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1.  Association of Chronic Hepatitis C Infection with T-Cell Phenotypes in HIV-Negative and HIV-Positive Women 
Background
Hepatitis C virus (HCV) viremia is thought to have broad, systemic effects on the cellular immune system that go beyond its impact on just those T-cells that are HCV-specific. However, prior studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV-negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV-positives did not address overall immune status (total CD4+ count).
Methods
We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4+ and CD8+ T-cells, Tregs, and T-cell differentiation phenotypes (naïve, central memory (CM), effector memory (EM), and terminally differentiated effector). This included 158 HIV-negatives and 464 HIV-positives, of whom 18 and 63, respectively, were HCV viremic.
Results
In multivariate models of HIV-negatives, HCV viremia was associated with 25% fewer naïve CD4+ (P=0.03), 33% more EM CD4+ (P=0.0002) and 37% fewer CM CD8+ (P=0.02) T-cells. Among HIV-positives we observed only one of these three relationships: higher percentage of EM CD4+ among HCV viremic women. Further, the association with EM CD4+ among HIV-positives was limited to individuals with diminished immune status (total CD4+ count ≤500 cells/μL), as were associations of HCV viremia with higher percentages of activated CD4+ and Tregs. Among HIV-positives with high CD4+ count, no significant associations were observed.
Conclusions
These data suggest that HCV viremia in HIV-negatives is associated with accelerated T-cell differentiation, but among HIV-positives the impact of HCV viremia is less straightforward and varies by total CD4+ count.
doi:10.1097/QAI.0000000000000310
PMCID: PMC4197408  PMID: 25314250
hepatitis C virus; HIV; T-cell; phenotype; activation; differentiation
2.  T-cell Activation, Both Pre- and Post-HAART Levels, Correlates with Carotid Artery Stiffness over 6.5 years among HIV-infected Women in the WIHS 
Objective
T-cell activation is a major pathway driving HIV disease progression. Little is known regarding the impact of T-cell activation on HIV-associated atherosclerosis and cardiovascular disease, a common co-morbidity in HIV infection. We hypothesized that T-cell activation will predict vascular stiffness, a measure of subclinical atherosclerosis.
Design
Linear regression models evaluated the covariate-adjusted association of T-cell activation with vascular stiffness.
Methods
CD38 and HLA-DR expression on CD4+ and CD8+ T-cells was assessed by flow cytometry among 59 HIV-negative and 376 HIV-infected (185 hepatitis-C co-infected) women in the Women's Interagency HIV Study (WIHS). T-cell activation was defined by CD8+CD38+DR+ and CD4+CD38+DR+. Multiple activation assessments over 6.5 years were averaged. In 140 women, T-cell activation was measured before and after HAART initiation. Carotid artery ultrasounds were completed a median of 6.5 years after last measurement of T- cell activation and carotid artery stiffness including distensibility and elasticity were calculated.
Results
Percentages of CD4+ and CD8+ T-cell activation were significantly higher in HIV- infected compared to HIV-negative women. Among HIV-negative women, T-cell activation was not associated with carotid artery stiffness. Among HIV-infected women, higher CD4+ T-cell activation significantly predicted increased arterial stiffness independent of CD4 cell count and HIV RNA. The association was stronger among HIV/HCV co-infected compared to HIV-mono- infected women; however, the difference was not statistically significant (p-for interaction>0.05). Pre- and post-HAART levels of CD4+ T-cell activation significantly predicted carotid artery stiffness.
Conclusions
Persistent T-cell activation, even after HAART initiation, can contribute to structural and/or functional vascular damage accelerating atherogenesis in HIV infection. These results need to be confirmed in a longitudinal prospective study.
doi:10.1097/QAI.0000000000000311
PMCID: PMC4197806  PMID: 25314253
T-cell activation; arterial stiffness; HIV-infection
3.  Association of Markers of Hemostasis with Death in HIV-infected Women 
In HIV-negatives, markers of hemostasis including D-dimer, Factor VIII, plasminogen activator inhibitor-1 antigen (PAI-1) and total protein S are associated with all-cause and cardiovascular disease mortality. In HIV-positives, studies of D-dimer and Factor VIII with death were limited to short follow-up; associations of PAI-1 and total protein S with death have not been examined.
In 674 HIV-infected women from the Women’s Interagency HIV Study (WIHS), markers from the first visit after enrollment were exposures of interest in multivariate analyses of death (AIDS and non-AIDS) in separate models at 5 and 16 years.
