Publications
127 results found
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.
Tiraboschi J, Fox J, Herrera C, et al., 2015, A Phase IV HIV PrEP study reveals limited ex vivo potency of oral Maraviroc against HIV-1, HIV MEDICINE, Vol: 16, Pages: 3-4, ISSN: 1464-2662
Stax MJ, Mouser EEIM, van Montfort T, et al., 2015, Colorectal Mucus Binds DC-SIGN and Inhibits HIV-1 <i>Trans</i>-Infection of CD4<SUP>+</SUP> T-Lymphocytes, PLOS ONE, Vol: 10, ISSN: 1932-6203
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- Citations: 11
Herrera C, Veazey R, Kashuba A, et al., 2014, Mucosal Tissue Explants as Surrogates for <i>In Vivo</i> Efficacy of Microbicides, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A60-A60, ISSN: 0889-2229
Herrera C, Olejniczak N, Garcia Perez J, et al., 2014, Preclinical Evaluation of Multi-targeting Antiretroviral Drug Based-combinations as Candidate Microbicides, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A262-A262, ISSN: 0889-2229
Herrera C, Veazey R, Schuetz A, et al., 2014, Evaluation of Mucosal Tissue Explants as <i>Ex Vivo</i> Surrogates of <i>In Vivo</i> Vaccination of Non-human Primates (NHPs) and Humans, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A24-A24, ISSN: 0889-2229
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- Citations: 1
Herrera C, Olejniczak N, Perez JG, et al., 2014, Combinations of Entry and Reverse Transcriptase Inhibitors as Candidate Microbicides, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A213-A213, ISSN: 0889-2229
Ekeruche-Makinde JN, Evans A, Herrera C, et al., 2014, Exploring Innovative Approaches to the Formulation of Microbicides to Boost Antiretroviral Drug Delivery and Activity at Mucosal Sites, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A150-A151, ISSN: 0889-2229
Herrera C, Olejniczak N, Plummer F, et al., 2014, Preliminary Evaluation of Serpins as Potential Candidate Microbicides, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A126-A126, ISSN: 0889-2229
Herrera C, Olejniczak N, Perez JG, et al., 2014, Combinations of Entry and Reverse Transcriptase Inhibitors as Candidate Microbicides, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: A213-A213, ISSN: 0889-2229
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
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
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
Dereuddre-Bosquet N, Morellato-Castillo L, Brouwers J, et al., 2012, MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV162P3 in cynomolgus macaques, PLoS Pathogens, Vol: 8, ISSN: 1553-7366
In complement to an effective vaccine, development of potent anti-HIV microbicides remains an important priority. Wehave previously shown that the miniCD4 M48U1, a functional mimetic of sCD4 presented on a 27 amino-acid stable scaffold,inhibits a broad range of HIV-1 isolates at sub-nanomolar concentrations in cellular models. Here, we report that M48U1inhibits efficiently HIV-1Ba-L in human mucosal explants of cervical and colorectal tissues. In vivo efficacy of M48U1 wasevaluated in nonhuman primate (NHP) model of mucosal challenge with SHIV162P3 after assessing pharmacokinetics andpharmacodynamics of a miniCD4 gel formulation in sexually matured female cynomolgus macaques. Among 12 females,half were treated with hydroxyethylcellulose-based gel (control), the other half received the same gel containing 3 mg/g ofM48U1, one hour before vaginal route challenge with 10 AID50 of SHIV162P3. All control animals were infected with a peakplasma viral load of 105–106 viral RNA (vRNA) copies per mL. In animals treated with miniCD4, 5 out of 6 were fully protectedfrom acquisition of infection, as assessed by qRT-PCR for vRNA detection in plasma, qPCR for viral DNA detection in PBMCand lymph node cells. The only infected animal in this group had a delayed peak of viremia of one week. These resultsdemonstrate that M48U1 miniCD4 acts in vivo as a potent entry inhibitor, which may be considered in microbicidedevelopments.
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
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- Citations: 29
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.
