Publications
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Shacklett BL, Blanco J, Hightow-Weidman L, et al., 2019, HIV Research for Prevention 2018: From research to impact: Conference summary and highlights, AIDS Research and Human Retroviruses, Vol: 35, Pages: 598-607, ISSN: 0889-2229
The HIV Research for Prevention (HIVR4P) conference is dedicated to advancing HIV prevention research, responding to a growing consensus that effective and durable prevention will require a combination of approaches as well as unprecedented collaboration among scientists, practitioners, and community workers from different fields and geographic areas. The conference theme in 2018, “From Research to Impact,” acknowledged an increasing focus on translation of promising research findings into practical, accessible, and affordable HIV prevention options for those who need them worldwide. HIVR4P 2018 was held in Madrid, Spain, on 21–25 October, with >1,400 participants from 52 countries around the globe, representing all aspects of HIV prevention research and implementation. The program included 137 oral and 610 poster presentations. This article presents a brief summary of highlights from the conference. More detailed information, complete abstracts as well as webcasts and daily Rapporteur summaries may be found on the conference website.
Herrera C, 2019, The pre-clinical toolbox of pharmacokinetics and pharmacodynamics: in vitro and ex vivo models, Frontiers in Pharmacology, Vol: 10, ISSN: 1663-9812
Prevention strategies against sexual transmission of human immunodeficiency virus (HIV) are essential to curb the rate of new infections. In the absence of a correlate of protection against HIV infection, pre-clinical evaluation is fundamental to facilitate and accelerate prioritization of prevention candidates and their formulations in a rapidly evolving clinical landscape. Characterization of pharmacokinetic (PK) and pharmacodynamic (PD) properties for candidate inhibitors is the main objective of pre-clinical evaluation. in vitro and ex vivo systems for pharmacological assessment allow experimental flexibility and adaptability at a relatively low cost without raising as significant ethical concerns as in vivo models. Applications and limitations of pre-clinical PK/PD models and future alternatives are reviewed in the context of HIV prevention.
Yavuz B, Morgan JL, Herrera C, et al., 2019, Sustained release silk fibroin discs: Antibody and protein delivery for HIV prevention, Journal of Controlled Release, Vol: 301, Pages: 1-12, ISSN: 0168-3659
With almost 2 million new HIV infections worldwide each year, the prevention of HIV infection is critical for stopping the pandemic. The only approved form of pre-exposure prophylaxis is a costly daily pill, and it is recognized that several options will be needed to provide protection to the various affected communities around the world. In particular, many at-risk people would benefit from a prevention method that is simple to use and does not require medical intervention or a strict daily regimen. We show that silk fibroin protein can be formulated into insertable discs that encapsulate either an antibody (IgG) or the potent HIV inhibitor 5P12-RANTES. Several formulations were studied, including silk layering, water vapor annealing and methanol treatment to stabilize the protein cargo and impact the release kinetics over weeks. In the case of IgG, high concentrations were released over a short time using methanol treatment, with more sustained results with the use of water vapor annealing and layering during device fabrication. For 5P12-RANTES, sustained release was obtained for 31 days using water vapor annealing. Further, we show that the released inhibitor 5P12-RANTES was functional both in vitro and in ex vivo colorectal tissue. This work shows that silk fibroin discs can be developed into formidable tools to prevent HIV infection.
