A5102881142- HIV Research and Treatment
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- HIV/AIDS Research and Interventions
- Immunotherapy and Immune Responses
- HIV/AIDS drug development and treatment
- vaccines and immunoinformatics approaches
- Immune Response and Inflammation
- Herpesvirus Infections and Treatments
- Carcinogens and Genotoxicity Assessment
- Bacteriophages and microbial interactions
- Mosquito-borne diseases and control
- Protein purification and stability
- Protist diversity and phylogeny
- Viral Infections and Outbreaks Research
- Genetic and Kidney Cyst Diseases
- COVID-19 epidemiological studies
- Microtubule and mitosis dynamics
- Biochemical and Molecular Research
- Nanoparticle-Based Drug Delivery
- Immunodeficiency and Autoimmune Disorders
- Virology and Viral Diseases
- Enzyme function and inhibition
- Infectious Encephalopathies and Encephalitis
Imperial College London
2014-2024
International AIDS Vaccine Initiative
2015-2024
Chelsea and Westminster Hospital NHS Foundation Trust
2022
MRC Human Immunology Unit
2017-2020
Institute of Infection and Immunity
2015
Chelsea and Westminster Hospital
2015
National Institute of Environmental Health Sciences
2014
National Institutes of Health
2014
St George's, University of London
2012
King's College London
2004-2007
BackgroundInhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers.ObjectiveWe sought evaluate Diversity Outbred (DO) mice as a tool for threshold assessment and identify genetic factors that influence benzene-induced genotoxicity.MethodsWe male DO (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation 28 days (6 hr/day 5 days/week). The study was repeated using two independent cohorts 300 animals each. We...
ABSTRACT Definition of the key parameters mediating effective antibody blocking HIV-1 acquisition within mucosal tissue may prove critical to vaccine development and prophylactic use monoclonal antibodies. Although direct antibody-mediated neutralization is highly against cell-free virus, antibodies targeting different sites envelope vulnerability display differential activity infection. Nonneutralizing (nnAbs) also impact transmission events through Fc-gamma receptor (FcγR)-mediated...
Antibody mediated viral aggregation may impede transfer across mucosal surfaces by hindering movement in mucus, preventing transcytosis, or reducing inter-cellular penetration of epithelia thereby limiting access to susceptible CD4 T cells and dendritic cells. These functions work together provide effective immune exclusion virus from tissue; however little is known about the antibody characteristics required induce HIV aggregation. Such knowledge be critical design successful immunization...
Abstract HIV-1 envelope proteins (Envs) play a critical role in HIV infection. In correct trimeric conformation, Env mediates virus–cell binding and fusion. Malfunctioning of this machinery renders virions incapable infecting cells. Each virion carries 10–14 Envs, therefore defective may not necessarily render non-infectious, since other on the same still be functional. Alternatively, it is possible that given either all spikes are or Here, we investigate conformations individual using our...
The induction of high levels systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly the clinic. Due to their closer similarity humans, minipigs may provide more accurate picture performance. Based on complementary signalling pathways, we assessed immune responses model antigens after co-administration with toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid (GLA-AF) or TLR7/8...
Abstract An LTR-based quantitative PCR (qPCR) assay was modified and optimized for the quantification of total HIV-1 nucleic acids in plasma PBMC. TaqMan qPCR primers probes were designed against NCBI/LANL compendium database by analyzing sequences used assays sensitive cross-clade detection as reported literature elucidating regions improved cross-subtype specificity. Inosine mixed nucleotide bases included at polymorphic sites. Real-time RT-qPCR performed on viral RNA cellular lysates. A...
The majority of new Human Immunodeficiency Virus (HIV)-1 infections are acquired via sexual transmission at mucosal surfaces. Partial efficacy (31.2%) the Thai RV144 HIV-1 vaccine trial has been correlated with Antibody-dependent Cellular Cytotoxicity (ADCC) mediated by non-neutralizing antibodies targeting V1V2 region envelope. This led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defense against acquisition infection. However,...
