270 results found
Herrera C, Schuetz A, Olejniczak N, et al., 2013, Preliminary Evaluation of Mucosal Immune Responses with Mucosal Explants in Humans Vaccinated with ALVAC/AIDSVAX B/E During the Ongoing RV305 Trial, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A181-A181, ISSN: 0889-2229
Herrera C, Olejniczak N, Karasavva N, et al., 2013, Use of Tissue Explants to Evaluate Mucosal Immune Responses in Non-Human Primates (NHPs) Vaccinated with ALVAC/AIDSVAX B/E, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A105-A105, ISSN: 0889-2229
Cosgrove CA, Lacey C, Cope AV, et al., 2013, A Phase I Clinical Trial of an HIV-1(CN54), Clade C, Trimeric Envelope Vaccine Delivered by Parenteral, Nasal and Vaginal Routes of Immunisation, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A9-A9, ISSN: 0889-2229
Klein K, Veazey RS, Warrier R, et al., 2013, Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge., Journal of virology, Vol: 87, Pages: 11604-11616
Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5 mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans.
Mann JFS, McKay PF, Arokiasamy S, et al., 2013, Pulmonary delivery of DNA vaccine constructs using deacylated PEI elicits immune responses and protects against viral challenge infection, JOURNAL OF CONTROLLED RELEASE, Vol: 170, Pages: 452-459, ISSN: 0168-3659
Hu K, Luo S, Tong L, et al., 2013, CCL19 and CCL28 Augment Mucosal and Systemic Immune Responses to HIV-1 gp140 by Mobilizing Responsive Immunocytes into Secondary Lymph Nodes and Mucosal Tissue, JOURNAL OF IMMUNOLOGY, Vol: 191, Pages: 1935-1947, ISSN: 0022-1767
Mann JFS, Mckay PF, Arokiasamy S, et al., 2013, Mucosal Application of gp140 Encoding DNA Polyplexes to Different Tissues Results in Altered Immunological Outcomes in Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203
Stieh DJ, Phillips JL, Rogers PM, et al., 2013, Dynamic electrophoretic fingerprinting of the HIV-1 envelope glycoprotein, Retrovirology, Vol: 10, ISSN: 1742-4690
Background: Interactions between the HIV-1 envelope glycoprotein (Env) and its primary receptor CD4 areinfluenced by the physiological setting in which these events take place. In this study, we explored the surfacechemistry of HIV-1 Env constructs at a range of pH and salinities relevant to mucosal and systemic compartmentsthrough electrophoretic mobility (EM) measurements. Sexual transmission events provide a more acidicenvironment for HIV-1 compared to dissemination and spread of infection occurring in blood or lymph node. Wehypothesize functional, trimeric Env behaves differently than monomeric forms.Results: The dynamic electrophoretic fingerprint of trimeric gp140 revealed a change in EM from strongly negativeto strongly positive as pH increased from that of the lower female genital tract (pHx) to that of the blood (pHy).Similar findings were observed using a trimeric influenza Haemagglutinin (HA) glycoprotein, indicating that thismay be a general attribute of trimeric viral envelope glycoproteins. These findings were supported bycomputationally modeling the surface charge of various gp120 and HA crystal structures. To identify the behaviorof the infectious agent and its target cells, EM measurements were made on purified whole HIV-1 virions andprimary T-lymphocytes. Viral particles had a largely negative surface charge, and lacked the regions of positivitynear neutral pH that were observed with trimeric Env. T cells changed their surface chemistry as a function ofactivation state, becoming more negative over a wider range of pH after activation. Soluble recombinant CD4(sCD4) was found to be positively charged under a wide range of conditions. Binding studies between sCD4 andgp140 show that the affinity of CD4-gp140 interactions depends on pH.Conclusions: Taken together, these findings allow a more complete model of the electrochemical forces involvedin HIV-1 Env functionality. These results indicate that the influence of the localized environment on the inter
King DFL, Siddiqui AA, Buffa V, et al., 2013, Mucosal Tissue Tropism and Dissemination of HIV-1 Subtype B Acute Envelope-Expressing Chimeric Virus, JOURNAL OF VIROLOGY, Vol: 87, Pages: 890-899, ISSN: 0022-538X
Buffa V, Klein K, Fischetti L, et al., 2012, Evaluation of TLR Agonists as Potential Mucosal Adjuvants for HIV gp140 and Tetanus Toxoid in Mice, PLOS ONE, Vol: 7, ISSN: 1932-6203