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
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
Herrera C, Armanasco N, King D, et al., 2011, Combinations of maraviroc and reverse transcriptase inhibitors as potential microbicides. (Oral communication and Poster by C. Herrera), Protection from HIV: Targeted Intervention Strategies (X8)
Multiple drug combinations are highly effective in HAART and may also be more effective as microbicides against HIV-1 than single drugs. The aim of this study was to assess the activity of combinations based on compounds with different HIV-1 inhibitory mechanisms. Antiviral efficacy of an entry inhibitor, maraviroc, combined with reverse transcriptase inhibitors (RTIs): PMPA, UC781 or TMC120, was assessed against clade B and transmitted founder clade C isolates, in cellular and colorectal explant models. Dual combinations of maraviroc with any of the RTIs tested in TZM-bell cells and colorectal explants, showed an increase of activity compared to the drugs used alone. Combinations were also more potent when assessed in cell-associated virus transmission from dendritic cells to T cells. The maraviroc-dapivirine combination was further investigated for its activity as a gel formulated microbicide. The increased activity of combinations of antiretroviral drugs inhibiting HIV transmission at different steps of the viral replication cycle (entry and reverse transcription), when compared to the activity of each drug alone, suggests these combinations have greater potential as microbicides. This work was funded by IPM.
Herrera C, Cranage M, McGowan I, et al., 2011, Using drug combinations to design effective colorectal microbicides: where is the limit?(Awarded Abstract of distinction), CURE: Digestive Diseases Research Center. 2 0 1 1 Annual Research Meeting
Background: Receptive anal intercourse is associated with the highest probability for sexualHIVinfection.The aim of the study was to assess the importance of reverse transcriptase inhibitor (RTI)combinations in the design of colorectal microbicides and the number of drugs required to obtain maximumefficacy against wild type isolates and RTI-escape mutants.Methodology: The antiviral efficacy of two nucleos(t)ides reverse transcriptase inhibitors (NRTI) PMPAand FTC, and two non-NRTIs (NNRTI) UC-781 and TMC120, used in double, triple and quadruplecombinations, was assessed in colorectal explants. Pre-incubation with the drugs individually or incombination, for one hour was followed by addition of virus. Infection was determined by measurement ofvirion protein (p24 antigen) in colorectal explants supernatants.Results: All combinations inhibited the isolates tested in colorectal explants, and produced, for at least oneof the compounds, a change in the dose response curve. Double and triple combinations incrementallyaugmented activity, even against RTI escape mutants, whereas quadruple combinations conferred littlefurther advantage. The colorectal explant model is key to identification of the best candidate molecules andtheir combinations at the preclinical stage.Conclusions: Triple combinations based on RTIs have potential as colorectal microbicides to prevent thetransmission of wild type and resistant isolates.
Herrera C, Shattock R, 2011, Efficacy of combinations. (Oral communication by C. Herrera), CHAARM Consortium Meeting Annual Meeting 2011
Burgers WA, Manrique A, Masopust D, et al., 2011, Measurements of immune responses for establishing correlates of vaccine protection against HIV, AIDS Res Hum Retroviruses
Well-defined correlates of protective immunity are an essential component of rational vaccine development. Despite years of basic science and three HIV vaccine efficacy trials, correlates of immunological protection from HIV infection remain undefined. In December 2010, a meeting of scientists engaged in basic and translational work towards developing HIV-1 vaccines was convened. The goal of this meeting was to discuss current opportunities and optimal approaches for defining correlates of protection, both for ongoing and future HIV-1 vaccine candidates with the engagement of young scientists. We discuss here the highlights from the meeting regarding the progress made and the way forward for a protective HIV-1 vaccine.
Berry N, Herrera C, 2010, Detection, quantification, and characterisation of HIV/SIV., Diagnostic Virology Protocols, Editors: Stephenson, Publisher: Humana Pr Inc, Pages: 133-160, ISBN: 9781607618164
Selected techniques for the detection, quantification, and characterisation of HIV1, HIV2, and SIV, as applied to diagnostic and research purposes, are described. Representative nucleic acid testing protocols including nested PCR, RT-PCR, and quantitative real-time PCR, as well as protocols based on virus infectivity, are presented.
