272 results found
van de Wijgert J, Shattock RJ, 2008, Vaginal microbicides: the importance of effective distribution, retention and coating of the mucosa, AIDS, Vol: 22, Pages: 1231-1232, ISSN: 0269-9370
Fichorova RN, Richardson-Harman N, Alfano M, et al., 2008, Biological and technical variables affecting immunoassay recovery of cytokines from human serum and simulated vaginal fluid: a multicenter study., Anal Chem, Vol: 80, Pages: 4741-4751
The increase of proinflammatory cytokines in vaginal secretions may serve as a surrogate marker of unwanted inflammatory reaction to microbicide products topically applied for the prevention of sexually transmitted diseases, including HIV-1. Interleukin (IL)-1beta and IL-6 have been proposed as indicators of inflammation and increased risk of HIV-1 transmission; however, the lack of information regarding detection platforms optimal for vaginal fluids and interlaboratory variation limit their use for microbicide evaluation and other clinical applications. This study examines fluid matrix variants relevant to vaginal sampling techniques and proposes a model for interlaboratory comparisons across current cytokine detection technologies. IL-1beta and IL-6 standards were measured by 12 laboratories in four countries, using 14 immunoassays and four detection platforms based on absorbance, chemiluminescence, electrochemiluminescence, and fluorescence. International reference preparations of cytokines with defined biological activity were spiked into (1) a defined medium simulating the composition of human vaginal fluid at pH 4.5 and 7.2, (2) physiologic salt solutions (phosphate-buffered saline and saline) commonly used for vaginal lavage sampling in clinical studies of cytokines, and (3) human blood serum. Assays were assessed for reproducibility, linearity, accuracy, and significantly detectable fold difference in cytokine level. Factors with significant impact on cytokine recovery were determined by Kruskal-Wallis analysis of variance with Dunn's multiple comparison test and multiple regression models. All assays showed acceptable intra-assay reproducibility; however, most were associated with significant interlaboratory variation. The smallest reliably detectable cytokine differences ( P < 0.05) derived from pooled interlaboratory data varied from 1.5- to 26-fold depending on assay, cytokine, and matrix type. IL-6 but not IL-1beta determinations were lower in both s
Shattock RJ, Haynes BF, Pulendran B, et al., 2008, Improving defences at the portal of HIV entry: mucosal and innate immunity - A summary report from a global HIV vaccine enterprise working group, PLOS MEDICINE, Vol: 5, Pages: 537-541, ISSN: 1549-1277
Harman SJ, Shattock RJ, 2008, Characterisation of small molecule entry inhibitors in human cervical and penile tissue models, Microbicides 2008
Fletcher PS, Shattock RJ, 2008, PRO-2000, an antimicrobial gel for the potential prevention of HIV infection, CURRENT OPINION IN INVESTIGATIONAL DRUGS, Vol: 9, Pages: 189-200, ISSN: 1472-4472
Fletcher PS, Harman SJ, Boothe AR, et al., 2008, Preclinical evaluation of lime juice as a topical microbicide candidate, RETROVIROLOGY, Vol: 5, ISSN: 1742-4690
Fletcher PS, Shattock RJ, 2008, PRO-2000, an antimicrobial gel for the potential prevention of HIV infection, Vol: 9, Pages: 189-200, ISSN: 1472-4472
Fletcher PS, Harman SJ, Boothe AR, et al., 2008, Preclinical evaluation of lime juice as a topical microbicide candidate, Vol: 5, ISSN: 1742-4690
Klasse PJ, Shattock R, Moore JP, 2008, Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission., Annu Rev Med, Vol: 59, Pages: 455-471, ISSN: 0066-4219
The development of a vaginal (and perhaps a rectal) microbicide would be of major benefit for slowing the global spread of human immunodeficiency virus type 1 (HIV-1). A microbicide is a gel or related device that, when inserted vaginally or rectally, acts to prevent infection of a woman or a man by HIV-1 during sexual intercourse. A practical microbicide must be not only effective, safe, and user-friendly but also economically affordable in the developing world. To date, the performance of microbicide candidates in efficacy trials has been disappointing, but next-generation concepts now in or approaching clinical trials offer improved prospects for efficacy. The most plausible approaches involve topical application of antiretroviral agents with specific activity against HIV-1, compounds similar to drugs used to treat HIV-1 infection. How these inhibitors are applied may also be critical, with sustained-release formulations and vaginal ring delivery systems now becoming a high priority.
