101 results found
Nash S, Dietrich J, Ssemata AS, et al., 2020, Combined HIV Adolescent Prevention Study (CHAPS): comparison of HIV pre-exposure prophylaxis regimens for adolescents in sub-Saharan Africa-study protocol for a mixed-methods study including a randomised controlled trial., Trials, Vol: 21, ISSN: 1745-6215
BACKGROUND: HIV remains a major public health issue, especially in Eastern and Southern Africa. Pre-exposure prophylaxis is highly effective when adhered to, but its effectiveness is limited by cost, user acceptability and uptake. The cost of a non-inferiority phase III trial is likely to be prohibitive, and thus, it is essential to select the best possible drug, dose and schedule in advance. The aim of this study, the Combined HIV Adolescent PrEP and Prevention Study (CHAPS), is to investigate the drug, dose and schedule of pre-exposure prophylaxis (PrEP) required for the protection against HIV and the acceptability of PrEP amongst young people in sub-Saharan Africa, and hence to inform the choice of intervention for future phase III PrEP studies and to improve strategies for PrEP implementation. METHODS: We propose a mixed-methods study amongst young people aged 13-24 years. The first component consists of qualitative research to identify the barriers and motivators towards the uptake of PrEP amongst young people in South Africa, Uganda and Zimbabwe. The second component is a randomised clinical trial (ClinicalTrials.gov NCT03986970, June 2019) using a novel ex vivo HIV challenge method to investigate the optimal PrEP treatment (FTC-TDF vs FTC-TAF), dose and schedule. We will recruit 144 amongst HIV-negative uncircumcised men aged 13-24 years from voluntary male medical circumcision clinics in two sites (South Africa and Uganda) and randomise them into one of nine arms. One group will receive no PrEP prior to surgery; the other arms will receive either FTC-TDF or FTC-TAF, over 1 or 2 days, and with the final dose given either 6 or 20 h prior to surgery. We will conduct an ex vivo HIV challenge on their resected foreskin tissue. DISCUSSION: This study will provide both qualitative and quantitative results to help decide the optimum drug, dose and schedule for a future phase III trial of PrEP. The study will also provide crucial information
Crakes KR, Herrera C, Morgan JL, et al., 2020, Efficacy of silk fibroin biomaterial vehicle for in vivo mucosal delivery of Griffithsin and protection against HIV and SHIV infection ex vivo, Journal of the International AIDS Society, Vol: 23, ISSN: 1758-2652
INTRODUCTION: The majority of new HIV infections occur through mucosal transmission. The availability of readily applicable and accessible platforms for anti-retroviral (ARV) delivery is critical for the prevention of HIV acquisition through sexual transmission in both women and men. There is a compelling need for developing new topical delivery systems that have advantages over the pills, gels and rings, which currently fail to guarantee protection against mucosal viral transmission in vulnerable populations due to lack of user compliance. The silk fibroin (SF) platform offers another option that may be better suited to individual circumstances and preferences to increase efficacy through user compliance. The objective of this study was to test safety and efficacy of SF for anti-HIV drug delivery to mucosal sites and for viral prevention. METHODS: We formulated a potent HIV inhibitor Griffithsin (Grft) in a mucoadhesive silk fibroin (SF) drug delivery platform and tested the application in a non-human primate model in vivo and a pre-clinical human cervical and colorectal tissue explant model. Both vaginal and rectal compartments were assessed in rhesus macaques (Mucaca mulatta) that received SF (n = 4), no SF (n = 7) and SF-Grft (n = 11). In this study, we evaluated the composition of local microbiota, inflammatory cytokine production, histopathological changes in the vaginal and rectal compartments and mucosal protection after ex vivo SHIV challenge. RESULTS: Effective Grft release and retention in mucosal tissues from the SF-Grft platform resulted in protection against HIV in human cervical and colorectal tissue as well as against SHIV challenge in both rhesus macaque vaginal and rectal tissues. Mucoadhesion of SF-Grft inserts did not cause any inflammatory responses or changes in local microbiota. CONCLUSIONS: We demonstrated that in vivo delivery of SF-Grft in rhesus macaques fully protects against SHIV challenge ex vivo after two
Gibani MM, Toumazou C, Sohbati M, et al., 2020, Assessing a novel, lab-free, point-of-care test for SARS-CoV-2 (CovidNudge): a diagnostic accuracy study., The Lancet Microbe, ISSN: 2666-5247
