286 results found
Mann JF, Tregoning JS, Aldon Y, et al., 2016, CD71 targeting boosts immunogenicity of sublingually delivered influenza haemagglutinin antigen and protects against viral challenge in mice., Journal of Controlled Release, Vol: 232, Pages: 75-82, ISSN: 1873-4995
The delivery of vaccines to the sublingual mucosa is an attractive prospect due to the ease and acceptability of such an approach. However, novel adjuvant and delivery approaches are required to optimally vaccinate at this site. We have previously shown that conjugation of protein antigen to the iron transport molecule, transferrin, can significantly enhance mucosal immune responses. We tested whether conjugating influenza haemagglutinin to transferrin could improve the immune response to sublingually delivered antigen. Transferrin conjugated haemagglutinin induced a significant antibody and T cell response in both naïve animals and previously immunized animals. The immune response generated was able to protect mice against influenza virus challenge. Sublingually administered antigen dispersed more widely through the gastro-intestinal tract than intranasally delivered antigen and transferrin conjugation had a more marked effect on sublingually delivered antigen than intranasal immunisation. From these studies we conclude that transferrin conjugation of antigen is effective at boosting immune responses to sublingually delivered antigen and may be an attractive approach for influenza vaccines, particularly when mass campaigns are required.
Badamchi-Zadeh A, McKay PF, Korber BT, et al., 2016, A multi-component prime-boost vaccination regimen with a consensus MOMP antigen enhances Chlamydia trachomatis clearance, Frontiers in Immunology, Vol: 7, ISSN: 1664-3224
Background: A vaccine for Chlamydia trachomatis is of urgent medical need. We explored bioinformatic approaches to generate an immunogen against C. trachomatis that would induce cross-serovar T cell responses as (i) CD4+ T cells have been shown in animal models and human studies to be important in chlamydial protection, and (ii) antibody responses may be restrictive and serovar-specific.Methods: A consensus antigen based on over 1,500 MOMP sequences provided high epitope coverage against the most prevalent C. trachomatis strains in silico. Having designed the T cell immunogen, we assessed it for immunogenicity in prime-boost regimens. This consensus MOMP transgene was delivered using plasmid DNA, Human Adenovirus-5 (HuAd5) or modified vaccinia Ankara (MVA) vectors with or without MF59® adjuvanted recombinant MOMP protein. Results: Different regimens induced distinct immune profiles. The DNA-HuAd5-MVA-Protein (DAMP) vaccine regimen induced a cellular response with a Th1 biased serum antibody response, alongside high serum and vaginal MOMP-specific antibodies. This regimen significantly enhanced clearance against intravaginal C. trachomatis serovar D infection in both BALB/c and B6C3F1 mouse strains. This enhanced clearance was shown to be CD4+ T cell dependent. Future studies will need to confirm the specificity and precise mechanisms of protection. Conclusions: A C. trachomatis vaccine needs to induce a robust cellular response with broad cross-serovar coverage and that a heterologous prime-boost regimen may be an approach to achieve this.
Fletcher P, Herrera C, Armanasco N, et al., 2016, Short Communication: Limited Anti-HIV-1 Activity of Maraviroc in Mucosal Tissues, AIDS Research and Human Retroviruses, Vol: 32, Pages: 334-338, ISSN: 0889-2229
The potential of maraviroc (MVC), a small-molecule CCR5 antagonist, as a candidate to prevent HIV-1 sexual transmission by oral or topical dosing has not yet been completely established. Using relevant cellular and mucosal tissue explant models, we show partial antiviral activity of MVC when tested in multiple preclinical dosing strategies.
Vamvaka E, Evans A, Ramessar K, et al., 2016, Cyanovirin-N produced in rice endosperm offers effective pre-exposure prophylaxis against HIV-1BaL infection in vitro, Plant Cell Reports, Vol: 35, Pages: 1309-1319, ISSN: 1432-203X
Cyanovirin-N (CV-N) is a lectin with potent antiviral activity that has been proposed as a component of microbicides for the prevention of infection with Human immunodeficiency virus (HIV). The production of protein-based microbicide components requires a platform that is sufficiently economical and scalable to meet the demands of the large at-risk population, particularly in resource poor developing countries. We, therefore, expressed CV-N in rice endosperm, because the dried seed is ideal for storage and transport and crude extracts could be prepared locally and used as a microbicide component without further purification. We found that crude extracts from rice seeds expressing up to 10 µg CV-N per gram dry seed weight showed dose-dependent gp120 binding activity, confirming that the protein was soluble, correctly folded and active. The recombinant lectin (OSCV-N) reduced the infectivity of HIV-1BaL (an R5 virus strain representing the majority of transmitted infections) by ~90 % but showed only weak neutralization activity against HIV-1RF (representative of X4 virus, rarely associated with transmission), suggesting it would be highly effective for pre-exposure prophylaxis against the vast majority of transmitted strains. Crude extracts expressing OSCV-N showed no toxicity towards human cells at working dilutions indicating that microbicide components produced in rice endosperm are safe for direct application as topical microbicides in humans.