Merbah M, Arakelyan A, Edmonds T, et al., 2012, HIV-1 Expressing the Envelopes of Transmitted/Founder or Control/Reference Viruses Have Similar Infection Patterns of CD4 T-Cells in Human Cervical Tissue Ex Vivo, PLOS ONE, Vol: 7, ISSN: 1932-6203
Pattani A, McKay PF, Garland MJ, et al., 2012, Microneedle mediated intradermal delivery of adjuvanted recombinant HIV-1 CN54gp140 effectively primes mucosal boost inoculations, JOURNAL OF CONTROLLED RELEASE, Vol: 162, Pages: 529-537, ISSN: 0168-3659
McKay PF, Cope AV, Swales J, et al., 2012, Antigen-specific T lymphocyte responses elicited by a DNA - MVA HIV CN54gp140 immunization regime are significantly altered by the TLR4 adjuvant GLA, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
McKay PF, Mann JF, Pattani A, et al., 2012, Intravaginal immunization using a novel antigen delivery device elicits robust vaccine antigen-specific systemic and mucosal humoral immune responses, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Mann JF, McKay PF, Swales J, et al., 2012, Optimising CN54gp140 plasmid delivery by comparing intramuscular and intradermal vaccination combinations with and without electroporation, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Du T, Hu K, Yang J, et al., 2012, Bifunctional CD4-DC-SIGN Fusion Proteins Demonstrate Enhanced Avidity to gp120 and Inhibit HIV-1 Infection and Dissemination, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 56, Pages: 4640-4649, ISSN: 0066-4804
Stefanidou M, Herrera C, Armanasco N, et al., 2012, Saquinavir Inhibits Early Events Associated with Establishment of HIV-1 Infection: Potential Role for Protease Inhibitors in Prevention, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 56, Pages: 4381-4390, ISSN: 0066-4804
Arias MA, Van Roey GA, Tregoning JS, et al., 2012, Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4 Agonist, Promotes Potent Systemic and Mucosal Responses to Intranasal Immunization with HIVgp140, PLOS One, Vol: 7, ISSN: 1932-6203
Successful vaccine development against HIV will likely require the induction of strong, long-lasting humoral and cellularimmune responses in both the systemic and mucosal compartments. Based on the known immunological linkage betweenthe upper-respiratory and urogenital tracts, we explored the potential of nasal adjuvants to boost immunization for theinduction of vaginal and systemic immune responses to gp140. Mice were immunized intranasally with HIV gp140 togetherwith micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA) and responseswere compared to R848, a TLR7/8 agonist, or chitosan, a non TLR adjuvant. GLA and chitosan but not R848 greatlyenhanced serum immunoglobulin levels when compared to antigen alone. Both GLA and chitosan induced high IgG andIgA titers in nasal and vaginal lavage and feces. The high IgA and IgG titers in vaginal lavage were associated with highnumbers of gp140-specific antibody secreting cells in the genital tract. Whilst both GLA and chitosan induced T cellresponses to immunization, GLA induced a stronger Th17 response and chitosan induced a more Th2 skewed response. Ourresults show that GLA is a highly potent intranasal adjuvant greatly enhancing humoral and cellular immune responses,both systemically and mucosally.
Ruffin N, Borggren M, Euler Z, et al., 2012, Rational design of HIV vaccines and microbicides: report of the EUROPRISE annual conference 2011, JOURNAL OF TRANSLATIONAL MEDICINE, Vol: 10, ISSN: 1479-5876
Huang W, Hu K, Luo S, et al., 2012, Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4(+) T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-beta Pathway, JOURNAL OF IMMUNOLOGY, Vol: 188, Pages: 6247-6257, ISSN: 0022-1767
Malcolm RK, Veazey RS, Geer L, et al., 2012, Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 56, Pages: 2251-2258, ISSN: 0066-4804
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
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
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
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
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.
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.
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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