Publications
382 results found
Pattani A, McKay PF, Curran RM, et al., 2012, Molecular investigations into vaginal immunization with HIV gp41 antigenic construct H4A in a quick release solid dosage form, VACCINE, Vol: 30, Pages: 2778-2785, ISSN: 0264-410X
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- Citations: 4
Moore JP, Klasse PJ, Veazey RA, et al., 2012, Towards Coitally-Independent Microbicides: Studies with Vaginal Rings and Silicone-Based Gel Delivery Systems, 13th Annual International Meeting of the Institute of Human Virology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 43-43, ISSN: 1525-4135
Mann JFS, Stieh D, Klein K, et al., 2012, Transferrin conjugation confers mucosal molecular targeting to a model HIV-1 trimeric gp140 vaccine antigen, JOURNAL OF CONTROLLED RELEASE, Vol: 158, Pages: 240-249, ISSN: 0168-3659
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- Citations: 14
Ochsenbauer C, Edmonds TG, Ding H, et al., 2012, Generation of Transmitted/Founder HIV-1 Infectious Molecular Clones and Characterization of Their Replication Capacity in CD4 T Lymphocytes and Monocyte-Derived Macrophages, JOURNAL OF VIROLOGY, Vol: 86, Pages: 2715-2728, ISSN: 0022-538X
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- Citations: 252
Harman SJ, Herrera C, Armanasco N, et al., 2012, Pre-clinical evaluation of the HIV-1 fusion inhibitor L'644 as a potential candidate microbicide., Antimicrobial Agents and Chemotherapy
Topical blockade of the gp41 fusogenic protein of HIV-1 is one possible strategy by which microbicides could prevent HIV transmission, working early against infection, by inhibiting viral entry into host cells. In this study we examined the potential of gp41 fusion inhibitors (FIs) as candidate anti-HIV microbicides. Preclinical evaluation of four FIs, C34, T20, T1249 and L'644, was performed using cellular and ex vivo genital and colorectal tissue explant models. Increased and sustained activity was detected for L'644, a cholesterol derivatized version of C34 relative to the other FIs. The higher potency of L'644 was further increased with sustained exposure of cells or tissue to the compound. The activity of L'644 was not affected by biological fluids and the compound was still active when tissue explants where treated after viral exposure. L'644 was also more active than other FIs against a viral escape mutant resistant to reverse transcriptase inhibitors (RTIs), demonstrating the potential of L'644 to be included as part of a multi-active ARV-combination based microbicide. These data support further development of L'644 for microbicide application.
Huang X, Jin W, Hu K, et al., 2012, Highly conserved HIV-1 gp120 glycans proximal to CD4-binding region affect viral infectivity and neutralizing antibody induction, VIROLOGY, Vol: 423, Pages: 97-106, ISSN: 0042-6822
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- Citations: 43
Van Roey GA, Arias MA, Tregoning JS, et al., 2012, Thymic stromal lymphopoietin (TSLP) acts as a potent mucosal adjuvant for HIV-1 gp140 vaccination in mice, European Journal of Immunology, Vol: 42, Pages: 353-363, ISSN: 1521-4141
The development of a successful vaccine against HIV is likely to require the induction of strong and long-lasting humoral immune responses at the mucosal portal of virus entry. Hence, the design of a vaccine strategy able to induce mucosal antibodies and in particular specific IgA, may be crucial to providing immune protection. Nasal immunisation is known to induce specific IgG and IgA responses in the cervicovaginal mucosa; however, there is an urgent need for the development of safe, effective and accessible mucosal adjuvants for nasal application in humans. To reduce the potential for adverse events associated with some nasal adjuvants, we have assessed whether the B-cell-activating cytokines APRIL, BAFF and TSLP enhance humoral immune responses to HIV-1 gp140. Following intranasal immunisation, TSLP but not APRIL or BAFF induced strong humoral responses both in serum and mucosa. The adjuvant effect of TSLP on humoral responses was similar to that of cholera toxin (CT). The use of TSLP as an adjuvant skewed both the cellular and humoral immune responses towards Th2 cells. This is the first time that TSLP has been demonstrated to have a positive effect as a mucosal adjuvant, and specifically to promote mucosal and systemic responses to HIV gp140.
