273 results found
Veazey RS, Siddiqui A, Klein K, et al., 2015, Evaluation of mucosal adjuvants and immunization routes for the induction of systemic and mucosal humoral immune responses in macaques, Human Vaccines & Immunotherapeutics, Vol: 11, Pages: 2913-2922, ISSN: 2164-5515
Delivering vaccine antigens to mucosal surfaces is potentially very attractive, especially as protection from mucosal infections may be mediated by local immune responses. However, to date mucosal immunization has had limited successes, with issues of both safety and poor immunogenicity. One approach to improve immunogenicity is to develop adjuvants that are effective and safe at mucosal surfaces. Differences in immune responses between mice and men have overstated the value of some experimental adjuvants which have subsequently performed poorly in the clinic. Due to their closer similarity, non-human primates can provide a more accurate picture of adjuvant performance. In this study we immunised rhesus macaques (Macaca mulatta) using a unique matrix experimental design that maximised the number of adjuvants screened while reducing the animal usage. Macaques were immunised by the intranasal, sublingual and intrarectal routes with the model protein antigens keyhole limpet haemocyanin (KLH), β-galactosidase (β-Gal) and ovalbumin (OVA) in combination with the experimental adjuvants Poly(I:C), Pam3CSK4, chitosan, Thymic Stromal Lymphopoietin (TSLP), MPLA and R848 (Resiquimod). Of the routes used, only intranasal immunization with KLH and R848 induced a detectable antibody response. When compared to intramuscular immunization, intranasal administration gave slightly lower levels of antigen specific antibody in the plasma, but enhanced local responses. Following intranasal delivery of R848, we observed a mildly inflammatory response, but no difference to the control. From this we conclude that R848 is able to boost antibody responses to mucosally delivered antigen, without causing excess local inflammation.
King DFL, McKay PF, Mann JFS, et al., 2015, Plasmid DNA Vaccine Co-Immunisation Modulates Cellular and Humoral Immune Responses Induced by Intranasal Inoculation in Mice, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundAn effective HIV vaccine will likely require induction of both mucosal and systemic cellularand humoral immune responses. We investigated whether intramuscular (IM) delivery ofelectroporated plasmid DNA vaccine and simultaneous protein vaccinations by intranasal(IN) and IM routes could be combined to induce mucosal and systemic cellular and humoralimmune responses to a model HIV-1 CN54 gp140 antigen in mice.ResultsCo-immunisation of DNA with intranasal protein successfully elicited both serum and vaginalIgG and IgA responses, whereas DNA and IM protein co-delivery did not induce systemicor mucosal IgA responses. Cellular IFNγ responses were preserved in coimmunisationprotocols compared to protein-only vaccination groups. The addition of DNAto IN protein vaccination reduced the strong Th2 bias observed with IN protein vaccinationalone. Luminex analysis also revealed that co-immunisation with DNA and IN proteininduced expression of cytokines that promote B-cell function, generation of TFH cells andCCR5 ligands that can reduce HIV infectivity.SignificanceThese data suggest that while IN inoculation alone elicits both cellular and humoralresponses, co-administration with homologous DNA vaccination can tailor these towards amore balanced Th1/Th2 phenotype modulating the cellular cytokine profile while elicitinghigh-levels of antigen-specific antibody. This work provides insights on how to generate differentialimmune responses within the same vaccination visit, and supports co-immunisationwith DNA and protein by a mucosal route as a potential delivery strategy for HIVvaccines.
