Alan Landay

Utrecht University, Utrecht, Utrecht, Netherlands

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Publications (423)2490.91 Total impact

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    ABSTRACT: Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying chronic rhinosinusitis. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison to healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS. This article is protected by copyright. All rights reserved.
    Clinical & Experimental Allergy 10/2015; DOI:10.1111/cea.12666 · 4.77 Impact Factor
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    ABSTRACT: Problem: Identification of the types of cells that produce IL-17 and IL-22 in the genital tract can clarify the roles that these cytokines play in responses to pathogens. Method of study: We isolated and stimulated cells from cervical tissue to identify and characterize cytokine-producing cells. Results: Upon stimulation of CD3(+) CD4(+) endocervical cells, 1.6, 3.4, and 1.5% were induced to produce IL-22, IL-17, and both cytokines, respectively. Stimulation of CD3(+) CD4(+) ectocervical cells resulted in 3.3% IL-22(+) , 5.5% IL-17(+) and 2.6% IL-22(+) IL17(+) cells. CD45(+) CD3(-) cells had relatively high endogenous levels of cytokine expression that did not increase upon stimulation. Innate lymphoid cells (ILCs) made up 5.7-8% of CD45(+) cervical cells and stimulation caused increases in IL-17 and IL-22. Conclusion: These studies show that the majority of the CD45(+) leukocytes that can be induced to produce IL-22 and IL-17 in cervix are CD3(+) CD4(+) , but ILCs are also present and can make both cytokines.
    American Journal Of Reproductive Immunology 10/2015; DOI:10.1111/aji.12435 · 2.44 Impact Factor
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    ABSTRACT: Three groups of CMV seropositive women (total n=164) were selected from the Chicago Women's Interagency HIV-1 Study to investigate the association between CMV co-infection and immune activation: 1) HIV-1 viremic; 2) HIV-1 aviremic; and 3) HIV-1 uninfected. Quantitative measures of CMV serum IgG, CMV DNA, and serum biomarkers IL-6, soluble CD163 (sCD163), soluble CD14 (sCD14), and IP-10 were obtained. Levels of CMV IgG, and the serum biomarkers were significantly higher in the HIV-1 viremic group compared to the aviremic and uninfected groups (p<0.001). No significant associations with CMV IgG levels were found for HIV-uninfected women. When each of the HIV-infected groups was analyzed, sCD14 levels in the viremic women were significantly associated with CMV IgG levels with p<0.02 when adjusted for age, CD4 count and HIV viral load. There was also a modest association (p=0.036) with IL-6 from plasma and cervical vaginal lavage specimens both unadjusted and adjusted for CD4 count and HIV viral load. The association of CMV IgG level with sCD14 implicates the monocyte as a potential site for interaction of the two viruses, which eventually may lead to non-AIDS-defining pathological conditions.
    AIDS research and human retroviruses 09/2015; DOI:10.1089/AID.2015.0169 · 2.33 Impact Factor
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    ABSTRACT: Objectives: In antiretroviral therapy (ART)-treated patients, to determine if AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is preceded by: elevated frequency of potentially malignant abnormal activated/germinal center-like B cells, elevated serum prevalence of B-cell stimulatory Toll-like receptor (TLR) ligands resulting from HIV infection-associated microbial translocation, dysregulated B-cell TLR expression/signaling, and perturbations in the frequency of immunoregulatory cells. Design: A case-control study nested with a cohort study of HIV-infected women. Methods: Prediagnostic AIDS-NHL cases (n = 12, collected 1-12 months before diagnosis) and controls (n = 42) from the Women's Interagency HIV Study cohort, were matched for HIV and ART status, age, race, and CD4 lymphocyte count. Serum levels of TLR ligands, the prevalence of malignancy-associated abnormal activated/germinal center-like (CD19CD10CD71CD86AID) B cells, TLR2 expression on B cells, expression of TLR2-modulating micro-RNA, and the frequency of regulatory T and B cells were assessed. Results: Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/germinal center-like CD19CD10CD71CD86AID B cells (P = 0.0072), elevated serum prevalence of the TLR2 ligand, and significantly elevated B-cell TLR2 expression (P = 0.0015), positively correlating with the frequency of activated/germinal center-like B cells (rho = 0.7273, P = 0.0144). In cases, a purified subset of activated/germinal center-like B cells exhibited decreased expression of microRNAs that modulate TLR2 signaling, including miR-21, 146a, 146b, and 155. Finally, cases also exhibited significantly elevated frequencies of antitumor immunity inhibitory regulatory B cells (P = 0.0024), but not regulatory T cells. Conclusions: Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of regulatory B cells, precede the diagnosis of AIDS-NHL in HIV-infected ART-treated patients.