There were 87 AIDS and 44 non-AIDS deaths at 5 years, and 159 AIDS and 113 non-AIDS deaths at 16 years. An inverse association of total protein S quartiles with non-AIDS deaths was observed at 5 (p-trend=0.002) and 16 years (p-trend=0.02); there was no association with AIDS deaths. The 3rd quartile of PAI-1 was associated with AIDS deaths at 5 (hazard ratio (HR)=4.0, 95% confidence interval (CI)=1.9–8.4) and 16 years (HR=3.4, 95% CI=1.9–5.9); and with non-AIDS deaths at 5 years (HR=4.8, 95%CI=1.6,13.9). D-dimer and Factor VIII were not associated with AIDS or non-AIDS death at 5 or 16 years.
Lower total Protein S was a consistent marker of non-AIDS death. We found no association between D-dimer with AIDS or non-AIDS death, in contrast to previous studies showing increased short term (<5 years) mortality, which may represent sex differences or population heterogeneity. Given longer survival on HAART, further studies of these markers are needed to determine their prognostic value.
doi:10.1097/QAI.0000000000000306
PMCID: PMC4197808  PMID: 25314249
4.  Echolucency of the Carotid Artery Intima‐Media Complex and Intima‐Media Thickness Have Different Cardiovascular Risk Factor Relationships: The Women's Interagency HIV Study 
Background
Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging.
Methods and Results
We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV‐infected and 510 HIV‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV‐infected and HIV‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group.
Conclusions
Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.
doi:10.1161/JAHA.114.001405
PMCID: PMC4345869  PMID: 25699995
carotid arteries; epidemiology; immune system; risk factors; ultrasonics
5.  Detectability and reproducibility of plasma levels of chemokines and soluble receptors☆ 
Results in Immunology  2013;3:79-84.
Background: Multiplex assays are available to measure an array of circulating chemokines, soluble cytokine receptors and growth factors. However, there is limited information regarding whether these analytes are suitable for large-scale epidemiological studies to assess their relationships with chronic diseases, including cancer.
Methods: We examined detectability, assay repeatability, and 3-year within-subject reproducibility of plasma levels of 25 chemokines and 11 soluble receptors of cytokines and growth factors selected from the Human Millipore Panels. Plasma samples were obtained from 36 men (average age 62 years) and 17 women (average age 32 years) who participated in two epidemiological studies. Inter-assay and within-subject reproducibility were assessed by intraclass correlation coefficients (ICC).
Results: All analytes, except lymphotactin (47% detectability), were detectable in >90% of plasma samples. Inter-assay reproducibility for all analytes in 36 men tested three times on separate days were good to excellent (ICCs: 0.71–1.00). Within-subject reproducibility in 17 women sampled three times in three years were excellent (ICC ≥ 0.75) for five chemokines (eotaxin, fractalkine, 6Ckine, eotaxin 3, and SDF-1α+β) and three soluble receptors (sIL-1R2, sIL-4R and sVEGFR2); ICCs were fair to good (0.4 ≤ ICC < 0.75) for 15 chemokines and eight soluble receptors. However, five chemokines (GRO, IP-10, MIP-1β, BCA-1, and MIP-3α) had ICC < 0.4, suggesting biological variability.
Conclusion: Multiplex assays for plasma levels of selected chemokines and soluble receptors showed good to excellent assay detectability and repeatability. Most analytes also had good 3-year within-subject reproducibility, indicating that a single measurement of these analytes may be used to assess biomarker-disease associations.
doi:10.1016/j.rinim.2013.07.001
PMCID: PMC3908322  PMID: 24600562
Chemokines; Soluble receptors; Within-subject variability; Biomarker; Limit of detection
6.  Hepatitis C Viremia Is Associated with Cytomegalovirus IgG Antibody Levels in HIV-Infected Women 
PLoS ONE  2013;8(4):e61973.
Background
Individuals with HIV infection exhibit high cytomegalovirus (CMV) IgG levels, but there are few data regarding the association of hepatitis C virus (HCV) with the immune response against CMV.
Methods
Associations of HCV with CMV seropositivity and CMV IgG levels were studied in 635 HIV-infected women, 187 of whom were HCV-seropositive, with adjustment in multivariable models for age, race/ethnicity, and HIV disease characteristics. Eighty one percent of the women reported receipt of highly active antiretroviral therapy (HAART) prior to or at CMV testing.
Results
In adjusted models women with chronic HCV had higher CMV IgG levels than those without HCV RNA (β = 2.86, 95% CI:0.89 – 4.83; P = 0.004). The association of HCV RNA with CMV IgG differed by age (Pinteraction = 0.0007), with a strong association observed among women in the low and middle age tertiles (≤45.3 years of age; β = 6.21, 95% CI:3.30 – 9.11, P<0.0001) but not among women in the high age tertile. CMV IgG levels were not associated with non-invasive measures of liver disease, APRI and FIB-4, or with HCV RNA level and adjustment for Epstein-Barr virus (EBV) IgG levels did not affect the association between HCV and CMV.