Badamchi-Zadeh A, McKay PF, Holland MJ, et al., 2015, Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies, PLOS ONE, Vol: 10, ISSN: 1932-6203
Mora-Peris B, Winston A, Garvey L, et al., 2015, HIV-1 CNS in vitro infectivity models based on clinical CSF samples, Journal of Antimicrobial Chemotherapy, Vol: 71, Pages: 235-243, ISSN: 1460-2091
Background The concentration of antiretrovirals in CSF is often utilized as a surrogate for CNS drug exposure. This measurement does not consider pharmacodynamic or combinative effects of ART. We have developed a novel endpoint measurement to assess antiretroviral activity of CSF from subjects on ART.Methods CSF samples were obtained from patients receiving tenofovir/emtricitabine (245/200 mg once daily) with either rilpivirine (25 mg once daily) or lopinavir/ritonavir/maraviroc (400/100/150 mg twice daily) and HIV-uninfected controls. Antiviral activity of ART-containing CSF was assessed in cell cultures using PBMCs and neuro-derived glial (U87) and astrocyte (373) cell lines. Infectivity model half-maximal inhibitory concentration (IMIC50) values were calculated and expressed as −log2IMIC50. Results were correlated with CSF antiretroviral concentrations.Results Compared with controls, CSF from both ART studies demonstrated in vitro antiretroviral activity in all models. CSF antiretroviral activity of patients on lopinavir/ritonavir/maraviroc was significantly greater than that of patients on rilpivirine [−log2IMIC50 (95% CI) 4.82 (4.74–4.89) versus 3.43 (3.33–3.54) in PBMCs, 3.06 (2.98–3.15) versus 2.56 (2.46–2.65) in U87 cells and 6.00 (6.11–5.88) versus 4.90 (5.09–4.72) in 373 cells, respectively]. Positive correlations were observed for individual CSF antiretroviral activity in different cellular models with CSF concentrations of rilpivirine (P = 0.040 in 373 cells) and lopinavir (P = 0.048 in 373 cells), but not maraviroc.Conclusions Antiviral activity of CSF from patients on ART was successfully calculated and was greater with a regimen containing four active drugs compared with three active drugs. The use of neuro-derived cell lines alongside PBMCs to assess the effect of ART on CSF may act as a useful future clinical research tool.
Stieh DJ, King DF, Klein K, et al., 2015, Discrete partitioning of HIV-1 Env forms revealed by viral capture, RETROVIROLOGY, Vol: 12, ISSN: 1742-4690
Santra S, Tomaras GD, Warrier R, et al., 2015, Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques., Plos Pathogens, Vol: 11, ISSN: 1553-7374
HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.
Li C, Guan X, Du T, et al., 2015, Inhibition of HIV-1 infection of primary CD4(+) T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9, JOURNAL OF GENERAL VIROLOGY, Vol: 96, Pages: 2381-2393, ISSN: 0022-1317
Okala SG, King DF, Shattock RJ, 2015, Comparison of HIV-1 envelope specific IgA and IgG antiviral ability to prevent HIV-1 infection: additive, inhibitory and synergistic effects, JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, Vol: 18
Nilsson C, Hejdeman B, Godoy-Ramirez K, et al., 2015, HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundWe compared safety and immunogenicity of intradermal (ID) vaccination with and withoutelectroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA primeHIV-MVA boost vaccine in healthy Swedish volunteers.MethodsHIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and Band RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteersreceived vaccine using a needle-free device (ZetaJet) with (n=16) or without (n=9) IDEP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVACMDRexpressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performedat weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 proteinboost together with HIV-MVA.ResultsThe ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statisticallysignificant difference was seen in the IFN-γ ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV-DNA ID recipients (1/7, 14%, p=0.6158).The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-γ ELISpot responserate to 18/19 (95%). CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrablein 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and71% responders, respectively. IFN-γ and IL-2 dominated the CD4+ T cell response to Gagand Env. The CD8+ response to Gag was broader with expression of IFN-γ, IL-2, MIP-1βand/or CD107. No differences were seen between DNA vaccine groups. Binding antibodieswere induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env,with the highest titers among EP/gp140 recipients.ConclusionIntradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediatedimmune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen,with or without intradermal electroporation use.