Herrera C, Armanasco N, Fletcher P, et al., 2010, Combinations of maraviroc and reverse transcriptase inhibitors as potential microbicides (Oral communication by C. Herrera), Annual Europrise Meeting 2010
Multiple drug combinations are highly effective in HAART and may also be more effective as microbicides against HIV-1 than single drugs. The aim of this study was to assess the activity of combinations based on compounds with different HIV-1 inhibitory mechanisms. Antiviral efficacy of an entry inhibitor, maraviroc, combined with reverse transcriptase inhibitors (RTIs): PMPA, UC781 or TMC120, was assessed in cellular and colorectal explant models. Dual combinations of maraviroc with any of the RTIs tested in TZM-bell cells and colorectal explants, showed an increase of activity compared to the drugs used alone. The maraviroc-dapivirine combination was further investigated for its activity in cell-associated virus transmission from dendritic cells to T cells, and for its activity as a gel formulated microbicide. The increased activity of combinations of antiretroviral drugs inhibiting HIV transmission at different steps of the viral replication cycle (entry and reverse transcription), when compared to the activity of each drug alone, suggests these combinations have greater potential as microbicides.
Herrera C, 2010, Ex vivo modeling of candidate colorectal anti-HIV microbicides (Oral communication by C. Herrera), ICMS Symposium: HIV research in 2010
Herrera C, Cranage M, McGowan I, et al., 2010, Using drug combinations to design colorectal microbicides:where is the limit? (Oral communication and poster by C. Herrera), Microbicides 2010: Building Bridges in HIV Prevention
Background: Receptive anal intercourse is associated with the highest probability for sexual HIV infection. The aim of the study was to assess the importance of reverse transcriptase inhibitor (RTI) combinations in the design of colorectal microbicides and the number of drugs required to obtain maximum efficacy against wild type isolates and RTI-escape mutants. Methodology: The antiviral efficacy of two nucleos(t)ides reverse transcriptase inhibitors (NRTI) PMPA and FTC, and two non-NRTIs (NNRTI) UC-781 and TMC120, used in double, triple and quadruple combinations, was assessed in colorectal explants. Pre-incubation with the drugs individually or in combination, for one hour was followed by addition of virus. Infection was determined by measurement of virion protein (p24 antigen) in colorectal explants supernatants. Results: All combinations inhibited the isolates tested in colorectal explants, and produced, for at least one of the compounds, a change in the dose response curve. Double and triple combinations incrementally augmented activity, even against RTI escape mutants, whereas quadruple combinations conferred little further advantage. The colorectal explant model is key to identification of the best candidate molecules and their combinations at the preclinical stage. Conclusions: Triple combinations based on RTIs have potential as colorectal microbicides to prevent the transmission of wild type and resistant isolates.
Herrera C, Armanasco N, Fletcher P, et al., 2010, Combinations of maraviroc and reverse transcriptase inhibitors as potential microbicides. (Oral communication by C. Herrera), Microbicides 2010: Building Bridges in HIV Prevention
Background: Multiple drug combinations are highly effective in HAART and may also be more effective as microbicides against HIV-1 than single drugs. The aim of this study was to assess the activity of combinations based on compounds with different HIV-1 inhibitory mechanisms. Methodology: The antiviral efficacy of an entry inhibitor, maraviroc, and three reverse transcriptase inhibitors (RTIs): a nucleotide reverse transcriptase inhibitor (NRTI), tenofovir (PMPA), and two non-nucleoside RTIs (NNRTI), UC-781 and dapivirine (TMC120), used in double combinations, was assessed in cellular (luciferase reporter TZM-bl cells, T cells and dendritic cells (DC) isolated from peripheral blood mononuclear cells) and colorectal explant models. Pre-incubation of cells or tissue with the drugs individually or in combination, for one hour was followed by addition of an R5-tropic virus, BaL. Infection was determined by measurement of luciferase expression (in TZM-bl cells) or virion protein (p24 antigen) in culture supernatants. Results: Dual combinations of maraviroc with any of the RTIs tested against BaL in TZM-bl cells showed an increase of activity compared to the drugs used alone, with an average 56% reduction of the IC50 