Le Grand R, Dereuddre-Bosquet N, Dispinseri S, et al., 2016, Superior efficacy of a human immunodeficiency virus vaccine combined with antiretroviral prevention in simian-human immunodeficiency virus-challenged nonhuman primates, Journal of Virology, Vol: 90, Pages: 5315-5328, ISSN: 1098-5514
Although vaccines and antiretroviral (ARV) prevention have demonstrated partial success against human immunodeficiency virus (HIV) infection in clinical trials, their combined introduction could provide more potent protection. Furthermore, combination approaches could ameliorate the potential increased risk of infection following vaccination in the absence of protective immunity. We used a nonhuman primate model to determine potential interactions of combining a partially effective ARV microbicide with an envelope-based vaccine. The vaccine alone provided no protection from infection following 12 consecutive low-dose intravaginal challenges with simian-HIV strain SF162P3, with more animals infected compared to naive controls. The microbicide alone provided a 68% reduction in the risk of infection relative to that of the vaccine group and a 45% reduction relative to that of naive controls. The vaccine-microbicide combination provided an 88% reduction in the per-exposure risk of infection relative to the vaccine alone and a 79% reduction relative to that of the controls. Protected animals in the vaccine-microbicide group were challenged a further 12 times in the absence of microbicide and demonstrated a 98% reduction in the risk of infection. A total risk reduction of 91% was observed in this group over 24 exposures (P = 0.004). These important findings suggest that combined implementation of new biomedical prevention strategies may provide significant gains in HIV prevention.IMPORTANCE There is a pressing need to maximize the impact of new biomedical prevention tools in the face of the 2 million HIV infections that occur each year. Combined implementation of complementary biomedical approaches could create additive or synergistic effects that drive improved reduction of HIV incidence. Therefore, we assessed a combination of an untested vaccine with an ARV-based microbicide in a nonhuman primate vaginal challenge model. The vaccine alone provided no protection (and ma
McKay PF, King DFL, Mann JFS, et al., 2016, TLR4 and TLR7/8 adjuvant combinations generate different vaccine antigen-specific immune outcomes in minipigs when administered via the ID or IN routes, PLOS One, Vol: 11, ISSN: 1932-6203
The induction of high levels of systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly in the clinic. Due to their closer similarity to humans, minipigs may provide a more accurate picture of adjuvant performance. Based on their complementary signalling pathways, we assessed humoral immune responses to model antigens after co-administration with the toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid adjuvant (GLA-AF) or the TLR7/8 agonist resiquimod (R848) (alone and in combination) via the intradermal (ID), intranasal (IN) or combined routes in the Gottingen minipig animal model. Surprisingly, we discovered that while GLA-AF additively enhanced the adjuvant effect of R848 when injected ID, it abrogated the adjuvant activity of R848 after IN inoculation. We then performed a route comparison study using a CN54 gp140 HIV Envelope model antigen adjuvanted with R848 + GLA-AF (ID) or R848 alone (IN). Animals receiving priming inoculations via one route were then boosted by the alternate route. Although differences were observed in the priming phase (IN or ID), responses converged upon boosting by the alternative route with no observable impact resultant from the order of administration (ID/IN vs IN/ID). Specific IgG responses were measured at a distal mucosal site (vaginal), although there was no evidence of mucosal linkage as these closely reflected serum antibody levels. These data indicate that the complex in vivo cross-talk between innate pathways are likely tissue specific and cannot be predicted by simple in vitro models.
Francis SC, Hou Y, Baisley K, et al., 2016, Immune activation in the female genital tract: expression profiles of soluble proteins in women at high risk for HIV infection, PLOS One, Vol: 11, ISSN: 1932-6203
Vamvaka E, Arcalis E, Ramessar K, et al., 2016, Rice endosperm is cost-effective for the production of recombinant griffithsin with potent activity against HIV, Plant Biotechnology Journal, Vol: 14, Pages: 1427-1437, ISSN: 1467-7652
Protein microbicides containing neutralizing antibodies and antiviral lectins may help to reduce the rate of infection with human immunodeficiency virus (HIV) if it is possible to manufacture the components in large quantities at a cost affordable in HIV-endemic regions such as sub-Saharan Africa. We expressed the antiviral lectin griffithsin (GRFT), which shows potent neutralizing activity against HIV, in the endosperm of transgenic rice plants (Oryza sativa), to determine whether rice can be used to produce inexpensive GRFT as a microbicide ingredient. The yield of OSGRFT in the best-performing plants was 223 μg/g dry seed weight. We also established a one-step purification protocol, achieving a recovery of 74% and a purity of 80%, which potentially could be developed into a larger-scale process to facilitate inexpensive downstream processing. OSGRFT bound to HIV glycans with similar efficiency to GRFT produced in Escherichia coli. Whole-cell assays using purified OSGRFT and infectivity assays using crude extracts of transgenic rice endosperm confirmed that both crude and pure OSGRFT showed potent activity against HIV and the crude extracts were not toxic towards human cell lines, suggesting they could be administered as a microbicide with only minimal processing. A freedom-to-operate analysis confirmed that GRFT produced in rice is suitable for commercial development, and an economic evaluation suggested that 1.8 kg/ha of pure GRFT could be produced from rice seeds. Our data therefore indicate that rice could be developed as an inexpensive production platform for GRFT as a microbicide component.
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
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