    AIDS (London, England) 09/2015; 29(13):1659-64. DOI:10.1097/QAD.0000000000000687 · 5.55 Impact Factor
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    ABSTRACT: Plasma HIV RNA is the most significant determinant of cervical HIV shedding. However, shedding is also associated with sexually transmitted infections (STIs) and cervical inflammation. The mechanism by which this occurs is poorly understood. There is evidence that systemic immune activation promotes viral entry, replication and HIV disease progression. We hypothesized that systemic immune activation would be associated with an increase in HIV genital shedding. Clinical assessments, HIV RNA in plasma and genital secretions, and markers of immune activation (CD38+DR+ and CD38-DR-) on CD4+ and CD8+ T cells in blood were evaluated in 226 HIV+ women enrolled in the Women's Interagency HIV Study. There were 569 genital evaluations of which 159 (28%) exhibited HIV RNA shedding, defined as HIV viral load > 80 copies/ml. We tested associations between immune activation and shedding using generalized estimating equations with logit link function. In the univariate model, higher levels of CD4+ and CD8+ T cell activation in blood were significantly associated with genital tract shedding. However, in the multivariate model adjusting for plasma HIV RNA, STIs and genital tract infections, only higher levels of resting CD8+ T cells (CD38-DR- ) were significantly inversely associated with HIV shedding in the genital tract (OR=0.44, 95% CI= 0.21-0.9, P= 0.02). The association of systemic immune activation with genital HIV shedding is multifactorial. Systemic T cell activation is associated with genital tract shedding in univariate analysis but not when adjusting for plasma HIV RNA, STIs and genital tract infections. In addition, women with high percentage of resting T cells are less likely to have HIV shedding compared to those with lower percentages. These findings suggest that a higher percentage of resting cells, as a result of maximal viral suppression with treatment, may decrease local genital activation, HIV shedding, and transmission.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2015; DOI:10.1097/QAI.0000000000000823 · 4.56 Impact Factor
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    ABSTRACT: Background: Therapeutic vaccination is being studied in eradication and "functional cure" strategies for HIV-1. The Profectus Biosciences (Tarrytown, NY) multiantigen (MAG) HIV-1 DNA vaccine encodes HIV-1 Gag/Pol, Nef/Tat/Vif, and Envelope, and interleukin-12 (IL-12) and is delivered by electroporation (EP) combined with intramuscular injection (IM-EP) Methods: Sixty-two HIV-1-infected patients on antiretroviral therapy (plasma HIV-1 RNA levels <=200 copies/mL; CD4+ T-cell counts >=500 cells/mm3) were randomly allocated 5:1 to receive vaccine or placebo. At weeks 0, 4 and 12, four consecutive cohorts received 3000 [micro]g HIV MAG pDNA with 0, 50, 250, or 1000 [micro]g of IL-12 pDNA by IM-EP. A 5th cohort received HIV MAG pDNA plus 1000 [micro]g of IL-12 pDNA by standard IM injection. Results: CD4+ T cells expressing IL-2 in response to Gag and Pol and interferon-[gamma] responses to Gag, Pol, and Env increased from baseline to week 14 in the low-dose (50-[mu]g) IL-12 arm vs. placebo (P < 0.05; intracellular cytokine staining). The total increase in the IL-2 expressing CD4+ T-cell responses to any antigen was also higher in the low-dose IL-12 arm vs. placebo (P = 0.04). Cytokine responses by CD8 T cells to HIV antigens were not increased in any vaccine arm relative to placebo. Conclusions: HIV-1 MAG/low-dose IL-12 DNA vaccine delivered by IM-EP augmented CD4+ but not CD8+ T-cell responses to multiple HIV-1 antigens. Copyright
    JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2015; DOI:10.1097/QAI.0000000000000830 · 4.56 Impact Factor

  • JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2015; DOI:10.1097/QAI.0000000000000832 · 4.56 Impact Factor