Human immunodeficiency virus type 1 (HIV-1) transmission results from infection with one or a small number of variants the donor quasispecies. Transmitted/founder (T/F) viruses have recently been identified acutely infected patients, but way in which they interact primary targets HIV-1 is poorly understood. We conducted biological characterization panel subtype B T/F acute and chronic envelope (Env)-expressing chimeric human target cells mucosal tissues. Both Envs preferentially replicated...
First identified as the etiological agent behind Acquired Immunodeficiency Syndrome (AIDS) in early 1980s, HIV-1 has continued to spread into a global pandemic and major public health concern. Despite success of antiretroviral therapy at reducing viremia preventing dramatic CD4+ T-cell collapse, infected individuals remain HIV positive for life. Unfortunately, it is increasingly clear that natural immunity not, may never be, protective against this pathogen. Therefore, efficacious vaccine...
The generation of effective levels antigen-specific immunity at the mucosal sites pathogen entry is a key goal for vaccinologists. We explored topical vaginal application as an approach to initiate local immunity, enhance previously existing systemic or re-target responses mucosae. To deliver protein vaccine formulation surface, we used novel ring device comprising silicone elastomer body into which three freeze-dried, rod-shaped, hydroxypropylmethylcellulose inserts were incorporated. Each...
As part of a Phase III trial with the Ebola vaccine rVSVΔG-ZEBOV-GP in Guinea, we invited frontline workers (FLWs) to participate sub-study provide additional information on immunogenicity vaccine.We conducted an open-label, non-randomized, single-arm evaluation one dose among healthy FLWs Guinea. who refused vaccination were offered as control group. We followed participants for 84 days subset followed-up 180 days. The primary endpoint was immune response, measured by ELISA...
Understanding why human immunodeficiency virus (HIV) preferentially infects some CD4(+) CD45RO(+) memory T cells has implications for antiviral immunity and pathogenesis. We report that differential expression of a novel secreted factor, ps20, previously implicated in tissue remodeling, may underlie CD4 are targeted. show (i) there is significant positive correlation between endogenous ps20 mRNA diverse T-cell populations vitro infection, (ii) ps20(+) permissive cell can be made less by...
The structure of HIV-1 envelope glycoprotein (Env) is flexible and heterogeneous on whole virions. Although functional Env complexes are thought to require trimerization cleaved gp41/gp120 heterodimers, variable processing can result in the potential incorporation non-functional uncleaved proteins (gp160), non-trimeric arrangements gp120 depleted gp41 stumps. distribution forms across replication-competent viral populations may have important implications for neutralizing non-neutralizing...
Delivering vaccine antigens to mucosal surfaces is potentially very attractive, especially as protection from infections may be mediated by local immune responses. However, date immunization has had limited successes, with issues of both safety and poor immunogenicity. One approach improve immunogenicity develop adjuvants that are effective safe at surfaces. Differences in responses between mice men have overstated the value some experimental which subsequently performed poorly clinic. Due...
A key aspect to finding an efficacious human immunodeficiency virus (HIV) vaccine is the optimization of schedules that can mediate efficient maturation protective immune responses. In present study, we investigated effect alternate booster regimens on responses a candidate HIV-1 clade C CN54gp140 envelope protein, which was coadministered with TLR4-agonist glucopyranosyl lipid A-aqueous formulation. Twelve study participants received common three-dose intramuscular priming series followed...
Abstract Background Interactions between the HIV-1 envelope glycoprotein (Env) and its primary receptor CD4 are influenced by physiological setting in which these events take place. In this study, we explored surface chemistry of Env constructs at a range pH salinities relevant to mucosal systemic compartments through electrophoretic mobility (EM) measurements. Sexual transmission provide more acidic environment for compared dissemination spread infection occurring blood or lymph node. We...
