lewis-x-antigen and HIV-Infections

Tuberculosis remains a leading cause of death globally despite curative treatment, partly due to the difficulty of identifying patients who will not respond to therapy. Simple host biomarkers that correlate with response to drug treatment would facilitate improvement in outcomes and the evaluation of novel therapies. In a prospective longitudinal cohort study, we evaluated neutrophil count and phenotype at baseline, as well as during TB treatment in 79 patients [50 (63%) HIV-positive] with microbiologically confirmed drug susceptible TB undergoing standard treatment. At time of diagnosis, blood neutrophils were highly expanded and surface expression of the neutrophil marker CD15 greatly reduced compared to controls. Both measures changed rapidly with the commencement of drug treatment and returned to levels seen in healthy control by treatment completion. Additionally, at the time of diagnosis, high neutrophil count, and low CD15 expression was associated with higher sputum bacterial load and more severe lung damage on chest x-ray, two clinically relevant markers of disease severity. Furthermore, CD15 expression level at diagnosis was associated with TB culture conversion after 2 months of therapy (OR: 0.14, 95% CI: 0.02, 0.89), a standard measure of early TB treatment success. Importantly, our data was not significantly impacted by HIV co-infection. These data suggest that blood neutrophil metrics could potentially be exploited to develop a simple and rapid test to help determine TB disease severity, monitor drug treatment response, and identify subjects at diagnosis who may respond poorly to treatment.

Topics: Adolescent; Adult; Antitubercular Agents; Biomarkers; Child; Coinfection; Female; HIV Infections; Humans; Leukocyte Count; Lewis X Antigen; Longitudinal Studies; Male; Neutrophils; Tuberculosis; Young Adult

Condylomata acuminata (anogenital warts [AGWs]) are prevalent in human immunodeficiency virus (HIV)-infected individuals and sexually active populations at risk for HIV acquisition and have been associated with HIV transmission. We compared AGW specimens to control tissue specimens for abundance, types, and location of HIV target cells and for susceptibility to HIV infection in vitro, to provide biologic evidence that AGWs facilitate HIV transmission.. We used immunohistologic staining to identify HIV target cells in AGW and control specimens. We also inoculated HIV in vitro into AGW and control specimens from HIV-negative men and assessed infection by means of TZM-bl and p24 assays.. CD1a+ dendritic cells, CD4+ T cells, and macrophages were significantly more abundant in the epidermis of AGW specimens than control specimens. These HIV target cells also often appeared in large focal accumulations in the dermis of AGW specimens. Two of 8 AGW specimens versus 0 of 8 control specimens showed robust infection with HIV in vitro.. Compared with normal skin, AGWs contain significantly higher concentrations of HIV target cells that may be susceptible to HIV infection. Condylomata may thus promote HIV transmission, especially in the setting of typical lesion vascularity and friability. Prevention or treatment of AGWs may decrease the sexual transmission of HIV.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Condylomata Acuminata; Dendritic Cells; Female; Granulocytes; HEK293 Cells; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Lewis X Antigen; Macrophages; Male; Middle Aged; Papillomaviridae; Papillomavirus Infections; Receptors, CXCR4; Skin; Young Adult

Mother-to-child transmission of human immunodeficiency virus-1 (HIV-1) occurs frequently via breast-feeding. HIV-1 targets DC-SIGN+ dendritic cells (DCs) in mucosal areas that allow efficient transmission of the virus to T cells. Here, we demonstrate that the epithelial mucin MUC1, abundant in milk, efficiently bound to DC-SIGN on DC. The O-linked glycans within the mucin domain contained Lewis X structures, that were specifically recognized by the receptor. Interestingly, MUC1 prevented DC-SIGN-mediated transmission of HIV-1 from DCs to CD4+ T cells. We hypothesize that repetitive units of Lewis X, within the mucin domain, play an important role in inhibiting transmission of HIV-1 from mother to child.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Adhesion Molecules; CHO Cells; Cricetinae; Cricetulus; Dendritic Cells; Female; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lectins, C-Type; Lewis X Antigen; Milk, Human; Mucin-1; Pregnancy; Receptors, Cell Surface