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    ABSTRACT: Glycogen expressed by the lower genital tract epithelium is believed to support Lactobacillus growth in vivo, although most genital isolates of Lactobacillus are not able to use glycogen as an energy source in vitro. We recently reported that α-amylase is present in the genital fluid of women and that it breaks down glycogen into small carbohydrates that support growth of lactobacilli. Since the pH of the lower genital tract can be very low, we determined how low pH affects glycogen processing by α-amylase. α-amylase in saliva degraded glycogen similarly at pH 6 and 7, but activity was reduced by 52% at pH 4. The glycogen degrading activity in nine genital samples from seven women showed a similar profile with an average reduction of more than 50% at pH 4. However, two samples collected from one woman at different times had a strikingly different pH profile with increased glycogen degradation at pH 4, 5 and 6 compared to pH 7. This second pH profile did not correlate with levels of human α-acid glucosidase or human intestinal maltase glucoamylase. High-performance anion-exchange chromatography showed that mostly maltose was produced from glycogen by samples with the second pH profile in contrast to genital α-amylase that yielded maltose, maltotriose and maltotetraose. These studies show that at low pH, α-amylase activity is reduced to low but detectable levels, which we speculate helps maintain Lactobacillus growth at a limited but sustained rate. Additionally, some women have a genital enzyme distinct from α-amylase with higher activity at low pH. Further studies are needed to determine the identity and distribution of this second enzyme, and whether its presence influences the makeup of genital microbiota.
    PLoS ONE 07/2015; 10(7):e0132646. DOI:10.1371/journal.pone.0132646 · 3.23 Impact Factor
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    ABSTRACT: Trichomonas vaginalis infection is associated with an increased risk of HIV infection in exposed-seronegative women (ESN) despite their unique immune quiescent profile. It is important to understand possible mechanisms, such as recruitment of activated T cells, by which T. vaginalis could facilitate HIV infection in this population. We conducted a cross-sectional study exploring the relationships between T. vaginalis infection, inflammatory markers and T cell activation in the cervix of ESN. During scheduled study visits, participants completed a behavioral questionnaire and physical exam, including sexually transmitted infection (STI) screening and collection of endocervical sponge and cytobrush specimens. T cell and monocyte phenotypes were measured in cervical cytobrush specimens using multi-parameter flow cytometry. Cervical sponge specimens were used to measure cytokines (IL-6, IL-8,IL-10, IP-10, RANTES) using Luminex immunoassays and the immune activation marker soluble TNF receptor 1 using ELISA. Specimens of 65 women were tested. Twenty-one of these women were infected with T. vaginalis. T. vaginalis infection was associated with significantly increased concentrations of IL-8 (1275pg/ml vs. 566pg/ml, p=.02) and sTNFr1 (430 pg/ml vs. 264 pg/ml, p=.005). However, T. vaginalis infection was not associated with increased percent expression of CCR5+ T cells nor increased CD38 and HLADR activation compared to uninfected women. It was also not associated with increased expression of CCR5+ monocytes. Among ESN T. vaginalis infection is associated with increased levels of genital pro-inflammatory/immune activation markers IL-8 and TNFr1, but was not associated with an increased percentage of activated endocervical T cells along the CD38 and HLADR pathways. Thus, while T.vaginalis infection may result in some reversal of the immune quiescent profile of ESN, enhanced recruitment of activated CD38 and HLADR expressing CD4+ cells into the endocervix may not be part of the mechanism by which Trichomonas infection alters HIV susceptibility in this unique subset of women.
