371 research outputs found
Preclinical evaluation of lime juice as a topical microbicide candidate
No full textBackground: The continued growth of the global HIV epidemic highlights the urgent need to develop novel prevention strategies to reduce HIV transmission. The development of topical microbicides is likely to take a number of years before such a product would be widely available.
This has resulted in a call for the rapid introduction of simpler vaginal intervention strategies in the interim period. One suggested practice would be vaginal douching with natural products including lime or lemon juice. Here we present a comprehensive preclinical evaluation of lime juice (LiJ) as a potential intervention strategy against HIV.
Results: Pre-treatment of HIV with LiJ demonstrated direct virucidal activity, with 10% juice inactivating the virus within 5 minutes. However, this activity was significantly reduced in the presence of seminal plasma, where inactivation required maintaining a 1:1 mixture of neat LiJ and seminal plasma for more than 5 minutes. Additionally, LiJ demonstrated both time and dosedependent
toxicity towards cervicovaginal epithelium, where exposure to 50% juice caused 75–90% toxicity within 5 minutes increasing to 95% by 30 minutes. Cervicovaginal epithelial cell monolayers were more susceptible to the effects of LiJ with 8.8% juice causing 50% toxicity after 5
minutes. Reconstructed stratified cervicovaginal epithelium appeared more resilient to LiJ toxicity with 30 minutes exposure to 50% LiJ having little effect on viability. However viability was reduced by 75% and 90% following 60 and 120 minutes exposure. Furthermore, repeat application (several times daily) of 25% LiJ caused 80–90% reduction in viability.
Conclusion: These data demonstrate that the virucidal activity of LiJ is severely compromised in the presence of seminal plasma. Potentially, to be effective against HIV in vivo, women would need to apply a volume of neat LiJ equal to that of an ejaculate, and maintain this ratio vaginally for 5–30 minutes after ejaculation. Data presented here suggest that this would have significant adverse
effects on the genital mucosa. These data raise serious questions about the plausibility and safety of such a prevention approach
Microbicides 2006 conference.
No full textCurrent HIV/AIDS statistics show that women account for almost 60% of HIV infections in Sub-Saharan Africa. HIV prevention tools such as male and female condoms, abstinence and monogamy are not always feasible options for women due to various socio-economic and cultural factors. Microbicides are products designed to be inserted in the vagina or rectum prior to sex to prevent HIV acquisition. The biannual Microbicides conference took place in Cape Town, South Africa from 23-26 April 2006. The conference was held for the first time on the African continent, the region worst affected by the HIV/AIDS pandemic. The conference brought together a record number of 1,300 scientists, researchers, policy makers, healthcare workers, communities and advocates. The conference provided an opportunity for an update on microbicide research and development as well as discussions around key issues such as ethics, acceptability, access and community involvement. This report discusses the current status of microbicide research and development, encompassing basic and clinical science, social and behavioural science, and community mobilisation and advocacy activities
Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants.
No full textBACKGROUND: Heterosexual intercourse remains the major route of HIV-1 transmission worldwide, with almost 5 million new infections occurring each year. Women increasingly bear a disproportionate burden of the pandemic, thus there is an urgent need to develop new strategies to reduce HIV-1 transmission that could be controlled by women themselves. The potential of topical microbicides to reduce HIV transmission across mucosal surfaces has been clearly identified, and some agents are currently under evaluation in clinical trials. Many of these "first generation" microbicides consist of polyanionic compounds designed to interfere with viral attachment. Here we have evaluated two candidate polyanion compounds in clinical trials, PRO 2000 and dextrin sulphate (DxS) to determine their safety and efficacy against in vitro HIV-1 and HSV-2 infection using cellular and tissue explant models.
RESULTS: PRO 2000 and DxS potently inhibited infection by HIV-1 X4 and R5 isolates when present during viral exposure. However PRO 2000 required 10-fold and DxS 2000-fold more compound to block infection with R5 virus than X4. While both compounds were virucidal for X4 HIV-1, neither was virucidal for R5 virus. PRO 2000 efficiently inhibited infection of cervical explants and dissemination of virus by migratory DC. DxS was less active, able to completely inhibit cervical explant infection, but providing only partial reduction of virus dissemination by DC. PRO 2000, but not DxS, also inhibited HIV-1 binding to DC-SIGN+ cells and trans infection of co-cultured target cells. The inflammatory potential of both compounds was screened by measurement of cytokine production from cervical explants, and statistically significant increases were only observed for IL-1beta and RANTES following treatment with PRO 2000. Both compounds also demonstrated potent activity against HSV-2 infection of cervical epithelial cells.