alpha-Defensins 1, 2, and 3 exert antiretroviral activity in vitro, but their role in controlling HIV-1 replication in vivo and the cells that produce them are controversial. This study sought to determine whether alpha-defensins are present in HIV-1-infected individuals' lymphoid tissues, the major site of HIV-1 replication, and to identify the cells that express them. alpha-Defensin expression was evaluated by immunostaining inguinal lymph node sections from 19 untreated HIV-1-infected individuals and 8 individuals at low risk or seronegative for HIV-1 infection. Percentages of tissue sections that stained positively for alpha-defensins were not significantly different between HIV-seropositive (median, 7.6%) and -seronegative (median, 5.5%) individuals. Conditions that could have produced lymph node inflammation were present in most seronegative subjects, and their lymph node weights correlated with alpha-defensin expression (Spearman rho = 0.833; P = 0.010). A median of 100% (range, 95%-100%) of alpha-defensin-expressing lymph node cells from 8 subjects coexpressed the granulocyte marker, CD15. CD15 and alpha-defensin staining correlated (Spearman rho = 0.622; P < 0.001). These data suggest that alpha-defensins within lymphoid tissue are expressed by granulocytes and are prevalent in HIV-1-seronegative individuals with inflammatory processes as well as HIV-1-infected individuals. The role of alpha-defensins in controlling HIV-1 replication merits further investigation.

Topics: alpha-Defensins; Female; Granulocytes; HIV Infections; Humans; Immunohistochemistry; Inflammation; Lewis X Antigen; Lymph Nodes; Lymphoid Tissue; Male; Microscopy, Fluorescence

A wide range of pathogens, including human immunodeficiency virus type 1 (HIV-1), hepatitis C virus, Ebola virus, cytomegalovirus, dengue virus, Mycobacterium, Leishmania, and Helicobacter pylori, can interact with dendritic cell (DC)-specific ICAM3-grabbing nonintegrin (DC-SIGN), expressed on DCs and a subset of B cells. More specifically, the interaction of the gp120 envelope protein of HIV-1 with DC-SIGN can facilitate the transfer of virus to CD4+ T lymphocytes in trans and enhance infection. We have previously demonstrated that a multimeric LeX component in human milk binds to DC-SIGN, preventing HIV-1 from interacting with this receptor. Biochemical analysis reveals that the compound is heat resistant, trypsin sensitive, and larger than 100 kDa, indicating a specific glycoprotein as the inhibitory compound. By testing human milk from three different mothers, we found the levels of DC-SIGN binding and viral inhibition to vary between samples. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blotting, and matrix-assisted laser desorption ionization analysis, we identified bile salt-stimulated lipase (BSSL), a Lewis X (LeX)-containing glycoprotein found in human milk, to be the major variant protein between the samples. BSSL isolated from human milk bound to DC-SIGN and inhibited the transfer of HIV-1 to CD4+ T lymphocytes. Two BSSL isoforms isolated from the same human milk sample showed differences in DC-SIGN binding, illustrating that alterations in the BSSL forms explain the differences observed. These results indicate that variations in BSSL lead to alterations in LeX expression by the protein, which subsequently alters the DC-SIGN binding capacity and the inhibitory effect on HIV-1 transfer. Identifying the specific molecular interaction between the different forms may aid in the future design of antimicrobial agents.

Topics: CD4-Positive T-Lymphocytes; Cell Adhesion Molecules; Cell Line; Female; HIV Infections; HIV-1; Humans; Lectins, C-Type; Lewis X Antigen; Milk, Human; Receptors, Cell Surface; Sterol Esterase