Conclusions
CMV IgG levels are higher in HCV/HIV co-infected women than in HIV mono-infected women. Further research on the association of HCV with CMV IgG is indicated because prior studies have found CMV IgG to be associated with morbidity and mortality in the general population and subclinical carotid artery disease in HIV-infected patients.
doi:10.1371/journal.pone.0061973
PMCID: PMC3629158  PMID: 23613990
7.  Associations of cardiovascular variables and HAART with cognition in middle-aged HIV-infected and uninfected women 
Journal of neurovirology  2011;17(5):469-476.
Despite use of HAART, cognitive impairment remains prevalent in HIV. Indeed, a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. Participants were members of the Women’s Interagency HIV Study (WIHS). In analysis of cross-sectional data using general linear models we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI: 3.5 to 17.5, p = 0.003, N = 1130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1130). Summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.
doi:10.1007/s13365-011-0052-3
PMCID: PMC3509940  PMID: 22006469
Cognition; HIV; Women; Hypertension; Atherosclerosis; Middle-Aged
8.  Associations of Insulin-Like Growth Factor (IGF)–I and IGF-Binding Protein–3 with HIV Disease Progression in Women 
The Journal of infectious diseases  2008;197(2):319-327.
Background
The insulin-like growth factor (IGF) axis has been hypothesized to influence the rate of human immunodeficiency virus (HIV) disease progression. This premise is based largely on laboratory models showing that IGF-I stimulates thymic growth and increases lymphocyte numbers and that IGF-binding protein (IGFBP)–3 has an opposing effect, inhibiting hematopoietic stem cell development.
Methods
We studied 1422 HIV-infected women enrolled in a large cohort that entailed semiannual follow-up (initiated in 1994). Baseline serum samples were tested for IGF-I and IGFBP-3 to determine their associations with incident clinical acquired immunodeficiency syndrome (AIDS) and CD4+ T cell count decline prior to April 1996 (before the era of highly active antiretroviral therapy [HAART]).
Results
Low IGF-I levels (Ptrend = .02) and high IGFBP-3 levels (Ptrend = .02) were associated with rapid CD4+ T cell count decline. Only IGFBP-3, however, was significantly associated with AIDS incidence (hazard ratio for highest vs. lowest quartile, 2.65 [95% confidence interval, 1.30–5.42]; Ptrend = .02) in multivariable models.
Conclusions
These findings suggest that serum levels of IGFBP-3 (and possibly IGF-I) are associated with the rate of HIV disease progression in women and, more broadly, that interindividual heterogeneity in the IGF axis may influence HIV pathogenesis. If correct, the IGF axis could be a target for interventions to slow HIV disease progression and extend the time before use of HAART becomes necessary.
doi:10.1086/524848
PMCID: PMC3127259  PMID: 18177247
9.  The Association of HIV Infection with Left Ventricular Mass/Hypertrophy 
Left ventricular hypertrophy (LVH) is an independent predictor of major cardiovascular events. Cardiovascular risk is increased among human immunodeficiency virus (HIV)-infected patients. To assess LV mass/hypertrophy in HIV infection, 654 women enrolled in the Women's Interagency HIV Study underwent transthoracic echocardiography. There were 454 HIV-infected and 200 uninfected women, mean age 40.8 ± 9.3 years. LV mass/height2.7 was similar between the HIV-infected and the HIV-uninfected groups (41.4 ± 11.1 vs. 39.9 ± 10.3 g/h2.7; p = 0.37). The prevalence of LVH was similar between the two groups (LVH by LV mass/height2.7 criteria 15.0% vs. 13.0%, p = 0.29). Relative wall thickness (RWT), defined as the ratio of LV wall thickness to cavity diameter, was also similar between the HIV-infected and HIV-uninfected groups (0.36 ± 0.05 vs. 0.37 ± 0.06, p = 0.16). On multiple linear regression analysis adjusting for age, W/H ratio, triceps skinfold thickness, systolic/diastolic BP, diabetes, hypertension and dyslipidemia; HIV status (b = 2.08, p = 0.02, CI 0.27–3.88); weight (b per kg = 0.15, p<0.01, CI 0.08–0.22); and smoking duration (b per one-year increase = 0.08, p = 0.03, CI 0.01–0.16) were independent correlates of LV mass/height2.7 (Model R2 = 0.20, p<0.001). Weight (aOR = 1.04, CI 1.01–1.06) and smoking duration (aOR = 1.03, CI 1.01–1.06) were independent correlates of LVH. Being HIV negative, increased age, increased triceps skinfold thickness, and higher W/H ratio were independent correlates of higher RWT. Among HIV-infected women, higher LV mass was not associated with a history of AIDS-defining illness, nadir CD4+ count <200 cells/μl, or with the duration of highly active antiretroviral therapy (HAART). Women taking NRTIs had higher LV mass. Higher RWT was associated with current CD4+ count. In conclusion, HIV infection is associated with greater LV mass but not with a higher prevalence of LVH. Among HIV-infected women, RWT, but not LV mass, is associated with the degree of immunosuppression.