McFadden K, Fletcher P, Rossi F, et al., 2012, Antiviral Breadth and Combination Potential of Peptide Triazole HIV-1 Entry Inhibitors, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 56, Pages: 1073-1080, ISSN: 0066-4804
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- Citations: 28
Shattock RJ, Rosenberg Z, 2012, Microbicides: topical prevention against HIV., Cold Spring Harb Perspect Med, Vol: 2
Microbicides represent a potential intervention strategy for preventing HIV transmission. Vaginal microbicides would meet the need for a discreet method that women could use to protect themselves against HIV. Although early-generation microbicides failed to demonstrate efficacy, newer candidates are based on more potent antiretroviral (ARV) products. Positive data from the CAPRISA 004 trial of tenofovir gel support use in women and represent a turning point for the field. This article reviews current progress in development of ARV-based microbicides. We discuss the consensus on selection criteria, the potential for drug resistance, rationale for drug combinations, and the use of pharmacokinetic (PK)/pharmacodynamic (PD) assessment in product development. The urgent need for continued progress in development of formulations for sustained delivery is emphasized. Finally, as the boundaries between different prevention technologies become increasingly blurred, consideration is given to the potential synergy of diverse approaches across the prevention landscape.
Herrera C, Shattock RJ, 2012, Potential Use of Protease Inhibitors as Vaginal and Colorectal Microbicides, CURRENT HIV RESEARCH, Vol: 10, Pages: 42-52, ISSN: 1570-162X
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- Citations: 17
Veazey RS, Shattock RJ, Klasse PJ, et al., 2012, Animal Models for Microbicide Studies, CURRENT HIV RESEARCH, Vol: 10, Pages: 79-87, ISSN: 1570-162X
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- Citations: 46
Shattock R, Rosenberg Z, 2012, Microbicides: Topical Prevention against HIV, HIV: From Biology to Prevention and Treatment, Editors: Bushman, Nabel, Swanstrom, Publisher: Cold Spring Harbor Laboratory Press, Pages: 505-521
Forbes CJ, Lowry D, Geer L, et al., 2011, Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc, JOURNAL OF CONTROLLED RELEASE, Vol: 156, Pages: 161-169, ISSN: 0168-3659
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- Citations: 45
Kelly CG, Shattock RJ, 2011, Specific microbicides in the prevention of HIV infection, JOURNAL OF INTERNAL MEDICINE, Vol: 270, Pages: 509-519, ISSN: 0954-6820
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- Citations: 24
Herrera C, Cranage M, McGowan I, et al., 2011, Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants, AIDS, Vol: 25, Pages: 1971-1979, ISSN: 0269-9370
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- Citations: 42
Huang X, Jin W, Griffin GE, et al., 2011, Removal of two high-mannose <i>N</i>-linked glycans on gp120 renders human immunodeficiency virus 1 largely resistant to the carbohydrate-binding agent griffithsin, JOURNAL OF GENERAL VIROLOGY, Vol: 92, Pages: 2367-2373, ISSN: 0022-1317
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- Citations: 31
Van Roey GA, Arias M, Tregoning JS, et al., 2011, TSLP: A Potential New Mucosal Adjuvant for Intranasal Immunisation with GP140, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT INC, Pages: A68-A68, ISSN: 0889-2229
Veazey R, Siddiqui AA, Buffa V, et al., 2011, Evaluation of Mucosal Immunization Routes for Induction of Vaginal Humoral Immunity in Macaques., Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT INC, Pages: A68-A68, ISSN: 0889-2229
Lewis DJ, Fraser CA, Mahmoud AN, et al., 2011, Phase I randomised clinical trial of an HIV-1(CN54), clade C, trimeric envelope vaccine candidate delivered vaginally, PLoS ONE, Vol: 6, ISSN: 1932-6203
We conducted a phase 1 double-blind randomised controlled trial (RCT) of a HIV-1 envelope protein (CN54 gp140) candidate vaccine delivered vaginally to assess immunogenicity and safety. It was hypothesised that repeated delivery of gp140 may facilitate antigen uptake and presentation at this mucosal surface. Twenty two healthy female volunteers aged 18–45 years were entered into the trial, the first receiving open-label active product. Subsequently, 16 women were randomised to receive 9 doses of 100 µg of gp140 in 3 ml of a Carbopol 974P based gel, 5 were randomised to placebo solution in the same gel, delivered vaginally via an applicator. Participants delivered the vaccine three times a week over three weeks during one menstrual cycle, and were followed up for two further months. There were no serious adverse events, and the vaccine was well tolerated. No sustained systemic or local IgG, IgA, or T cell responses to the gp140 were detected following vaginal immunisations. Repeated vaginal immunisation with a HIV-1 envelope protein alone formulated in Carbopol gel was safe, but did not induce local or systemic immune responses in healthy women.