Peters PJ, Gonzalez-Perez MP, Musich T, et al., 2015, Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes, Retrovirology, Vol: 12, ISSN: 1742-4690
Background: HIV-1 variants carrying non-macrophage-tropic HIV-1 R5 envelopes (Envs) are predominantly trans‑mitted and persist in immune tissue even in AIDS patients who have highly macrophage-tropic variants in the brain.Non-macrophage-tropic R5 Envs require high levels of CD4 for infection contrasting with macrophage-tropic Envs,which can efficiently mediate infection of cells via low CD4. Here, we investigated whether non-macrophage-tropicR5 Envs from the acute stage of infection (including transmitted/founder Env) mediated more efficient infection ofectocervical explant cultures compared to non-macrophage-tropic and highly macrophage-tropic R5 Envs from latedisease.Results: We used Env+ pseudovirions that carried a GFP reporter gene to measure infection of the first cells targetedin ectocervical explant cultures. In straight titrations of Env+ pseudovirus supernatants, mac-tropic R5 Envs from latedisease mediated slightly higher infectivities for ectocervical explants although this was not significant. Surprisingly,explant infection by several T/F/acute Envs was lower than for Envs from late disease. However, when infectivity forexplants was corrected to account for differences in the overall infectivity of each Env+ pseudovirus (measured onhighly permissive HeLa TZM-bl cells), non-mac-tropic early and late disease Env+ pseudoviruses mediated signifi‑cantly higher infection. This observation suggests that cervical tissue preferentially supports non-mac-tropic Env+viruses compared to mac-tropic viruses. Finally, we show that T-cells were the main targets for infection regardless ofwhether explants were stimulated with T-cell or monocyte/macrophage cytokines. There was no evidence of mac‑rophage infection even for pseudovirions carrying highly mac-tropic Envs from brain tissue or for the highly mactropic,laboratory strain, BaL, which targeted T-cells in the explant tissue.Conclusions: Our data support ectocervical tissue as a favorable environment for non-mac-trop
Liu Y, Luo S, He S, et al., 2015, Tetherin restricts HSV-2 release and is counteracted by multiple viral glycoproteins, VIROLOGY, Vol: 475, Pages: 96-109, ISSN: 0042-6822
Li C, Jin W, Du T, et al., 2014, Binding of HIV-1 virions to α4β 7 expressing cells and impact of antagonizing α4β 7 on HIV-1 infection of primary CD4+ T cells., Virol Sin, Vol: 29, Pages: 381-392
HIV-1 envelope glycoprotein is reported to interact with α4β7, an integrin mediating the homing of lymphocytes to gut-associated lymphoid tissue, but the significance of α4β7 in HIV-1 infection remains controversial. Here, using HIV-1 strain BaL, the gp120 of which was previously shown to be capable of interacting with α4β7, we demonstrated that α4β7 can mediate the binding of whole HIV-1 virions to α4β7-expressing transfectants. We further constructed a cell line stably expressing α4β7 and confirmed the α4β7-mediated HIV-1 binding. In primary lymphocytes with activated α4β7 expression, we also observed significant virus binding which can be inhibited by an anti-α4β7 antibody. Moreover, we investigated the impact of antagonizing α4β7 on HIV-1 infection of primary CD4(+) T cells. In α4β7-activated CD4(+) T cells, both anti-α4β7 antibodies and introduction of short-hairpin RNAs specifically targeting α4β7 resulted in a decreased HIV-1 infection. Our findings indicate that α4β7 may serve as an attachment factor at least for some HIV-1 strains. The established approach provides a promising means for the investigation of other viral strains to understand the potential roles of α4β7 in HIV-1 infection.