Thornhill J, Herrera C, Hoare J, et al., 2019, The impact of vorinostat and therapeutic vaccine on gut HIV DNA: the RIVER gut study, Publisher: WILEY, Pages: 7-7, ISSN: 1464-2662
Fox J, Herrera C, Lwanga J, et al., 2019, The role of raltegravir alone or combined with lamivudine as PrEP: a phase 2 randomised controlled clinical trial, Publisher: WILEY, Pages: 5-6, ISSN: 1464-2662
Thornhill J, Pace M, Martin G, et al., 2019, CD32 expression identifies B cell-T cell doublets in gut-associated lymphoid tissue that are enriched for T follicular helper cells but not for HIV DNA, Publisher: WILEY, Pages: 24-25, ISSN: 1464-2662
Herrera C, Gil Ordonez A, Ortega-Gutierrez S, et al., 2018, Reversible Modulation of the Endocannabinoid System as an Anti-HIV-1 Prevention Strategy, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 356-356, ISSN: 0889-2229
Yavuz B, Morgan JL, Showalter L, et al., 2018, Pharmaceutical Approaches to HIV Treatment and Prevention, ADVANCED THERAPEUTICS, Vol: 1
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Nash S, Herrera C, Serwanga J, et al., 2018, Novel Protocol to Compare PrEP Drugs, Dosing and Schedule Using Ex Vivo Challenge on Resected Foreskin Tissue: Protocol for the CHAPS RCT, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 364-364, ISSN: 0889-2229
Herrera C, Veazey R, Lemke M, et al., 2018, Vaccination with ALVAC-HIV/AIDSVAX® B/E of Non-human Primates (NHPs) Elicits Distinct Mucosal and Systemic Responses, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 306-306, ISSN: 0889-2229
Chenine A-L, Merbah M, Wieczorek L, et al., 2018, Neutralization sensitivity of a novel HIV-1 CRF01_AE panel of infectious molecular clones, Journal of Acquired Immune Deficiency Syndromes, Vol: 78, Pages: 348-355, ISSN: 1525-4135
BACKGROUND: HIV-1 CRF01_AE is dominant in Thailand where RV144 vaccine trial was conducted. To study immune correlates of protection in ongoing trials, CRF01_AE derived reagents are essential. Here we present a panel of 14 HIV-1 infectious molecular clones (IMC) identified from different stages of infection, and characterization of their neutralization sensitivity using two standard assays. METHODS: One full-length IMC was constructed using a transmitted-founder virus to express Renilla luciferase (LucR) reporter gene and full-length envelopes (envs) of exogenous HIV-1. A panel of IMCs was generated, expressing envs of viruses from acute (Fiebig stages I/II and I-IV) and chronic (>Febig VI) infection. Neutralization assays were performed using TZM-bl or A3R5 cell lines, and sera or monoclonal antibodies (mAbs). Wilcoxon matched-paired test was used to assess neutralization differences between assays and reagents; correlation coefficients were evaluated by linear regression. RESULTS: Neutralization potency observed was significantly higher in the A3R5 assay when testing mAbs and serum pools (p<0.0001); the stage of infection from which env was derived did not associate with IMC neutralization sensitivity. Neutralization values from A3R5 and TZM-bl assays were strongly correlated when mAbs were tested (R=0.7, p<0.0001), but a weaker association was seen with serum pools (R=0.17, p=0.03). CONCLUSIONS: This novel panel of CRF01_AE reporter-IMC is useful for assessing vaccine-induced neutralizing antibodies in multiple assays, including those utilizing primary cell targets. The significant differences in TZM-bl and A3R5 neutralization sensitivity, as well as the poor association when using polyclonal sera indicates the need for caution in choosing one specific platform.
