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Loss of CXCR4 on non-classical monocytes in participants of the Women's Interagency HIV Study (WIHS) with subclinical atherosclerosis.

ABSTRACT: AIMS:To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women. METHODS AND RESULTS:sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into four sets (n?=?23 each) by HIV and sCVD status (HIV-/sCVD-, HIV-/sCVD+, HIV+/sCVD-, and HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometry was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the four groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression [median fluorescence intensity (MFI)] in non-classical monocytes was highest among HIV-/CVD- [628, interquartile range (IQR) (295-1389)], followed by HIV+/CVD- [486, IQR (248-699)], HIV-/CVD+ (398, IQR (89-901)), and lowest in HIV+/CVD+ women [226, IQR (73-519)), P?=?0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV-/CVD- vs. HIV+/CVD+ remained significant with P?=?0.005 (HIV-/CVD- vs. HIV+/CVD- P?=?0.04, HIV-/CVD- vs. HIV-/CVD+ P?=?0.06, HIV+/CVD+ vs. HIV+/CVD- P?=?0.88, HIV+/CVD+ vs. HIV-/CVD+ P?=?0.81, HIV+/CVD- vs. HIV-/CVD+, P?=?0.99). All pairwise comparisons with HIV-/CVD- were individually significant (P?=?0.050 vs. HIV-/CVD+, P?=?0.028 vs. HIV+/CVD-, P?=?0.009 vs. HIV+/CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD- (501.5, IQR (249.5-887.3)) vs. CVD+ (297, IQR (81.75-626.8) individuals (P?=?0.028, n?=?46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV-related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P?

SUBMITTER: Mueller KAL

PROVIDER: S-EPMC6735712 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Loss of CXCR4 on non-classical monocytes in participants of the Women's Interagency HIV Study (WIHS) with subclinical atherosclerosis.

Mueller Karin A L KAL Hanna David B DB Ehinger Erik E Xue Xiaonan X Baas Livia L Gawaz Meinrad P MP Geisler Tobias T Anastos Kathryn K Cohen Mardge H MH Gange Stephen J SJ Heath Sonya L SL Lazar Jason M JM Liu Chenglong C Mack Wendy J WJ Ofotokun Igho I Tien Phyllis C PC Hodis Howard N HN Landay Alan L AL Kaplan Robert C RC Ley Klaus K

Cardiovascular research 20190501 6

<h4>Aims</h4>To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women.<h4>Methods and results</h4>sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into four sets (n = 23 each) by HIV and sCVD statu ...[more]

PMID: 30520941

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Project description:Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples.

Project description:Bacterial vaginosis (BV) is the most common female reproductive tract infection and is associated with an increased risk of acquiring and transmitting HIV by a mechanism that is not well understood. Gamma delta (GD) T cells are essential components of the adaptive and innate immune system, are present in the female reproductive tract, and play an important role in epithelial barrier protection. GD1 cells predominate in the mucosal tissue and are important in maintaining mucosal integrity. GD2 cells predominate in peripheral blood and play a role in humoral immunity and in the immune response to pathogens. HIV infection is associated with changes in GD T cells frequencies in the periphery and in the female reproductive tract. The objective of this study is to evaluate if changes in vaginal flora occurring with BV are associated with changes in endocervical GD T cell responses, which could account for increased susceptibility to HIV. Seventeen HIV-infected (HIV+) and 17 HIV-uninfected (HIV-) pre-menopausal women underwent collection of vaginal swabs and endocervical cytobrushes. Vaginal flora was assessed using the Nugent score. GD T cells were assessed in cytobrush samples by flow cytometry. Median Nugent score was 5.0 and 41% of women had abnormal vaginal flora. In HIV uninfected women there was a negative correlation between Nugent score and cervical GD1 T cells (b for interaction = - 0.176, p<0.01); cervical GD1 T cells were higher in women with normal vaginal flora than in those with abnormal flora (45.00% vs 9.95%, p = 0.005); and cervical GD2 T cells were higher in women with abnormal flora than in those with normal flora (1.70% vs 0.35%, p = 0.023). GD T cells in the genital tract are protective (GD1) and are targets for HIV entry (GD2). The decrease in cervical GD1 and increase in GD2 T cells among women with abnormal vaginal flora predisposes women with BV to HIV acquisition. We propose to use GD T cell as markers of female genital tract vulnerability to HIV.

Dataset Information

Loss of CXCR4 on non-classical monocytes in participants of the Women's Interagency HIV Study (WIHS) with subclinical atherosclerosis.

Publications

Loss of CXCR4 on non-classical monocytes in participants of the Women's Interagency HIV Study (WIHS) with subclinical atherosclerosis.

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