Stieh D, King DF, Klein K, et al., 2014, Aggregate complexes of HIV-1 induced by multimeric antibodies., Retrovirology, Vol: 11, ISSN: 1742-4690
BackgroundAntibody mediated viral aggregation may impede viral transfer across mucosal surfaces by hindering viral movement in mucus, preventing transcytosis, or reducing inter-cellular penetration of epithelia thereby limiting access to susceptible mucosal CD4 T cells and dendritic cells. These functions may work together to provide effective immune exclusion of virus from mucosal tissue; however little is known about the antibody characteristics required to induce HIV aggregation. Such knowledge may be critical to the design of successful immunization strategies to facilitate viral immune exclusion at the mucosal portals of entry.ResultsThe potential of neutralizing and non-neutralizing IgG and IgA monoclonals (mAbs) to induce HIV-1 aggregation was assessed by Dynamic light scattering (DLS). Although neutralizing and non-neutralizing IgG mAbs and polyclonal HIV-Ig efficiently aggregated soluble Env trimers, they were not capable of forming viral aggregates. In contrast, dimeric (but not monomeric) IgA mAbs induced stable viral aggregate populations that could be separated from uncomplexed virions. Epitope specificity influenced both the degree of aggregation and formation of higher order complexes by dIgA. IgA purified from serum of uninfected RV144 vaccine trial responders were able to efficiently opsonize viral particles in the absence of significant aggregation, reflective of monomeric IgA.ConclusionsThese results collectively demonstrate that dIgA is capable of forming stable viral aggregates providing a plausible basis for testing the effectiveness of aggregation as a potential protection mechanism at the mucosal portals of viral entry.
Le Grand R, Bosquet NN, Dispinseri S, et al., 2014, Microbicide-vaccine Combination Provides Significant Protection against Vaginal SHIV-162P3 Challenge in Cynomolgous Monkeys, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A26-A26, ISSN: 0889-2229
Okala SG, King DF, Rogers PM, et al., 2014, Antibody Isotypes Differ in their Capacity to Bind, Capture and Aggregate HIV-1 Virions, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A64-A64, ISSN: 0889-2229
Lewis DJM, Wang Y, Huo Z, et al., 2014, Effect of Vaginal Immunization with HIVgp140 and HSP70 on HIV-1 Replication and Innate and T Cell Adaptive Immunity in Women, JOURNAL OF VIROLOGY, Vol: 88, Pages: 11648-11657, ISSN: 0022-538X
McKay PF, King DFL, Mann JFS, et al., 2014, Combinations of TLR4 and TLR7/8 Adjuvants Administered via the ID or IN Routes Generate Different Vaccine Antigen-specific Immune Outcomes in Minipigs, Symposium on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: A194-A195, ISSN: 0889-2229
King DFL, McKay PF, Mann JFS, et al., 2014, Single and Combined Vaccination Modalities Result in Distinct Immunological Profiles in HIV-1 gp140-immunised Mice, Symposium on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: A244-A244, ISSN: 0889-2229
Cheeseman HM, Klein K, Evans A, et al., 2014, Functional Assessment of Antibody Activity in Mucosal Tissue Explant and Cellular Inhibition Assays, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A230-A230, ISSN: 0889-2229
Cope AV, Moog C, Shattock RJ, et al., 2014, A Phase I Clinical Trial with a Novel gp41 HIV Vaccine (EN41-FPA2) in Healthy Female Volunteers: A Mucosal Prime and Intramuscular Boost Regimen, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A187-A188, ISSN: 0889-2229
Arakelyan A, King D, Grivel J-C, et al., 2014, Heterogeneous Conformation of HIV-1 Envelopes on Individual Virions, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A78-A79, ISSN: 0889-2229
Klein K, Mann JFS, Rogers P, et al., 2014, Polymeric penetration enhancers promote humoral immune responses to mucosal vaccines, JOURNAL OF CONTROLLED RELEASE, Vol: 183, Pages: 43-50, ISSN: 0168-3659
Walters AA, Kinnear E, Shattock RJ, et al., 2014, Comparative analysis of enzymatically produced novel linear DNA constructs with plasmids for use as DNA vaccines, Gene Therapy, Vol: 21, Pages: 645-652, ISSN: 1476-5462
Forbes CJ, Mccoy CF, Murphy DJ, et al., 2014, Modified Silicone Elastomer Vaginal Gels for Sustained Release of Antiretroviral HIV Microbicides, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol: 103, Pages: 1422-1432, ISSN: 0022-3549
Malcolm RK, Lowry D, Boyd P, et al., 2014, Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 69, Pages: 1325-1329, ISSN: 0305-7453