Arias MA, Jaramillo G, Lopez YP, et al., 2007, Mycobacterium tuberculosis antigens specifically modulate CCR2 and MCP-1/CCL2 on lymphoid cells from human pulmonary hilar lymph nodes, JOURNAL OF IMMUNOLOGY, Vol: 179, Pages: 8381-8391, ISSN: 0022-1767
van de Wijgert JHHM, Shattock RJ, 2007, Vaginal microbicides: moving ahead after an unexpected setback, AIDS, Vol: 21, Pages: 2369-2376, ISSN: 0269-9370
Hu Q, Mahmood N, Shattock RJ, 2007, High-mannose-specific deglycosylation of HIV-1 gp120 induced by resistance to cyanovirin-N and the impact on antibody neutralization, VIROLOGY, Vol: 368, Pages: 145-154, ISSN: 0042-6822
Tao J, Hu Q, Yang J, et al., 2007, In vitro anti-HIV and -HSV activity and safety of sodium rutin sulfate as a microbicide candidate., Antiviral Res, Vol: 75, Pages: 227-233, ISSN: 0166-3542
Sodium rutin sulfate (SRS) is a sulfated rutin modified from the natural flavonol glycoside rutin. Here, we investigated its in vitro anti-HIV and -HSV activities and its cytotoxic profile. Fifty percent inhibitory concentration (IC(50)) values of SRS against HIV-1 X4 virus IIIB, HIV-1 R5 isolates Ada-M and Ba-L were 2.3+/-0.2, 4.5+/-2.0 and 8.5+/-3.8 microM with a selectivity index (SI) of 563, 575 and 329, respectively. Its IC(50) against primary R5 HIV-1 isolate from Yunnan province in China was 13.1+/-5.5 microM, with a SI of 197. In contrast, unsulfated rutin had no activity against any of the HIV-1 isolates tested. Further study indicated that SRS blocked viral entry and virus-cell fusion likely through interacting with the HIV-1 envelope glycoprotein. SRS also demonstrated some activity against human herpes simplex virus (HSV) with an IC(50) of 88.3+/-0.1 microM and a SI of 30. The 50% cytotoxicity concentration (CC(50)) of SRS was >3.0 mM, as determined in human genital ME180, HeLa and primary human foreskin fibroblast cells. Minimum inhibitory concentration of SRS for vaginal lactobacilli was >3.0 mM. These results collectively indicate that SRS represents a novel candidate for anti-HIV-1/HSV microbicide development.
Madan RP, Mesquita PMM, Cheshenko N, et al., 2007, Molecular umbrellas: a novel class of candidate topical microbicides to prevent human immunodeficiency virus and herpes simplex virus infections, JOURNAL OF VIROLOGY, Vol: 81, Pages: 7636-7646, ISSN: 0022-538X
Grivel J-C, Elliott J, Lisco A, et al., 2007, HIV-1 pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with CCR5-and CXCR4-tropic HIV-1, AIDS, Vol: 21, Pages: 1263-1272, ISSN: 0269-9370
McFadden K, Cocklin S, Gopi H, et al., 2007, A recombinant allosteric lectin antagonist of HIV-1 envelope gp120 interactions., Proteins, Vol: 67, Pages: 617-629
The first, critical stage of HIV-1 infection is fusion of viral and host cellular membranes initiated by a viral envelope glycoprotein gp120. We evaluated the potential to form a chimeric protein entry inhibitor that combines the action of two gp120-targeting molecules, an allosteric peptide inhibitor 12p1 and a higher affinity carbohydrate-binding protein cyanovirin (CVN). In initial mixing experiments, we demonstrated that the inhibitors do not interfere with each other and instead show functional synergy in inhibiting viral cell infection. Based on this, we created a chimera, termed L5, with 12p1 fused to the C-terminal domain of CVN through a linker of five penta-peptide repeats. L5 revealed the same broad specificity as CVN for gp120 from a variety of clades and tropisms. By comparison to CVN, the L5 chimera exhibited substantially increased inhibition of gp120 binding to receptor CD4, coreceptor surrogate mAb 17b and gp120 antibody F105. These binding inhibition effects by the chimera reflected both the high affinity of the CVN domain and the allosteric action of the 12p1 domain. The results open up the possibility to form high potency chimeras, as well as noncovalent mixtures, as leads for HIV-1 envelope antagonism that can overcome potency limits and potential virus mutational resistance for either 12p1 or CVN alone.