Background: Access to rapid diagnosis is key to the control and management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory RT-PCR testing is the current standard of care but usually requires a centralised laboratory and significant infrastructure. We describe our diagnostic accuracy assessment of a novel, rapid point-of-care real time RT-PCR CovidNudge test, which requires no laboratory handling or sample pre-processing. Methods: Between April and May, 2020, we obtained two nasopharyngeal swab samples from individuals in three hospitals in London and Oxford (UK). Samples were collected from three groups: self-referred health-care workers with suspected COVID-19; patients attending emergency departments with suspected COVID-19; and hospital inpatient admissions with or without suspected COVID-19. For the CovidNudge test, nasopharyngeal swabs were inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as sample adequacy control. Swab samples were tested in parallel using the CovidNudge platform, and with standard laboratory RT-PCR using swabs in viral transport medium for processing in a central laboratory. The primary analysis was to compare the sensitivity and specificity of the point-of-care CovidNudge test with laboratory-based testing. Findings: We obtained 386 paired samples: 280 (73%) from self-referred health-care workers, 15 (4%) from patients in the emergency department, and 91 (23%) hospital inpatient admissions. Of the 386 paired samples, 67 tested positive on the CovidNudge point-of-care platform and 71 with standard laboratory RT-PCR. The overall sensitivity of the point-of-care test compared with laboratory-based testing was 94% (95% CI 86-98) with an overall specificity of 100% (99-100). The sensitivity of the test varied
Gomara MJ, Perez Y, Gomez-Gutierrez P, et al., 2020, Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide., Sci Rep, Vol: 10
Based on the structure of an HIV-1 entry inhibitor peptide two stapled- and a retro-enantio peptides have been designed to provide novel prevention interventions against HIV transmission. The three peptides show greater inhibitory potencies in cellular and mucosal tissue pre-clinical models than the parent sequence and the retro-enantio shows a strengthened proteolytic stability. Since HIV-1 fusion inhibitor peptides need to be embedded in the membrane to properly interact with their viral target, the structural features were determined by NMR spectroscopy in micelles and solved by using restrained molecular dynamics calculations. Both parent and retro-enantio peptides demonstrate a topology compatible with a shared helix-turn-helix conformation and assemble similarly in the membrane maintaining the active conformation needed for its interaction with the viral target site. This study represents a straightforward approach to design new targeted peptides as HIV-1 fusion inhibitors and lead us to define a retro-enantio peptide as a good candidate for pre-exposure prophylaxis against HIV-1.
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.
Thornhill J, Pace M, Genevieve M, et al., 2019, CD32 expressing doublets in HIV infected gut-associated lymphoid are associated with a T follicular helper cell, Mucosal Immunology, Vol: 12, Pages: 1212-1219, ISSN: 1933-0219
Gut-associated lymphoid tissue (GALT) is a key location for the HIV reservoir. The observation that B-cell–T-cell doublets are enriched for CD32a (a low-affinity IgG receptor) in peripheral blood raises interesting questions, especially as these cells have been associated with HIV DNA in some studies. We sought to determine if similar doublets were present in GALT, the significance of these doublets, and their implications for the HIV reservoir. Given the importance of GALT as a reservoir for HIV, we looked for expression of CD32 on gut CD4 T cells and for evidence of doublets, and any relationship with HIV DNA in HIV + individuals initiated on antiretroviral therapy (ART) during primary HIV infection (PHI). Tonsil tissue was also available for one individual. As previously shown for blood, CD32high CD4 cells were mainly doublets of CD4 T cells and B cells, with T-cell expression of ICOS in tonsil and gut tissue. CD4 T cells associated with CD32 (compared with ‘CD32−' CD4 cells) had higher expression of follicular markers CXCR5, PD-1, ICOS, and Bcl-6 consistent with a T follicular helper (TFH) phenotype. There was a significant correlation between rectal HIV DNA levels and CD32 expression on TFH cells. Together, these data suggest that CD32high doublets are primarily composed of TFH cells, a subset known to be preferentially infected by HIV.
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.
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, 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
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
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 (R) 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
Yavuz B, Morgan JL, Showalter L, et al., 2018, Pharmaceutical Approaches to HIV Treatment and Prevention, ADVANCED THERAPEUTICS, Vol: 1
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
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-3 alpha 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.
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
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, 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, 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
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
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
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