Van Roey G, Arias M, Tregoning J, et al., 2011, TSLP, a potential new mucosal adjuvant for intranasal immunisation with HIV-1 gp140, AIDS Vaccine Conference, Bangkok, Thailand
Liard C, Munier S, Arias M, et al., 2011, Targeting of HIV-p24 particle-based vaccine into differential skin layers induces distinct arms of the immune responses, VACCINE, Vol: 29, Pages: 6379-6391, ISSN: 0264-410X
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- Citations: 50
Veazey RS, Klasse PJ, Shattock RJ, et al., 2011, Vaginal application of anti-gp120 monocloncal antibody b12 prevents SHIV-162P vaginal transmission to macaques., Pages: 51-57
Shattock RJ, Warren M, McCormack S, et al., 2011, Turning the Tide Against HIV, SCIENCE, Vol: 333, Pages: 42-43, ISSN: 0036-8075
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- Citations: 69
Donnelly L, Curran RM, Tregoning JS, et al., 2011, Intravaginal immunization using the recombinant HIV-1 clade-C trimeric envelope glycoprotein CN54gp140 formulated within lyophilized solid dosage forms, Vaccine, Vol: 29, Pages: 4512-4520, ISSN: 1873-2518
Vaccine-mediated prevention of primary HIV-1 infection at the heterosexual mucosal portal of entry may be facilitated by highly optimised formulations or drug delivery devices for intravaginal (i.vag) immunization. Previously we described hydroxyethylcellulose (HEC)-based rheologically structured gel vehicles (RSVs) for vaginal immunization of an HIV-1 vaccine candidate, a soluble recombinant trimeric HIV-1 clade-C envelope glycoprotein designated CN54gp140. Here we investigated the efficacy of lyophilized solid dosage formulations (LSDFs) for prolonging antigen stability and as i.vag delivery modalities. LSDFs were designed and developed that upon i.vag administration they would reconstitute with the imbibing of vaginal fluid to mucoadhesive, site-retentive semi-solids. Mice were immunized with lyophilized equivalents of (i) RSVs, (ii) modified versions of the RSVs more suited to lyophilization (sodium carboxymethyl cellulose (NaCMC)-based gels) and (iii) Carbopol® gel, all containing CN54gp140. NaCMC-based LSDFs provided significantly enhanced antigen stability compared to aqueous-based RSVs. Rheological analysis indicated the NaCMC-based LSDFs would offer enhanced vaginal retention in woman compared to more conventional vaginal gel formulations. All LSDFs were well tolerated in the mouse model. Following i.vag administration, all LSDFs boosted systemic CN54gp140-specific antibody responses in sub-cutaneously primed mice. Induction of CN54gp140-specific antibody responses in the female genital tract was evident. Of all the LSDFs the fastest releasing which was lyophilized Carbopol® gel elicited immune responses comparable to buffer instillation of antigen suggesting that rather than slower sustained release, initial high burst release from the LSDFs may suffice. The boosting of specific immune responses upon i.vag administration indicates that LSDFs are viable mucosal vaccine delivery modalities promoting antigen stability and facilitating intimate exposur
Brinckmann S, da Costa K, van Gils MJ, et al., 2011, Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010, JOURNAL OF TRANSLATIONAL MEDICINE, Vol: 9
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- Citations: 8
Cranage MP, Fraser CA, Cope A, et al., 2011, Antibody responses after intravaginal immunisation with trimeric HIV-1(CN54) clade C gp140 in Carbopol gel are augmented by systemic priming or boosting with an adjuvanted formulation, Vaccine, Vol: 29, Pages: 1421-1430, ISSN: 0264-410X