Arias MA, Pantoja AE, Jaramillo G, et al., 2007, Chemokine/cytokine production by mononuclear cells from human lymphoid tissues and their modulation by Mycobacterium tuberculosis antigens, FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY, Vol: 49, Pages: 272-279, ISSN: 0928-8244
Fairhurst D, Rowell RL, Monahan IM, et al., 2007, Microbicides for HIV/AIDS. 2. Electrophoretic fingerprinting of CD4+ T-cell model systems., Langmuir, Vol: 23, Pages: 2680-2687, ISSN: 0743-7463
New measurements of the dependence of the surface charge on the pH and electrolyte concentration for three living human white blood cell lines that are the principal targets of the HIV-1 virus are reported. Comparison of the electrophoretic fingerprint (EF) pattern, especially the line of zero mobility, with that of reference colloids establishes the separate individual identities and shows that all three exhibit a zwitterionic surface. With the EF results as a guide, preliminary biological infectivity measurements showed that small polyvalent cations modulate the negative charge on the T-cell surface in a way that strongly affects the infection kinetics. H9 cells were exposed to an infectious virus (X4), and the data showed that HIV interaction with target cells is enhanced by physiological fluids. The nondestructive methodology described is generally applicable to characterization of the surface charge and determination of the colloidal stability of any aqueous charged colloidal system without reference to any model of the double layer.
Hu Q, Younson J, Griffin GE, et al., 2006, Pertussis toxin and its binding unit inhibit HIV-1 infection of human cervical tissue and macrophages involving a CD14 pathway, JOURNAL OF INFECTIOUS DISEASES, Vol: 194, Pages: 1547-1556, ISSN: 0022-1899
Current HIV/AIDS statistics show that women account for almost 60% of HIV infections in Sub-Saharan Africa. HIV prevention tools such as male and female condoms, abstinence and monogamy are not always feasible options for women due to various socio-economic and cultural factors. Microbicides are products designed to be inserted in the vagina or rectum prior to sex to prevent HIV acquisition. The biannual Microbicides conference took place in Cape Town, South Africa from 23-26 April 2006. The conference was held for the first time on the African continent, the region worst affected by the HIV/AIDS pandemic. The conference brought together a record number of 1,300 scientists, researchers, policy makers, healthcare workers, communities and advocates. The conference provided an opportunity for an update on microbicide research and development as well as discussions around key issues such as ethics, acceptability, access and community involvement. This report discusses the current status of microbicide research and development, encompassing basic and clinical science, social and behavioural science, and community mobilisation and advocacy activities.
Klasse PJ, Shattock RJ, Moore JP, 2006, Which topical microbicides for blocking HIV-1 transmission will work in the real world?, PLOS MEDICINE, Vol: 3, Pages: 1501-1507, ISSN: 1549-1676
Siddiqui AA, Shattock RJ, Harrison TS, 2006, Role of capsule and interleukin-6 in long-term immune control of Cryptococcus neoformans infection by specifically activated human peripheral blood mononuclear cells, INFECTION AND IMMUNITY, Vol: 74, Pages: 5302-5310, ISSN: 0019-9567
Soilleux EJ, Sarno EN, Hernandez MO, et al., 2006, DC-SIGN association with the Th2 environment of lepromatous leprosy lesions: cause or effect?, 190th Meeting of the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: JOHN WILEY & SONS LTD, Pages: 55-55, ISSN: 0022-3417
Fletcher PS, Wallace GS, Mesquita PMM, et al., 2006, Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants, RETROVIROLOGY, Vol: 3, ISSN: 1742-4690
Fletcher PS, Elliott J, Grivel J-C, et al., 2006, Ex vivo culture of human colorectal tissue for the evaluation of candidate microbicides, AIDS, Vol: 20, Pages: 1237-1245, ISSN: 0269-9370
Arias MA, Pantoja AE, Jaramillo G, et al., 2006, Chemokine receptor expression and modulation by Mycobacterium tuberculosis antigens on mononuclear cells from human lymphoid tissues, IMMUNOLOGY, Vol: 118, Pages: 171-184, ISSN: 0019-2805
Soilleux EJ, Sarno EN, Hernandez MO, et al., 2006, DC-SIGN association with the Th2 environment of lepromatous lesions: cause or effect?, J Pathol, Vol: 209, Pages: 182-189, ISSN: 0022-3417
The clinical spectrum of leprosy is related to patients' immune responses. Non-responsiveness towards Mycobacterium leprae (ML) seems to correlate with a Th2 cytokine profile. The reason for such a polarized immune response remains unclear. The C-type lectin, DC-SIGN, expressed by subsets of dendritic cells (DCs) and macrophages, has previously been associated with Th2 responses. Here we show abundant DC-SIGN expression in lepromatous but not borderline tuberculoid leprosy, in both HIV-positive and HIV-negative patients. Moreover, we demonstrate that DC-SIGN can act as an entry receptor for ML, as it does for M. tuberculosis, through the cell wall component lipoarabinomannan. DC-SIGN is expressed on virtually all ML-containing cells, providing further evidence for its role as a receptor. DC-SIGN may therefore be induced on macrophages in lepromatous leprosy and may then contribute to mycobacterial entry into these cells.
