 mixing among different provinces. Data revealed an exponential increase in infections among MSM during the early-to-mid 2000s and stable or decreasing transmission dynamics in recent years (2017–2019). Phylogeographic inference showed significant (Bayes factor, BF > 3) HIV-1 dissemination from Coast to Nairobi and Nyanza provinces, and from Nairobi to Nyanza province. Strengthening HIV-1 prevention programs to MSM in geographic locations with higher HIV-1 prevalence among MSM (such as Coast and Nairobi) may reduce HIV-1 incidence among MSM in Kenya.
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| 12. |
- Nduva, George M., et al.
(författare)
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Quantifying rates of HIV-1 flow between risk groups and geographic locations in Kenya : A country-wide phylogenetic study
- 2022
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Ingår i: Virus Evolution. - : Oxford University Press (OUP). - 2057-1577. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- In Kenya, HIV-1 key populations including men having sex with men (MSM), people who inject drugs (PWID) and female sex workers (FSW) are thought to significantly contribute to HIV-1 transmission in the wider, mostly heterosexual (HET) HIV-1 transmission network. However, clear data on HIV-1 transmission dynamics within and between these groups are limited. We aimed to empirically quantify rates of HIV-1 flow between key populations and the HET population, as well as between different geographic regions to determine HIV-1 'hotspots' and their contribution to HIV-1 transmission in Kenya. We used maximum-likelihood phylogenetic and Bayesian inference to analyse 4058 HIV-1 pol sequences (representing 0.3 per cent of the epidemic in Kenya) sampled 1986-2019 from individuals of different risk groups and regions in Kenya. We found 89 per cent within-risk group transmission and 11 per cent mixing between risk groups, cyclic HIV-1 exchange between adjoining geographic provinces and strong evidence of HIV-1 dissemination from (i) West-to-East (i.e. higher-to-lower HIV-1 prevalence regions), and (ii) heterosexual-to-key populations. Low HIV-1 prevalence regions and key populations are sinks rather than major sources of HIV-1 transmission in Kenya. Targeting key populations in Kenya needs to occur concurrently with strengthening interventions in the general epidemic.
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| 13. |
- Nduva, George M., et al.
(författare)
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Temporal trends and transmission dynamics of pre-treatment HIV-1 drug resistance within and between risk groups in Kenya, 1986–2020
- 2024
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Ingår i: Journal of Antimicrobial Chemotherapy. - 0305-7453. ; 79:2, s. 287-296
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence on the distribution of pre-treatment HIV-1 drug resistance (HIVDR) among risk groups is limited in Africa. We assessed the prevalence, trends and transmission dynamics of pre-treatment HIVDR within and between MSM, people who inject drugs (PWID), female sex workers (FSWs), heterosexuals (HETs) and perinatally infected children in Kenya. Methods: HIV-1 partial pol sequences from antiretroviral-naive individuals collected from multiple sources between 1986 and 2020 were used. Pre-treatment reverse transcriptase inhibitor (RTI), PI and integrase inhibitor (INSTI) mutations were assessed using the Stanford HIVDR database. Phylogenetic methods were used to determine and date transmission clusters. Results: Of 3567 sequences analysed, 550 (15.4%, 95% CI: 14.2–16.6) had at least one pre-treatment HIVDR mutation, which was most prevalent amongst children (41.3%), followed by PWID (31.0%), MSM (19.9%), FSWs (15.1%) and HETs (13.9%). Overall, pre-treatment HIVDR increased consistently, from 6.9% (before 2005) to 24.2% (2016–20). Among HETs, pre-treatment HIVDR increased from 6.6% (before 2005) to 20.2% (2011–15), but dropped to 6.5% (2016–20). Additionally, 32 clusters with shared pre-treatment HIVDR mutations were identified. The majority of clusters had R0 ≥ 1.0, indicating ongoing transmissions. The largest was a K103N cluster involving 16 MSM sequences sampled between 2010 and 2017, with an estimated time to the most recent common ancestor (tMRCA) of 2005 [95% higher posterior density (HPD), 2000–08], indicating propagation over 12 years. Conclusions: Compared to HETs, children and key populations had higher levels of pre-treatment HIVDR. Introduction of INSTIs after 2017 may have abrogated the increase in pre-treatment RTI mutations, albeit in the HET population only. Taken together, our findings underscore the need for targeted efforts towards equitable access to ART for children and key populations in Kenya.
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| 14. |
- Rohl, Maria, et al.
(författare)
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HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment
- 2021
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Ingår i: Vaccines. - : MDPI AG. - 2076-393X. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- 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(+)CD25(hi)FoxP3(+)CD127(lo)CD4(+) 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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| 15. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 16. |
- Wang, Haidong, et al.
(författare)
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Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015 : the Global Burden of Disease Study 2015.
- 2016
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Ingår i: The lancet. HIV. - : Elsevier. - 2352-3018. ; 3:8, s. e361-e387
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.METHODS: For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification.FINDINGS: Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95% uncertainty interval [UI] 3·1-3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5-2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6-40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7-1·9 million) in 2005, to 1·2 million deaths (1·1-1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections.INTERPRETATION: Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030.
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