Optimum strategies to elicit and maintain antibodies at mucosal portals of virus entry are critical for the development of vaccines against human immunodeficiency virus (HIV). Here we show in non-human primates that a novel regimen of repeated intravaginal delivery of a non-adjuvanted, soluble recombinant trimeric HIV-1(CN54) clade C envelope glycoprotein (gp140) administered in Carbopol gel can prime for B-cell responses even in the absence of seroconversion. Following 3 cycles of repeated intravaginal administration, throughout each intermenses interval, 3 of 4 macaques produced or boosted systemic and mucosally-detected antibodies upon intramuscular immunisation with gp140 formulated in AS01 adjuvant. Reciprocally, a single intramuscular immunisation primed 3 of 4 macaques for antibody boosting after a single cycle of intravaginal immunisation. Virus neutralising activity was detected against clade C and clade B HIV-1 envelopes but was restricted to highly neutralisation sensitive pseudoviruses. (C) 2010 Elsevier Ltd. All rights reserved.
Arias MA, Loxley A, Eatmon C, et al., 2011, Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen, VACCINE, Vol: 29, Pages: 1258-1269, ISSN: 0264-410X
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- Citations: 26
Grivel J-C, Shattock RJ, Margolis LB, 2011, Selective transmission of R5 HIV-1 variants: where is the gatekeeper?, JOURNAL OF TRANSLATIONAL MEDICINE, Vol: 9, ISSN: 1479-5876
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- Citations: 101
Wegmann F, Krashias G, Luehn K, et al., 2011, A Novel Strategy for Inducing Enhanced Mucosal HIV-1 Antibody Responses in an Anti-Inflammatory Environment, PLOS ONE, Vol: 6, ISSN: 1932-6203
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- Citations: 11
Hijazi K, Wang Y, Scala C, et al., 2011, DC-SIGN increases the affinity of HIV-1 envelope glycoprotein interaction with CD4., PLoS One, Vol: 6
Mannose-binding C-type lectin receptors, expressed on Langerhans cells and subepithelial dendritic cells (DCs) of cervico-vaginal tissues, play an important role in HIV-1 capture and subsequent dissemination to lymph nodes. DC-SIGN has been implicated in both productive infection of DCs and the DC-mediated trans infection of CD4(+) T cells that occurs in the absence of replication. However, the molecular events that underlie this efficient transmission have not been fully defined. In this study, we have examined the effect of the extracellular domains of DC-SIGN and Langerin on the stability of the interaction of the HIV-1 envelope glycoprotein with CD4 and also on replication in permissive cells. Surface plasmon resonance analysis showed that DC-SIGN increases the binding affinity of trimeric gp140 envelope glycoproteins to CD4. In contrast, Langerin had no effect on the stability of the gp140:CD4 complex. In vitro infection experiments to compare DC-SIGN enhancement of CD4-dependent and CD4-independent strains demonstrated significantly lower enhancement of the CD4-independent strain. In addition DC-SIGN increased the relative rate of infection of the CD4-dependent strain but had no effect on the CD4-independent strain. DC-SIGN binding to the HIV envelope protein effectively increases exposure of the CD4 binding site, which in turn contributes to enhancement of infection.
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