CONCLUSION: Our results demonstrate that PRO 2000 is a potent inhibitor of R5 HIV-1 infection and dissemination pathways in human cervical explants. DxS, while demonstrating significant inhibition of R5 infection, was less active against DC mediated dissemination pathways. PRO 2000 has now entered human phase III efficacy trials
Corrigendum: Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination
No full textA corrigendum on Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination by Kratochvil S, McKay PF, Chung AW, Kent SJ, Gilmour J, Shattock RJ. Front Immunol (2017) 8:1883. doi: 10.3389/fimmu.2017.01883. An author name was incorrectly spelled as Jill Gilmore. The correct spelling is Jill Gilmour. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.</p
Vaccine adjuvants: A priority for vaccine research
No full textThe workshop on vaccine adjuvants was held in July of 2009 at the European Commission in Brussels, with the goal of identifying key scientific priorities as they pertain to the development of effective vaccines against life-threatening diseases especially those associated with poverty, including HIV/AIDS, malaria and tuberculosis as well as neglected infectious diseases. On the basis of new advances in adjuvant research and related technology as well as potential challenges and roadblocks, six priorities were identified to accelerate development of improved or novel vaccine adjuvants for human use
Development of vaccine platforms for membrane display of surface antigens using HIV-1 Env as model immunogen
No full textThe HIV-1 pandemic remains a major public health concern worldwide with over 1.5 million new infections every year. Despite the many effective prevention tools now available, access to treatment and implementations of these tools are proving difficult. Thus, developing an effective vaccine to prevent HIV-1 transmission remains of upmost importance. To date, HIV-1 vaccines failed to induce robust protective immunity and prophylactic vaccines that will elicit long-lasting protective immune responses still remain to be developed.
The HIV-1 Envelope glycoprotein (Env) has been the main target of immunogen design with the aim of inducing neutralizing antibodies. In order to cover Env diversity, prophylactic vaccines are expected to induce broadly neutralizing antibodies (bNAbs). This will likely require Env trimers that limit exposure of non-neutralizing antibody (nNAb) epitopes within stabilized closed pre-fusion Envs that exhibit bNAb epitopes.
In this thesis, an iterative design process generated membrane-bound Env immunogens that present stabilized native-like trimers. This ultimately resulted in the ConSOSL.UFO.750 trimer that preferentially binds quaternary-specific bNAbs relative to nNAbs. Further characterization of the soluble ConSOSL.UFO.664 confirmed presentation of a closed pre-fusion native-like structure. Immunogenicity studies demonstrated that ConSOSL.UFO.664 can induce autologous Tier 2 neutralization in rabbits and showed that ConSOSL.UFO.750 can modulate the T helper response in a mouse model. To improve the potential of the membrane-bound designs to induce relevant immune responses, virus-like particles (VLPs) based on Mumps and PIV5 pseudotyping were developed. These VLPs displayed Env immunogens and were able to modulate the immune response by intrastructural help in mice.
Work presented in this thesis shows the successful design of immunogens that preserve the pre-fusion native-like structure of Env, amenable to various vaccination platforms. The ConSOSL.UFO design has now been moved into phase I clinical trial within the EAVI2020 consortium which will provide critical information for the development of an effective vaccine.Open Acces
Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers
No full textThe HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations. We derived a stabilized HIV-1 trimer, ConSOSL.UFO.750, which displays a dramatic reduction in nNAb binding while maintaining high quaternary and MPER-specific bNAb binding. Its soluble counterpart, ConSOSL.UFO.664, displays similar antigenicity, and its native-like Env structure is confirmed by negative stain-EM and glycosylation profiling of the soluble ConSOSL.UFO.664 trimer. A rabbit immunization study demonstrated that the ConSOSL.UFO.664 can induce autologous tier 2 neutralization. We have successfully designed a stabilized native-like Env trimer amenable to nucleic acid or viral vector-based vaccination strategies
Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference.
No full textEUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper
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