Thornhill JP, Martin GE, Hoare J, et al., 2018, Follicular CD8+T-cells in gut-associated lymphoid tissue are associated with lower HIV-1 reservoir in the terminal ileum after ART initiated during primary HIV infection, Publisher: JOHN WILEY & SONS LTD, Pages: 96-96
Sibeko S, Herrera C, Andrews S, et al., 2018, MIP-3α does not appear to play an important role in amplifying human infection with HIV-1 in the female genital tract, Publisher: WILEY, Pages: S40-S40, ISSN: 1464-2662
Zhang L, Herrera C, Coburn J, et al., 2017, Stabilization and Sustained Release of HIV Inhibitors by Encapsulation in Silk Fibroin Disks, ACS BIOMATERIALS SCIENCE & ENGINEERING, Vol: 3, Pages: 1654-1665, ISSN: 2373-9878
Topical microbicides have the potential to provide effective protection against sexual transmission of HIV. Challenges in developing microbicides include their application in resource-poor settings with high temperatures and a lack of refrigeration, and low user adherence to a rigorous daily regimen. Several protein-based HIV inhibitors show great promise as microbicides, being highly specific and not expected to lead to resistance that would affect the efficacy of current antiretroviral treatments. We show that four potent protein HIV inhibitors, 5P12-RANTES, 5P12-RANTES-L-C37, Grft, and Grft-L-C37 can be formulated into silk fibroin (SF) disks and remain functional for 14 months at 25, 37, and 50 °C. These HIV inhibitor-encapsulated SF disks show excellent inhibition properties in PBMC and in human colorectal and cervical tissue explants, and do not induce inflammatory cytokine secretion. Further, the SF provides a mechanically robust matrix with versatile material formats for this type of application. Finally, a formulation was developed to allow sustained release of functional Grft for 4 weeks at levels sufficient to inhibit HIV transmission. This work establishes the suitability of HIV inhibitor-encapsulated SF disks as topical HIV microbicides that can be further developed to allow easy insertion for extended protection.
Koutsoudakis G, Paris de Leon A, Herrera C, et al., 2017, Oligonucleotide-Lipid Conjugates Forming G-Quadruplex Structures Are Potent and Pangenotypic Hepatitis C Virus Entry Inhibitors In Vitro and Ex Vivo, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 61, ISSN: 0066-4804
A hepatitis C virus (HCV) epidemic affecting HIV-infected men who have sex with men (MSM) is expanding worldwide. In spite of the improved cure rates obtained with the new direct-acting antiviral drug (DAA) combinations, the high rate of reinfection within this population calls urgently for novel preventive interventions. In this study, we determined in cell culture and ex vivo experiments with human colorectal tissue that lipoquads, G-quadruplex DNA structures fused to cholesterol, are efficient HCV pangenotypic entry and cell-to-cell transmission inhibitors. Thus, lipoquads may be promising candidates for the development of rectally applied gels to prevent HCV transmission.
Thornhill J, Herrera C, Olejniczak N, et al., 2017, Impact of ART in primary HIV infection on T cell immune exhaustion in gut-associated lymphoid tissue: implications for HIV persistence, Publisher: WILEY, Pages: 6-6, ISSN: 1464-2662
Richardson-Harman N, Parody R, Anton P, et al., 2016, Analytical advances in the ex vivo challenge efficacy assay, AIDS Research and Human Retroviruses, Vol: 33, Pages: 395-403, ISSN: 0889-2229
The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power, and ex vivo HIV growth kinetics. Data were p24 antigen (pg/ml) measurements collected from clinical trials of candidate microbicides where rectal (n = 502), cervical (n = 88), and vaginal (n = 110) tissues were challenged with HIV-1BaL ex vivo. Imputation of missing data using a nonlinear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha = 0.05), but a larger sample size was predicted to be needed for either cervical (n = 21) or vaginal (n = 10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.
Fox J, Tiraboschi JM, Herrera C, et al., 2016, Pharmacokinetic/Pharmacodynamic Investigation of Single-Dose Oral Maraviroc in the Context of HIV-1 Pre-exposure Prophylaxis, JAIDS-Journal of Acquired Immune Deficiency Syndromes, Vol: 73, Pages: 252-257, ISSN: 1525-4135
To investigate the pharmacokinetics/pharmacodynamics ofsingle-dose maraviroc 300 mg in HIV-1 exposure compartments.Maraviroc concentrations in blood, secretions (vaginal, urethral, oral,and rectal), and tissue (vaginal and rectal) were measured, and ex vivochallenge was performed in 54 healthy volunteers to study protectionfrom HIV infection. Maraviroc Cmax occurred within 4 hours inmost compartments. Concentrations from 4 to 72 hours were aboveintracellular (IC) IC90 in all compartments, range 15–8095 ng/mL. MeanAUC0-72 compartment-to-plasma ratios were highest in the rectum (45–819) and urethra (144) compared with the female genital tract (1.6–4.8)and saliva (0.2). No sex differences in AUC0-72 or Cmax were observed.No ex vivo protection from HIV-1BaL occurred in rectal or vaginaltissue. Despite high and sustained concentrations, single-dose maravirocwas not protective against ex vivo challenge of vaginal/rectal tissue.