    PLoS ONE 06/2015; 10(6):e0130146. DOI:10.1371/journal.pone.0130146 · 3.23 Impact Factor
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    ABSTRACT: Background: There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)-containing ART. Methods: This was a double-blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) >1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1:1), stratified by VL <100 000 or ≥100 000 copies/mL and age <30 or ≥30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X-ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population. Results: We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log10 copies/mL and CD4 count was 390 cells/µL. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of -1.51% [-2.93%, -0.11%] vs -2.40% [-4.30%, -1.32%] for TDF (P < .001). Lumbar spine BMD decline was also less with MVC (median -0.88% vs -2.35%; P < .001). Similar proportions of subjects in both arms achieved VL ≤50 copies/mL in as-treated and ITT analyses. Conclusions: MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss. Clinical trials registration: NCT01400412.
    Clinical Infectious Diseases 06/2015; 61(7). DOI:10.1093/cid/civ455 · 8.89 Impact Factor
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    ABSTRACT: HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c(+) and CD1c(neg)) and plasmacytoid DCs in untreated HIV-1-infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c(+) mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percentage of CD83(+)CD1c(+) mDCs negatively correlated with frequencies of interferon-γ-producing colon CD4(+) and CD8(+) T cells. CD40 expression on CD1c(+) mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and Prevotella stercorea but negatively associated with a number of low prevalence mucosal species, including Rumminococcus bromii. CD1c(+) mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that, during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation.Mucosal Immunology advance online publication, 29 April 2015; doi:10.1038/mi.2015.33.
    Mucosal Immunology 04/2015; DOI:10.1038/mi.2015.33 · 7.37 Impact Factor
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    ABSTRACT: Background: Individuals infected with human immunodeficiency virus (HIV) live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood. Methods: We prospectively examined 1011 women (74% HIV-infected) in the Women's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors. Results: Unadjusted mean CCA-IMT increased (725 to 752 µm in women, 757 to 790 µm in men), but CCA-IMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (relative risk [RR] 1.61, 95% CI, 1.12-2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI, 1.07-2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/µL had plaque risk not statistically different from uninfected individuals. Conclusions: HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection.
    Clinical Infectious Diseases 04/2015; 61(4). DOI:10.1093/cid/civ325 · 8.89 Impact Factor
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    ABSTRACT: Tissue factor (TF) is a protein that mediates the initiation of the coagulation cascade. TF expression is increased in patients with poorly-controlled HIV, and may be associated with increased immune activation that leads to cardiovascular morbidity. The role of TF in immune activation in liver disease in hepatitis C virus (HCV)-monoinfection and HIV/HCV-coinfection has not been explored. Fifty-nine patients were stratified: A) HIV-monoinfection (N = 15), B) HCV-monoinfection with chronic hepatitis C (CHC) (N = 15), C) HIV/HCV-coinfection with CHC (N = 14), and D) HIV/HCV-seropositive with cleared-HCV (N = 15). All HIV+ patients had undetectable HIV viremia. Whole blood was collected for CD4/CD8 immune activation markers by flow cytometry and plasma was assayed for microparticle TF (MPTF) activity. Subjects underwent transient elastography (TE) to stage liver fibrosis. Undetectable versus detectable MPTF was compared across strata using Fisher's Exact test. MPTF activity was more frequently detected among patients with HCV-monoinfection (40%), compared to HIV-monoinfection and HIV/HCV-seropositive with cleared HCV (7%) and HIV/HCV-coinfection with CHC (14%)(p = 0.02). Mean TE-derived liver stiffness score in kPa was higher in patients with detectable MPTF (12.4 ± 8.5) than those with undetectable MPTF (6.4 ± 3.0)(p = 0.01). Mean CD4 + HLADR+ and CD4 + CD38-HLADR+ expression were higher in those with detectable MPTF (44 ± 9.8% and 38 ± 8.7%, respectively) than those with undetectable MPTF (36 ± 11% and 31 ± 10.4% respectively)(p = 0.05 and 0.04 respectively). HCV-monoinfection and HIV/HCV-coinfection with CHC were associated with MPTF activity. MPTF activity is also associated with advanced liver fibrosis and with CD4 + HLADR+ immune activation.