doi:10.1089/aid.2008.0170
PMCID: PMC2801578  PMID: 19397399
10.  The Association of HIV Infection with Left Ventricular Mass/Hypertrophy 
Abstract
Left ventricular hypertrophy (LVH) is an independent predictor of major cardiovascular events. Cardiovascular risk is increased among human immunodeficiency virus (HIV)-infected patients. To assess LV mass/hypertrophy in HIV infection, 654 women enrolled in the Women's Interagency HIV Study underwent transthoracic echocardiography. There were 454 HIV-infected and 200 uninfected women, mean age 40.8 ± 9.3 years. LV mass/height2.7 was similar between the HIV-infected and the HIV-uninfected groups (41.4 ± 11.1 vs. 39.9 ± 10.3 g/h2.7; p = 0.37). The prevalence of LVH was similar between the two groups (LVH by LV mass/height2.7 criteria 15.0% vs. 13.0%, p = 0.29). Relative wall thickness (RWT), defined as the ratio of LV wall thickness to cavity diameter, was also similar between the HIV-infected and HIV-uninfected groups (0.36 ± 0.05 vs. 0.37 ± 0.06, p = 0.16). On multiple linear regression analysis adjusting for age, W/H ratio, triceps skinfold thickness, systolic/diastolic BP, diabetes, hypertension and dyslipidemia; HIV status (b = 2.08, p = 0.02, CI 0.27–3.88); weight (b per kg = 0.15, p < 0.01, CI 0.08–0.22); and smoking duration (b per one-year increase = 0.08, p = 0.03, CI 0.01–0.16) were independent correlates of LV mass/height2.7 (Model R2 = 0.20, p < 0.001). Weight (aOR = 1.04, CI 1.01–1.06) and smoking duration (aOR = 1.03, CI 1.01–1.06) were independent correlates of LVH. Being HIV negative, increased age, increased triceps skinfold thickness, and higher W/H ratio were independent correlates of higher RWT. Among HIV-infected women, higher LV mass was not associated with a history of AIDS-defining illness, nadir CD4+ count <200 cells/μl, or with the duration of highly active antiretroviral therapy (HAART). Women taking NRTIs had higher LV mass. Higher RWT was associated with current CD4+ count. In conclusion, HIV infection is associated with greater LV mass but not with a higher prevalence of LVH. Among HIV-infected women, RWT, but not LV mass, is associated with the degree of immunosuppression.
doi:10.1089/aid.2008.0170
PMCID: PMC2801578  PMID: 19397399
11.  Oxidant Stress in HIV-Infected Women from the Women’s Interagency HIV Study 
Antiviral therapy  2009;14(6):763-769.
Background
Oxidant stress contributes to the pathogenesis of multiple conditions and can be assessed by measuring plasma F2-isoprostane concentrations. We hypothesized that oxidant stress is associated with plasma homocysteine concentration and risk factors for atherosclerosis in HIV-infected women.
Methods
We measured plasma F2-isoprostane concentrations in a cross-sectional study of 249 HIV-infected women attending the Bronx site of the Women’s Interagency HIV Study and assessed associations with plasma homocysteine concentration and other metabolic parameters by linear regression.
Results
In multivariate analysis, HCV viremia, waist circumference, homocysteine concentration, and serum aspartate transanimase level were positively associated with log F2-isoprostane concentration (all P < 0.005). There was a trend for an inverse association between log F2-isoprostane and CD4% (P = 0.06). Among women with HCV infection, the FIB-4 index, an indirect marker of liver fibrosis derived from routine laboratory tests, was positively associated with log F2-isoprostane concentration.
Conclusion
In this cross-sectional study of HIV-infected women, plasma F2-isoprostane concentration was positively associated with homocysteine concentration, as well as HCV infection, abdominal obesity, and aspartate transaminase level.
doi:10.3851/1290
PMCID: PMC2760028  PMID: 19812438
Oxidant stress; oxidative stress; F2-isoprostanes; homocysteine; HIV; HCV

Results 1-11 (11)