Ekeruche-Makinde J, Herrera C, Evans A, et al., 2016, Targeting Cellular Drug Transporters to Boost Antiretroviral Drug Activity at Mucosal Sites, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 221-221, ISSN: 0889-2229
Herrera C, Kelly C, Shattock RJ, 2016, Preclinical Evaluation of a Reverse Transcriptase and Protease Inhibitory Combination as a Candidate Microbicide, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 233-233, ISSN: 0889-2229
Herrera C, Romas L, Olejniczak N, et al., 2016, Preclinical Evaluation of Serpins as Potential Colorectal Microbicides, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 295-295, ISSN: 0889-2229
Zhang L, Herrera C, Coburn J, et al., 2016, Silk Fibroin Provides Both Temperature Stabilization and Sustained Release of Protein-based HIV Inhibitors, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 225-225, ISSN: 0889-2229
Herrera C, Olejniczak N, Zhang L, et al., 2016, Silk-formulated Antiretrovirals as Candidate Microbicides, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 210-210, ISSN: 0889-2229
Herrera C, Veazey R, Schuetz A, et al., 2016, Ex Vivo Evaluation of Mucosal Cytokine Responses to in Vivo Vaccination with ALVAC-HIV/AIDSVAX (R) B/E of Non-human Primates (NHPs) and Humans, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 75-75, ISSN: 0889-2229
Herrera C, Harman S, Rogers P, et al., 2016, Increased Activity of the Entry Inhibitor DS003, a BMS-378806 Analogue, through Binding to the CD4-induced Epitope in HIV-1 gp120, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 233-233, ISSN: 0889-2229
Herrera C, Armanasco N, García-Pérez J, et al., 2016, Maraviroc and reverse transcriptase inhibitors combinations as potential pre-exposure prophylaxis candidates, AIDS, Vol: 30, Pages: 1015-1025, ISSN: 0269-9370
Objective: Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a program to develop an effective prevention strategy, we performed an ex-vivo preclinical evaluation to determine the efficacy of multiple double combinations of maraviroc (MVC) and reverse transcriptase inhibitors (RTIs).Design: The entry inhibitor, MVC, a nucleotide RTI, tenofovir and two non-nucleoside RTIs, UC781 and TMC120 (dapivirine, DPV), were used in double, combinations against a panel of CCR5-using clade B and clade C HIV-1 isolates and against MVC-escape variants. A gel-formulated version of MVC-DPV combination was also tested.Methods: Indicator cells, cocultures of immature dendritic cells with CD4+T cells, and colorectal tissue explants were used to assess antiviral activity of drug combinations.Results: All dual MVC-RTI combinations tested inhibited MVC-sensitive and resistant isolates in cellular and colorectal explants models. All the combinations were positive with no reduction in the activity of MVC. In tissue explants, the combinations against all viral isolates tested produced an increase in the activity of MVC. An initial gel-formulation of MVC-DPV combination showed greater and prolonged antiviral activity of MVC in mucosal tissue explants.Conclusion: This study demonstrates that combinations based on antiretroviral drugs inhibiting HIV transmission at viral entry and reverse transcription have potential as prevention strategies against colorectal transmission of HIV-1 including MVC-resistant isolates. Preclinical evaluation with colorectal tissue explants indicates that a gel-formulation of MVC-DPV is an effective candidate colorectal microbicide.
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.
Rice A, Wordsworth H, Moyle G, et al., 2016, An interim report of a study investigating longitudinal changes in sensory profiles in HIV-positive patients with and without HIV-associated sensory neuropathy, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 46-47, ISSN: 1464-2662
Tiraboschi J, Davies O, Fox J, et al., 2016, Single dose Maraviroc provides high drug levels in all sites; no gender differences, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 17-17, ISSN: 1464-2662
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
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