DC-specific ICAM3-grabbing non-integrin (DC-SIGN), which is expressed on DCs, can interact with a variety of pathogens such as HIV-1, hepatitis C, Ebola, cytomegalovirus, Dengue virus, Mycobacterium, Leishmania, and Candida albicans. We demonstrate that human milk can inhibit the DC-SIGN-mediated transfer of HIV-1 to CD4+ T lymphocytes as well as viral transfer by both immature and mature DCs. The inhibitory factor directly interacted with DC-SIGN and prevented the HIV-1 gp120 envelope protein from binding to the receptor. The human milk proteins lactoferrin, alpha-lactalbumin, lysozyme, beta-casein, and secretory leukocyte protease inhibitor did not bind DC-SIGN or demonstrate inhibition of viral transfer. The inhibitory effect could be fully alleviated with an Ab recognizing the Lewis X (LeX) sugar epitope, commonly found in human milk. LeX in polymeric form or conjugated to protein could mimic the inhibitory activity, whereas free LeX sugar epitopes could not. We reveal that a LeX motif present in human milk can bind to DC-SIGN and thereby prevent the capture and subsequent transfer of HIV-1 to CD4+ T lymphocytes. The presence of such a DC-SIGN-binding molecule in human milk may both influence antigenic presentation and interfere with pathogen transfer in breastfed infants.

Topics: CD4-Positive T-Lymphocytes; Cell Adhesion Molecules; Cell Line, Tumor; Cells, Cultured; Dendritic Cells; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lectins, C-Type; Lewis X Antigen; Milk, Human; Protein Binding; Receptors, Cell Surface; Trisaccharides

Human immunodeficiency virus-associated Hodgkin lymphoma frequently involves the bone marrow and is usually recognized at staging after Hodgkin lymphoma diagnosis on a lymph node or other tissue biopsies, but occasionally the marrow involvement is the only apparent manifestation of disease. In the latter setting, diagnosis can be problematic. From a total of 42 patients with newly diagnosed human immunodeficiency virus-associated Hodgkin lymphoma, 22 subjects had positive marrow involvement at diagnosis; 16 of them had additional substantial histological and/or clinical extramedullary Hodgkin lymphoma. In the remaining 6 patients the bone marrow was the only site of disease at diagnosis. In all six cases, bone marrow biopsy revealed obvious lymphomatous involvement. Reed-Sternberg cells were identified both morphologically and immunophenotypically in all cases. Spared marrow tissue consistently showed fibrosis. All patients were males with a median age of 35 years (range, 31-58 years). All presented with fever, blood cytopenias, and severe CD4+ lymphocyte depletion (median, 70 cells/mm(3)). After diagnosis, all staging procedures were negative, and all patients were treated with chemotherapy. Median survival was 4 months (range, 2-118 mo). Longer survival was achieved in the patients who completed chemotherapy regimens; three subjects, however, died shortly before the full completion of chemotherapy, two of them from Hodgkin lymphoma. Isolated bone marrow HIV-associated Hodgkin lymphoma may be an underestimated condition in HIV-infected patients; in those individuals with unexplained fever and blood cytopenias, bone marrow biopsy should be performed with the aim of assessing for Hodgkin lymphoma, even in the absence of nodal and visceral lymphomatous involvement. A rapid diagnosis of isolated bone marrow HIV-associated Hodgkin lymphoma could expedite therapy.

Topics: Adult; Bone Marrow; Fatal Outcome; Herpesvirus 4, Human; HIV Infections; Hodgkin Disease; Humans; Immunohistochemistry; In Situ Hybridization; Ki-1 Antigen; Lewis X Antigen; Male; Middle Aged; RNA, Viral

Novel carbohydrate antigen expressions were observed on T lymphocytes from HIV infected patients using flowcytometric analysis with four mAbs; BM-1, ACFH-18, FH-2 and C-6. These carbohydrate antigens were also expressed on oncogenic transformed cells but were either not expressed or were weakly expressed in lymphocyte populations from healthy subjects. A dramatic change in glycosylation was induced on CD8+T cells from HIV infected patients. The glycosylation change correlated with the progression of the disease. The incidence of Ley antigen expression on CD8+T cells increased as the disease progressed with the ongoing impairment of immune function. The phenotype change that occurred with Ley antigen expression might reflect the abnormal activation of T lymphocytes of some specific, but unknown, population of CD8+T cells. Thus, carbohydrate changes on the cell surface may induce immunological abnormality and accelerate the damage within the CD4+T cell subset, resulting in an impairment of the antigen specific immune system.

Topics: Adult; Antibodies, Monoclonal; Blood Cells; Carbohydrates; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line; Cell Membrane; Female; Flow Cytometry; HIV Infections; Humans; Leukocytes; Lewis X Antigen; Lymphocytes; Male; Middle Aged