    BMC Infectious Diseases 04/2015; 15(1):190. DOI:10.1186/s12879-015-0920-1 · 2.61 Impact Factor
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    ABSTRACT: Measurement of CD4+ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration. Studies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/μl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/μl, bias ranged from -35.2 to +13.1 cells/μl while at counts >350 cells/μl, bias ranged from -70.7 to +47 cells/μl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/μl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained. A wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed.
    PLoS ONE 03/2015; 10(3):e0115019. DOI:10.1371/journal.pone.0115019 · 3.23 Impact Factor
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    ABSTRACT: All-cause mortality and serious non-AIDS events (SNAEs) in individuals with HIV-1 infection receiving antiretroviral therapy are associated with increased production of interleukin-6 which appears to be driven by monocyte/macrophage activation. Plasma levels of other cytokines or chemokines associated with immune activation might also be biomarkers of an increased risk of mortality and/or SNAEs. Baseline plasma samples from 142 participants enrolled into the Strategies for Management of Antiretroviral Therapy study, who subsequently died, and 284 matched controls, were assayed for levels of 15 cytokines and chemokines. Cytokine and chemokine levels were analysed individually and when grouped according to function (innate/proinflammatory response, cell trafficking and cell activation/proliferation) for their association with the risk of subsequent death. Higher plasma levels of proinflammatory cytokines (interleukin-6 and tumour necrosis factor-α) were associated with an increased risk of all-cause mortality but in analyses adjusted for potential confounders, only the association with interleukin-6 persisted. Increased plasma levels of the chemokine CXCL8 were also associated with all-cause mortality independently of hepatitis C virus status but not when analyses were adjusted for all confounders. In contrast, higher plasma levels of cytokines mediating cell activation/proliferation were not associated with a higher mortality risk and exhibited a weak protective effect when analysed as a group. Whereas plasma levels of interleukin-6 are the most informative biomarker of cytokine dysregulation associated with all-cause mortality in individuals with HIV-1 infection, assessment of plasma levels of CXCL8 might provide information about causes of mortality and possibly SNAEs.
    AIDS (London, England) 02/2015; 29(7). DOI:10.1097/QAD.0000000000000618 · 5.55 Impact Factor
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    ABSTRACT: Chronic inflammation and immune activation occur in both HIV infection and normal ageing and are associated with inflammatory disease. However, the degree to which HIV influences age-related innate immune changes, and the biomarkers which best reflect them, remains unclear. We measured established innate immune ageing biomarkers in 309 individuals including 88 virologically-suppressed (VS) and 52 viremic (viral load ≤ and >50 copies/ml respectively) HIV+ individuals. Levels of soluble (ie. CXCL10, soluble CD163, neopterin) and cellular (ie. proportions of inflammatory CD16+ monocytes) biomarkers of monocyte activation were increased in HIV+ individuals and were only partially ameliorated by viral suppression. Viremic and VS HIV+ individuals show levels of age-related monocyte activation biomarkers that are similar to uninfected controls aged 12 and 4 years older respectively. Viremic HIV infection was associated with an accelerated rate of change of some monocyte activation markers (eg. neopterin) with age, whilst in VS individuals, subsequent age-related changes occurred at a similar rate as in controls, albeit at a higher absolute level. We further identified CXCL10 as a robust soluble biomarker of monocyte activation, highlighting the potential utility of this chemokine as a prognostic marker. These findings may partially explain the increased prevalence of inflammatory, age-related diseases in HIV+ individuals and potentially indicate the pathological mechanisms underlying these diseases which persist despite viral suppression.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2015; 69(1). DOI:10.1097/QAI.0000000000000559 · 4.56 Impact Factor
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    ABSTRACT: With the advent of antiretroviral therapy that can control virus replication below the detection levels of conventional assays, a new clinical landscape of AIDS emerged, in which non-AIDS complications prevail over AIDS-defining conditions. These comorbidities are diverse and affect multiple organs, thus resulting in cardiovascular, kidney, neurocognitive and liver disease, osteopenia/osteoporosis, and cancers. A common feature of these conditions is that they are generally associated with accelerated aging. The mechanism behind these comorbidities is chronic excessive inflammation induced by HIV infection, which persists under antiretroviral therapy. Progressive simian immunodeficiency virus (SIV) infection of nonhuman primates (NHPs) closely reproduces these comorbidities and offers a simplified system in which most of the traditional human risk factors for comorbidities (i.e., smoking, hyperlipidemia) are absent. Additionally, experimental conditions can be properly controlled during a shorter course of disease for SIV infection. As such, NHPs can be employed to characterize new paradigms of AIDS pathogenesis and to test the efficacy of interventions aimed at alleviating non-AIDS-related comorbidities.