value of each drug used in combination. When double combinations were tested in colorectal explants a higher shift in the dose response curves was detected when maraviroc was combined with tenofovir or dapivirine. These two double combinations (maraviroc-tenofovir and maraviroc-dapivirine) were further investigated for their activity in cell-associated virus transmission in two models: DC to T cell, and T cell to T cell. Both combinations were also positive in these two models of cell-to-cell transmission. Conclusions: The increased activity of combinations of drugs inhibiting HIV transmission at different steps of the viral replication cycle (entry and reverse transcription), when compared with the activity of each drug alone, suggests these combinations hav
Herrera C, McRaven M, Hope T, et al., 2010, Early colorectal responses to HIV-1 and modulation by microbicides, Microbicides 2010: Building Bridges in HIV Prevention
Background: The extreme vulnerability of the colorectal tract to HIV-1 infection is likely due to histological and immunological characteristics of the intestinal mucosae. The aims of this study were to determine the genomic responses to HIV-1 exposure in the colorectum and if these responses are dependent upon infection and/or modulated by microbicides. Methodology: Colorectal explants were incubated with or without drugs for one hour before addition of virus. Viral penetration within colorectal lamina propia was assessed with fluorescent viral particles (BaLPAGFPGag). Early responses to viral exposure were analyzed by Luminex and RNA microarray, at two set time points: 6 h (representing responses induced by viral attachment, entry and early reverse transcription) and 24 h (corresponding to viral integration and productive infection).Results: Viral exposure studies using fluorescent BaLPAGFPGag demonstrated virus penetration of up to 39 μm into the lamina propia within 6 h. HIV exposure to tissue for 6 h induced an increase in the levels of IL-1a, IL-1b, IL-6, IL-8, MCP-1 and GCSF secretion. Further secretion of these pro-inflammatory cytokines was detected after 24 h of incubation independently of viral tropism. The X4-isolate NL4.3 induced higher levels of RANTES, MIP-1α and MIP-1β secretion than R5-HIV-1 YU.2. Potential drug candidates for colorectal microbicides, including entry, fusion or reverse transcriptase inhibitors demonstrated differential capacity to modulate these responses.Conclusions: Gene expression is differentially affected by viral tropism and time. Early responses of colorectal tissue after exposure to HIV-1 can be modulated by RTI and entry inhibitors.
Herrera C, Harman S, Nuttall J, et al., 2010, Pre-clinical evaluation of fusion and reverse transcriptase inhibitors in combinations as potential microbicides (Oral communication by C. Herrera), Microbicides 2010: Building Bridges in HIV Prevention
Background: The microbicide field has recently started to develop products containing combinations of drugs, based on the principle that combinations may provide increased efficacy. In this study, we evaluated the activity of fusion (F) and reverse transcriptase (RT) inhibitors (I) used in double combinations against a panel of wild type HIV-1 isolates and RTI-resistant viruses. Methodology: A panel of peptide fusion inhibitors (T1249, enfuvirtide (T20) and L’644), were tested for their activity alone and in dual combinations with three RTIs: a nucleotide reverse transcriptase inhibitor (NRTI), tenofovir (PMPA), and two non-NRTIs (NNRTI), UC-781 and dapivirine (TMC120). TZM-bl cells were incubated with the drugs individually or in combination for one hour, followed by addition of virus. Infection was determined by measurement of luciferase expression in cell lysates. Results: Dual combinations of fusion inhibitors with any of the RTIs tested against the panel of wild type isolates in TZM-bl cells showed for at least one of the compounds, a change in the dose response curve. Dual FI-RTI combinations were also able to inhibit RTI-resistant isolates. In a few cases, a slight, non significant, decrease in activity was detected for a FI used in combination with an RTI against an isolate resistant to that RTI, however the presence of a FI allowed the combination to maintain inhibitory activity against the isolate. Conclusions: These experiments indicate that dual FI-RTI combinations may have benefit as microbicides over those containing a single drug since they may be able to prevent transmission of both wild type and RTI-resistant isolates.
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