Biotech's role in advancing HIV vaccine development.

HIV vaccine development has been hindered by significant challenges over four decades. Despite persistent efforts, all efficacy trials to date have yielded disappointing results. This has pushed the field back to the discovery phase and created uncertainty about the future involvement of large pharmaceutical companies.

Perspectives on Design Approaches for HIV Prevention Efficacy Trials.

The challenge of designing future HIV prevention efficacy trials in a rapidly evolving HIV prevention landscape was explored through a series of virtual stakeholder's engagement meetings convened online between October 2020 and April 2021. A broad array of stakeholders from the HIV prevention research community reviewed current trial designs and lessons learned, explored issues specific to unique product classes, and concluded with specialist-focused examinations of statistical design concepts and the importance of community engagement in research. The aim was to reflect on current approaches and evaluate new trial design approaches for evaluating efficacy of a candidate prevention strategy in the context of an active-controlled trial, which does not include a placebo arm.

Experimental Medicine for HIV Vaccine Research and Development.

The development of safe and effective HIV vaccines has been a scientific challenge for more than 40 years. Despite disappointing results from efficacy clinical trials, much has been learnt from years of research and development. In a rapidly evolving HIV prevention landscape, swift evaluation of multiple vaccine approaches eliciting cross-reactive humoral and cellular responses is needed to ensure the development of efficacious vaccine candidates.

Mitigation strategies to safely conduct HIV treatment research in the context of COVID-19.

Introduction: The International AIDS Society convened a multidisciplinary committee of experts in December 2020 to provide guidance and key considerations for the safe and ethical management of clinical trials involving people living with HIV (PLWH) during the SARS-CoV-2 pandemic. This consultation did not discuss guidance for the design of prevention studies for people at risk of HIV acquisition, nor for the programmatic delivery of antiretroviral therapy (ART).

Discussion: There is strong ambition to continue with HIV research from both PLWH and the research community despite the ongoing SARS-CoV-2 pandemic.

A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes.

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity.

Strain-dependent and distinctive T-cell responses to HIV antigens following immunisation of mice with differing chimpanzee adenovirus vaccine vectors.

In vivo vaccination studies are conventionally conducted in a single mouse strain with results, only reflecting responses to a single immunogenetic background. We decided to examine the immune response to an HIV transgene (gag, pol and nef fusion protein) in 3 strains of mice (CBA, C57BL/6 and BALB/c) to determine the spectrum of responses and in addition to determine whether the serotype of the adenoviral vector used (ChAd3 and ChAd63) impacted the outcome of response. Our results demonstrated that all three strains of mice responded to the transgene and that the magnitude of responses were different between the strains.

Boosting with Subtype C CN54rgp140 Protein Adjuvanted with Glucopyranosyl Lipid Adjuvant after Priming with HIV-DNA and HIV-MVA Is Safe and Enhances Immune Responses: A Phase I Trial.

Background: A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA).

Methods: Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination.

Analysis of T cell responses to chimpanzee adenovirus vectors encoding HIV gag-pol-nef antigen.

Adenoviruses have been shown to be both immunogenic and efficient at presenting HIV proteins but recent trials have suggested that they may play a role in increasing the risk of HIV acquisition. This risk may be associated with the presence of pre-existing immunity to the viral vectors. Chimpanzee adenoviruses (chAd) have low seroprevalence in human populations and so reduce this risk.

Alphavirus replicon DNA expressing HIV antigens is an excellent prime for boosting with recombinant modified vaccinia Ankara (MVA) or with HIV gp140 protein antigen.

Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells and antibodies. Studies in humans have shown that DNA vaccines are safe, but their immunogenicity needs further improvement. As a step towards this goal, we have previously demonstrated that immunogenicity is increased with the use of an alphavirus DNA-launched replicon (DREP) vector compared to conventional DNA vaccines.

Glucopyranosyl lipid A adjuvant significantly enhances HIV specific T and B cell responses elicited by a DNA-MVA-protein vaccine regimen.

Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNA-poxvirus-protein strategy in mice and rabbits, administering MVA and protein immunizations either sequentially or simultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef) with HIV CN54gp140 protein (+/-GLA-AF adjuvant) and either co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. The DNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to the boost vaccines.

Postexposure prophylaxis, preexposure prophylaxis or universal test and treat: the strategic use of antiretroviral drugs to prevent HIV acquisition and transmission.

This review considers the use of antiretroviral drugs specifically to prevent HIV transmission. Antiretroviral therapy (ART) can be implemented for the protection of uninfected individuals both before (preexposure prophylaxis) and after (postexposure prophylaxis) exposure to HIV infection. Preexposure prophylaxis may be used coitally dependently when individuals are intermittently exposed or by continuous daily dosing for those constantly exposed; postexposure prophylaxis is used in 28-day courses.

Phylometabonomic patterns of adaptation to high fat diet feeding in inbred mice.

Insulin resistance plays a central role in type 2 diabetes and obesity, which develop as a consequence of genetic and environmental factors. Dietary changes including high fat diet (HFD) feeding promotes insulin resistance in rodent models which present useful systems for studying interactions between genetic background and environmental influences contributing to disease susceptibility and progression. We applied a combination of classical physiological, biochemical and hormonal studies and plasma (1)H NMR spectroscopy-based metabonomics to characterize the phenotypic and metabotypic consequences of HFD (40%) feeding in inbred mouse strains (C57BL/6, 129S6, BALB/c, DBA/2, C3H) frequently used in genetic studies.

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice.

Aims/hypothesis: Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with diet-induced NAFLD.

Materials And Methods: Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks.

A conditionally immortalized cell line model for the study of human prostatic epithelial cell differentiation.

In the normal human prostate, undifferentiated proliferative cells reside in the basal layer and give rise to luminal secretory cells. There are, however, few epithelial cell lines that have a basal cell phenotype and are able to differentiate. We set out to develop a cell line with these characteristics that would be suitable for the study of the early stages of prostate epithelial cell differentiation.

Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice.

Here, we study the intricate relationship between gut microbiota and host cometabolic phenotypes associated with dietary-induced impaired glucose homeostasis and nonalcoholic fatty liver disease (NAFLD) in a mouse strain (129S6) known to be susceptible to these disease traits, using plasma and urine metabotyping, achieved by (1)H NMR spectroscopy. Multivariate statistical modeling of the spectra shows that the genetic predisposition of the 129S6 mouse to impaired glucose homeostasis and NAFLD is associated with disruptions of choline metabolism, i.e.

The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis.

Aim: Chemokines or chemotactic cytokines are known to be important in the directional migration or chemotaxis of leucocytes in conditions of homeostasis and in inflammatory or immunological responses. However, the role of chemokines is extending beyond their involvement in mediating leucocyte trafficking with an increasing body of evidence suggesting these proteins are intimately involved in many stages of tumour development and progression. Our aim was to study the role of the CXCL12:CXCR4 chemokine ligand:receptor complex in determining the organ-specific metastasis of prostate cancer.

Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines.

The nuclear receptor peroxisome proliferator-activated receptor delta [PPARdelta/beta (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARdelta by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARdelta selective agonists.

Insulin-like Growth Factor (IGF) Network and Prostate Pathologies.

The Insulin-like Growth Factor (IGF) network in prostate tissue represents a key element in normal and tumour growth. It can provide us with new markers for prognosis or diagnosis and targets for treatment of prostate diseases. This short review introduces the IGF network in general and in the prostate gland, summarises the modifications observed in tumours and discusses the importance of a new family of low affinity IGF-binding proteins.

Diclofenac antagonizes peroxisome proliferator-activated receptor-gamma signaling.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are used as cancer chemopreventative agents, their mechanism is unclear because NSAIDs have cyclooxygenase-independent actions. We investigated an alternative target for NSAIDs, peroxisome proliferator-activated receptor-gamma (PPARgamma), activation of which decreases cancer cell proliferation. NSAIDs have been shown to activate this receptor, but only at high concentrations.