    Current HIV/AIDS Reports 01/2015; 12(1). DOI:10.1007/s11904-014-0245-5 · 3.80 Impact Factor
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    ABSTRACT: Interleukin-8 (IL-8, CXCL8) plays important roles in immune responses at mucosal sites including in the lower genital tract. Since several types of bacteria produce proteases that cleave IL-8 and many types of bacteria can be present in lower genital tract microbiota, we assessed genital fluids for IL-8 cleavage/alteration. Genital fluids collected by lavage from 200 women (23 HIV-seronegative and 177 HIV-seropositive) were tested for IL-8 cleavage/alteration by ELISA. IL-8 cleaving/altering activity was observed in fluids from both HIV-positive (28%) and HIV-negative women (35%). There was no clear relationship between the activity and the types of bacteria present in the lower genital tract as determined by high-throughput sequencing of the 16S rRNA gene. Protease inhibitors specific for matrix metalloproteinases (MMPs) reduced the activity and a multiplex assay that detects both inactive and active MMPs showed the presence of multiple MMPs, including MMP-1, -3, -7, -8, -9, -10 and -12 in genital secretions from many of the women. The IL-8-cleaving/altering activity significantly correlated with active MMP-9 as well as with cleavage of a substrate that is acted on by several active MMPs. These studies show that multiple MMPs are present in the genital tract of women and strongly suggest that MMP-9 in genital secretions can cleave IL-8 at this mucosal site. These studies suggest that MMP-mediated cleavage of IL-8 can modulate inflammatory responses in the lower genital tract.
    PLoS ONE 01/2015; 10(1):e0116911. DOI:10.1371/journal.pone.0116911 · 3.23 Impact Factor
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    ABSTRACT: Despite the use of HAART to control HIV, systemic immune activation and inflammation persists with the consequence of developing serious non-AIDS events. The mechanisms that contribute to persistent systemic immune activation have not been well defined. The intestine is the major source of "sterile" inflammation and plays a critical role in immune function; thus, we sought to determine whether intestinal gene expression was altered in virally controlled HIV+ individuals. Gene expression was compared in biopsy samples collected from HIV- and HIV+ individuals from the ileum, right colon (ascending colon), and left colon (sigmoid). Affymetrix gene arrays were performed on tissues and pathway analyses were conducted. Gene expression was correlated with systemic markers of intestinal barrier dysfunction and inflammation and intestinal microbiota composition. Genes involved in cellular immune response, cytokine signaling, pathogen-influenced signaling, humoral immune response, apoptosis, intracellular and second messenger signaling, cancer, organismal growth and development, and proliferation and development were upregulated in the intestine of HIV+ individuals with differences observed in the ileum, right, and left colon. Gene expression in the ileum primarily correlated with systemic markers of inflammation (e.g., IL7R, IL2, and TLR2 with serum TNF) whereas expression in the colon correlated with the microbiota community (e.g., IFNG, IL1B, and CD3G with Bacteroides). These data demonstrate persistent, proinflammatory changes in the intestinal mucosa of virally suppressed HIV+ individuals. These changes in intestinal gene expression may be the consequence of or contribute to barrier dysfunction and intestinal dysbiosis observed in HIV.