Herrera C, Shattock RJ, 2014, Candidate Microbicides and Their Mechanisms of Action, MICROBICIDES FOR PREVENTION OF HIV INFECTION, Vol: 383, Pages: 1-25, ISSN: 0070-217X
Mann JFS, Mckay PF, Fiserova A, et al., 2014, Enhanced immunogenicity of an HIV-1 DNA vaccine delivered with electroporation via combined intramuscular and intradermal routes, Journal of Virology, Vol: 88, Pages: 6959-6969, ISSN: 1098-5514
It is accepted that an effective prophylactic HIV-1 vaccine is likely to have the greatest impact on viral transmission rates. As previous reports have implicated DNA-priming, protein boost regimens to be efficient activators of humoral responses, we sought to optimize this regimen to further augment vaccine immunogenicity. Here we evaluated single versus concurrent intradermal (i.d.) and intramuscular (i.m.) vaccinations as a DNA-priming strategy for their abilities to elicit humoral and cellular responses against a model HIV-1 vaccine antigen, CN54-gp140. To further augment vaccine-elicited T and B cell responses, we enhanced cellular transfection with electroporation and then boosted the DNA-primed responses with homologous protein delivered subcutaneously (s.c.), intranasally (i.n.), i.m., or transcutaneously (t.c.). In mice, the concurrent priming regimen resulted in significantly elevated gamma interferon T cell responses and high-avidity antigen-specific IgG B cell responses, a hallmark of B cell maturation. Protein boosting of the concurrent DNA strategy further enhanced IgG concentrations but had little impact on T cell reactivity. Interestingly protein boosting by the subcutaneous route increased antibody avidity to a greater extent than protein boosting by either the i.m., i.n., or t.c. route, suggesting that this route may be preferential for driving B cell maturation. Using an alternative and larger animal model, the rabbit, we found the concurrent DNA-priming strategy followed by s.c. protein boosting to again be capable of eliciting high-avidity humoral responses and to also be able to neutralize HIV-1 pseudoviruses from diverse clades (clades A, B, and C). Taken together, we show that concurrent multiple-route DNA vaccinations induce strong cellular immunity, in addition to potent and high-avidity humoral immune responses.
Jones C, Kaye S, Shattock R, et al., 2014, Can we measure HIV viral load in mucosal secretions in men?, HIV MEDICINE, Vol: 15, Pages: 145-145, ISSN: 1464-2662
Jones C, Quinn K, Miller A, et al., 2014, What are the best methods to recruit healthy volunteers into HIV vaccine trials?, HIV MEDICINE, Vol: 15, Pages: 146-146, ISSN: 1464-2662
McKay PF, Cope AV, Mann JFS, et al., 2014, Glucopyranosyl lipid A adjuvant significantly enhances HIV specific T and B cell responses elicited by a DNA-MVA-protein vaccine regimen, PLOS One, Vol: 9, ISSN: 1932-6203
Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNApoxvirus-proteinstrategy in mice and rabbits, administering MVA and protein immunizations either sequentially orsimultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef) with HIV CN54gp140 protein (+/2GLA-AF adjuvant) andeither co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. TheDNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to theboost vaccines. The greatest antigen-specific antibody response was observed in animals that received all vaccinecomponents. Moreover, a high proportion of the total mucosal IgG (20 – 50%) present in the vaginal vault of thesevaccinated animals was vaccine antigen-specific. The potent elicitation of antigen-specific immune responses to this vaccinemodality was also confirmed in rabbits. Importantly, co-administration of MVA-C with the GLA-AF adjuvanted HIVCN54gp140 protein significantly augmented the antigen-specific T cell responses to the Gag antigen, a transgene productexpressed by the MVA-C vector in a separate quadriceps muscle. We have demonstrated that co-administration of MVA andGLA-AF adjuvanted HIV CN54gp140 protein was equally effective in the generation of humoral responses as a sequentialvaccination modality thus shortening and simplifying the immunization schedule. In addition, a significant further benefit ofthe condensed vaccination regime was that T cell responses to proteins expressed by the MVA-C were potently enhanced,an effect that was likely due to enhanced immunostimulation in the presence of systemic GLA-AF.
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