Harman SJ, Fletcher P, Shattock RJ, et al., 2006, Preclinical evaluation of lime juice as a potential microbicide, Microbicides 2006
Lu H, Zhao Q, Wallace G, et al., 2006, Cellulose acetate 1,2-benzenedicarboxylate inhibits infection by cell-free and cell-associated primary HIV-1 isolates., AIDS Res Hum Retroviruses, Vol: 22, Pages: 411-418, ISSN: 0889-2229
Cellulose acetate 1,2-benzenedicarboxylate (CAP), a pharmaceutical excipient used for enteric film coating of capsules and tablets, was previously shown to have potent inhibitory activity against infection by human immunodeficiency virus type 1 (HIV-1) T cell line-adapted (TCLA) strains. In the present study, we determined the inhibitory activity of CAP against infection by cell-free and cell-associated primary HIV-1 isolates with distinct genotypes and biotypes in cervical explants, peripheral blood mononuclear cells (PBMCs), monocytederived macrophages (MDMs), and CEMx174 5.25M7 cells. CAP blocked infection by cell-free and cell-associated HIV-1 in cervical explants. It inhibited infection by cell-free primary HIV-1 isolates (clades A to G and group O) in PBMCs, MDMs, and CEMx174 5.25M7 cells and blocked transmissions of the cell-associated primary HIV-1 isolates from dendritic cells (DCs) to PBMCs, from MDMs to PBMCs, and from PBMCs to CEMx174 5.25M7 cells. The inhibitory activity of CAP on infection by the cell-free and cell-associated primary HIV-1 isolates is independent of viral subtypes and coreceptor usage. These data suggest that CAP is a good microbicide candidate that can be further developed for preventing sexual transmission of HIV-1.
Khadra A, Fletcher P, Luzzi G, et al., 2006, Interleukin-8 levels in seminal plasma in chronic prostatitis/chronic pelvic pain syndrome and nonspecific urethritis., BJU Int, Vol: 97, Pages: 1043-1046, ISSN: 1464-4096
OBJECTIVE: To investigate whether a range of cytokines were detectable in the seminal plasma and urine of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and nonspecific urethritis (NSU), and whether cytokine levels correlated with symptom severity in CP/CPPS. PATIENTS AND METHODS: In all, 87 men participated, 33 with CP/CPPS, 31 with NSU, and 23 controls. Interleukin (IL)-1beta, IL-2, IL-6, IL-8 and IL-10 were measured in seminal plasma and first pass urine, and the results were correlated with scores for pain, urinary symptoms and quality-of-life impact using a validated symptom index, the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). RESULTS: Seminal plasma levels of IL-8 were higher in men with CP/CPPS and NSU than in controls (P < 0.001), and the levels correlated with NIH-CPSI symptom scores in men with CP/CPPS. There were no significant differences in urinary IL-8 levels in the three groups, and no significant differences in levels of the other cytokines in either semen or urine. CONCLUSION: Semen IL-8 levels correlate with subjective symptoms in men with CP/CPPS. IL-8 might contribute to the pathophysiology of CP/CPPS and NSU, and elevated levels might be a useful marker of the condition.
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