During combined anti-retroviral treatment, a latent HIV reservoir persists within resting memory CD4 T cells that initiates viral recrudescence upon treatment interruption. Strategies for HIV-1 cure have largely focused on latency reversing agents (LRAs) capable of reactivating and eliminating this reservoir. Previously investigated LRAs failed to achieve robust reversal sufficient reduction pool or the potential virus-free remission in absence treatment.
HIV-1 transmission is associated with a severe bottleneck in which limited number of variants from pool genetically diverse quasispecies establishes infection. The IAVI protocol C cohort discordant couples, female sex workers, other heterosexuals and men who have (MSM) present varying risks HIV infection, subtypes represent unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome known. To identify the TF, repertoire 38 MSM participants' samples was sequenced...
Background: The world needs an effective HIV-1/AIDS vaccine. Even in the broader context of antiretroviral treatment and prevention, a vaccine remains best solution likely key component any package truly ending AIDS epidemic. Vaccine is particularly needed most affected regions like sub-Saharan Africa, where HIV-1 significantly impacts people's lives economy.Methods: CD8+ killer T cells impose selective pressure on their protective potential should be utilized for vaccination. Our program...
Aim: To characterize HIV-1 Gag p24-specific CD4 cell responses in HIV-exposed-seronegative (ES) individuals. Methodology: Twelve ES individuals, of diverse ethnicity and wild type for the CCR5 Δ-32 mutation, were identified. Controls HIV-negative blood donors. total Vβ+ cells that expressed MIP-1β, IFN-γ IL-2 enumerated by intracytoplasmic cytokine staining. β-Chemokine expression was correlated with susceptibility to R5 infection, as measured polymerase chain reaction integrated p24...
Full characterisation of functional HIV-1-specific T-cell responses, including identification recognised epitopes linked with antiviral would aid development effective vaccines but is hampered by HIV-1 sequence diversity. Typical approaches to identify utilising extensive peptide sets require subjects’ cell numbers that exceed feasible sample volumes. To address this, CD8 T-cells were polyclonally expanded from PBMC 13 anti-retroviral naïve subjects living HIV using CD3/CD4 bi-specific...
The cellular basis of HIV associated dementia has been correlated with microglial activation and neuronal dysfunction in symptomatic HIV-1 disease. As a model infection brain tissue vitro, we established stationary human aggregate (SHBA) system to compare SF162 (R5 virus) that IIIB (X4 virus). Aggregates were analysed by immunohistochemistry, morphometry, flow cytometry p24 ELISA. SHBAs had 1 mm(3) size mixed composition 36% neurones, 27% astrocytes, 2% macrophages/microglia 14%...
Background An effective HIV vaccine will likely require induction of both mucosal and systemic cellular humoral immune responses. We investigated whether intramuscular (IM) delivery electroporated plasmid DNA simultaneous protein vaccinations by intranasal (IN) IM routes could be combined to induce responses a model HIV-1 CN54 gp140 antigen in mice. Results Co-immunisation with successfully elicited serum vaginal IgG IgA responses, whereas co-delivery did not or Cellular IFNγ were preserved...
Introduction Immunological protection against human immunodeficiency virus-1 (HIV-1) infection is likely to require both humoral and cell-mediated immune responses, the latter involving cytotoxic CD8 T-cells. Characterisation of T-cell mediated direct anti-viral activity would provide understanding potential correlates identification critical epitopes associated with HIV-1 control. Methods The present report describes a functional viral inhibition assay (VIA) assess T-cell-mediated...
ABSTRACT The ability of vaccine-induced T cells to inhibit viral replication may contribute protect against human immunodeficiency virus (HIV) acquisition. Here, we tested ex vivo inhibitory activity cell responses induced by a multivalent HIV vaccine based on the replication-incompetent recombinant adenovirus serotype 26 vector with mosaic immunogen strategy (Ad26.Mos.HIV), designed for broad immune coverage diverse HIV-1 strains. Using clinical trial samples range measured IFN-γ ELISpot,...