    AIDS (London, England) 01/2015; 29(5). DOI:10.1097/QAD.0000000000000569 · 5.55 Impact Factor
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    ABSTRACT: Previous studies have suggested that glycogen expression in the vaginal epithelium decreases during menopause, resulting in reduced levels of lactobacilli. However, free glycogen in genital fluids and its relationship with Lactobacillus levels have not been compared in premenopausal and postmenopausal women. Eighty-two cervicovaginal lavage samples were collected at different phases of the menstrual cycle from 11 premenopausal (4 HIV-uninfected and 7 HIV-infected) and 12 postmenopausal (7 HIV-uninfected and 5 HIV-infected) women during a 1- to 3-month period. Free glycogen was quantified in genital fluids. Lactobacillus levels were quantified by real-time polymerase chain reaction. Estrogen and progesterone levels in blood were determined by enzyme-linked immunosorbent assay. Free glycogen was detected in both premenopausal and postmenopausal women. Across all samples, those from postmenopausal women had significantly lower levels of free glycogen than those from premenopausal women (median, 0.002 vs 0.065 μg/μL, respectively; P = 0.03). Lactobacillus levels correlated positively with free glycogen in both premenopausal (Spearman r = 0.68, P < 0.0001) and postmenopausal (r = 0.60, P < 0.002) women. Samples from premenopausal women had higher Lactobacillus levels and lower vaginal pH (median log, 8.1; median pH, 4) than those from postmenopausal women (median log, 7.1; median pH, 4.6), although these differences were not significant. HIV status had no significant effect on these relationships. Free glycogen is detected in both premenopausal and postmenopausal women and correlates with Lactobacillus in both groups. These results point to the complexity of the relationship between menopause and vaginal microbiota and indicate that more careful studies of the role of glycogen are warranted.
    Menopause (New York, N.Y.) 12/2014; 22(7). DOI:10.1097/GME.0000000000000397 · 3.36 Impact Factor

Publication Stats

17k Citations
2,490.91 Total Impact Points


  • 2013-2015
    • Utrecht University
      • Division of Pharmacology
      Utrecht, Utrecht, Netherlands
  • 1997-2015
    • Rush University Medical Center
      • Department of Immunology and Microbiology
      Chicago, Illinois, United States
    • Beth Israel Medical Center
      • Division of Infectious Disease
      New York, New York, United States
  • 2014
    • Drexel University College of Medicine
      • Division of Infectious Diseases & HIV Medicine
      Filadelfia, Pennsylvania, United States
  • 1987-2012
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1986-2010
    • Rush Medical College
      Chicago, Illinois, United States
  • 2009
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 1999-2003
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1988-2003
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2002
    • University of Texas Medical Branch at Galveston
      • Department of Internal Medicine
      Galveston, Texas, United States
    • Treatment Research Institute, Philadelphia PA
      Filadelfia, Pennsylvania, United States
  • 2001
    • CSU Mentor
      Long Beach, California, United States
  • 2000
    • Beth Israel Deaconess Medical Center
      • Division of Viral Pathogenesis
      Boston, MA, United States
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • National Cancer Institute (USA)
      • Experimental Immunology Branch
      Maryland, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
    • Ottawa Hospital Research Institute
      Ottawa, Ontario, Canada
  • 1998-1999
    • Case Western Reserve University
      • Center for AIDS Research
      Cleveland, Ohio, United States
    • The University of Chicago Medical Center
      • Department of Microbiology and Immunology
      Chicago, Illinois, United States
  • 1991-1997
    • National Institutes of Health
      • Branch of Experimental Immunology
      Bethesda, MD, United States
    • Northwestern University
      Evanston, Illinois, United States
    • University of Wisconsin, Madison
      • Department of Human Oncology
      Madison, MS, United States
    • Abbott Laboratories
      North Chicago, Illinois, United States
  • 1994
    • Cancer Research Institute
      New York, New York, United States
  • 1993
    • University of Washington Seattle
      • Department of Laboratory Medicine
      Seattle, Washington, United States
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 1990
    • Pennsylvania State University
      • Department of Medicine
      University Park, Maryland, United States
  • 1989
    • Aurora St. Luke's Medical Center
      Milwaukee, Wisconsin, United States
  • 1983-1986
    • University of Alabama at Birmingham
      • • Comprehensive Cancer Center
      • • Department of Pediatrics
      Birmingham, Alabama, United States