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International Journal of Molecular... Feb 2022The UNAIDS objective for 2020 was 500,000 new HIV-1 infections per year; however, the latest annual reported data confirmed 1.7 million new HIV-1 infections in that...
The UNAIDS objective for 2020 was 500,000 new HIV-1 infections per year; however, the latest annual reported data confirmed 1.7 million new HIV-1 infections in that year. Those data evidences the need for new prevention strategies and prophylactic treatments. This prevention crisis occurred in spite of the knowledge and availability of efficient prevention strategies. The G2-S16 is a microbicidal polyanionic carbosilane dendrimer currently being tested for topical vaginal application, which has been shown to be efficient in the prevention of HIV-1 infection. However, safety tests were lacked. For this purpose, we injected intravenously G2-S16 dendrimer to CD1 mice, thereby analyzing the hemogram, blood biochemical markers of systemic damage, accumulation in the organs and organ-tissue damage in heart, spleen, kidney, liver and brain. This work shows that even if the G2-S16 dendrimer penetrates the epithelial tissue, it does not cause vaginal irritation or tissue damage. Moreover, the i.v. injection of the G2-S16 dendrimer did not cause a damaging effect on the studied organs and it did not modify the hemogram or the biochemical plasma markers. In conclusion, the G2-S16 dendrimer has a very good safety profile, indicating that this molecule can be a very safe and efficient vaginal microbicide.
Topics: Animals; Anti-Infective Agents; Dendrimers; Female; HIV Infections; HIV-1; Mice; Silanes
PubMed: 35269708
DOI: 10.3390/ijms23052565 -
Nanoscale May 2019Acquired immune deficiency syndrome (AIDS) due to human immunodeficiency virus type-1 (HIV-1) represents one of the most important sexually transmitted infections (STI)...
Acquired immune deficiency syndrome (AIDS) due to human immunodeficiency virus type-1 (HIV-1) represents one of the most important sexually transmitted infections (STI) worldwide. Great international efforts have been made to stop new infections but, to date, several compounds failed as microbicides at different stages of clinical trials. The quest to design new molecules that could prevent these infections is essential. In this work, we synthesized the first, second and third generations of anionic dendrimers having carboxylate and sulfonate terminal groups, respectively named G1C, G2C, G3C and G1S, G2S, and G3S, starting from a family of poly(alkylideneamine) dendrimers with nitrile termini. The anionic terminal groups of these dendrimers were expected to prompt them to act against HIV-1 infection. All dendrimers were fully characterized by 1H- and 13C-NMR, FTIR, MS and zeta potential techniques. Importantly, they were able to remain stable in the solid state and aqueous solutions at least for one and a half years. Screening of these six new dendrimers was then performed to shed light on their potential anti-HIV-1 activity and their mechanism of action. Results showed that the dendrimers were cytocompatible and that G1C and G1S dendrimers had important activity against R5-HIV-1NLAD8 and X4-HIV-1NL4.3 isolates by acting directly on viral particles and blocking their entry in host cells. Additionally, G1C and G1S dendrimers maintained their inhibitory effect at different pH values. Through a vaginal irritation assay carried out in BALB/c mice, the safety of these new dendrimers for topical application was also shown. Taken together, our results clearly show that G1C and G1S dendrimers are strong candidates for developing an effective microbicide to prevent HIV-1 new infections.
Topics: Animals; Anions; Anti-Infective Agents; Carboxylic Acids; Cell Line; Cell Survival; Dendrimers; Female; HIV Infections; HIV-1; Humans; Mice; Mice, Inbred BALB C; Sulfonic Acids; Vagina; Virus Internalization
PubMed: 31066407
DOI: 10.1039/c9nr00303g -
Current HIV Research Oct 2013Although the development of a protective vaccine remains the most effective strategy for the global control of HIV/AIDS, another practical form of medical intervention... (Review)
Review
Although the development of a protective vaccine remains the most effective strategy for the global control of HIV/AIDS, another practical form of medical intervention would be a microbicide capable of preventing HIV-1 transmission at the mucosal level. A broad spectrum of antiviral molecules have demonstrated in vitro efficacy in proofof- principle studies, and a selected few have already been tested in pre-clinical and clinical microbicide trials. Nevertheless, major hurdles remain to be overcome and there is still much uncertainty about the choice of inhibitors, formulations and administration vehicles for obtaining a safe and effective microbicide. A special category of HIV-1 microbicides are those based on proteins or peptides that interfere with the earliest steps in the viral infectious cycle. Besides a high degree of target specificity and a limited, if any, systemic absorption, proteinbased microbicides offer the unique advantage of being suitable to in vivo expression by engineered bacteria or viral vectors, which might ensure prolonged protection without the need for planned, intercourse-coordinated application. In this respect, vaginal or rectal microbiota such as Lactobacillus spp. represent ideal expression systems as they would not only produce the inhibitor of choice at the mucosal surface, but also easily blend within the resident microflora and offer additional valuable homeostatic effects. In this article, we review the current state of the art on protein-based microbicides.
Topics: Anti-HIV Agents; Anti-Infective Agents; Biological Products; Disease Transmission, Infectious; Drug Delivery Systems; HIV Infections; Humans; Lactobacillus; Microbiota; Recombinant Proteins
PubMed: 24382025
DOI: 10.2174/1570162x11666140101120709 -
Pharmacotherapy Aug 2002The human immunodeficiency virus (HIV) is the number one killer worldwide among infectious disease-causing agents. Because of the speed at which the epidemic has spread,... (Review)
Review
The human immunodeficiency virus (HIV) is the number one killer worldwide among infectious disease-causing agents. Because of the speed at which the epidemic has spread, it is crucial for the global community to expand female-controlled preventive options such as the use of microbicides. Much of microbicide research explores how HIV crosses the mucous membranes of the female genital tract and how the virus can be blocked at that point. The field of microbicides has reached a point where increased political will and expanded investment are required to get products to market in the near future.
Topics: Administration, Intravaginal; Anti-Infective Agents, Local; Condoms, Female; Female; Gels; HIV; HIV Infections; Humans; International Cooperation; Nonoxynol; Sexually Transmitted Diseases, Viral
PubMed: 12173795
DOI: 10.1592/phco.22.12.1074.33610 -
PloS One 2021Low adherence in vaginal microbicide clinical trials for HIV prevention has impeded interpretation of trial results and hindered evaluation of potentially efficacious...
Low adherence in vaginal microbicide clinical trials for HIV prevention has impeded interpretation of trial results and hindered evaluation of potentially efficacious HIV prevention gels. Understanding the underlying reasons why women join trials and their barriers to product use can support identification of ways to improve adherence and its reporting. Eight focus group discussion workshops were conducted with 46 former microbicide trial participants in Durban, South Africa and Mwanza, Tanzania. Participants provided feedback on why women join trials, the barriers to using study gel and reporting adherence accurately, and how clinical trial design can be improved to support better adherence and its reporting. Women join microbicide trials for a number of important reasons such as healthcare and financial reimbursement. Fear of adverse effects from the investigational product was the most important reason why participants reported not using the gel. The key reason for inaccurate reporting of gel use was fear of removal from the trial. Participants made concrete suggestions for improving microbicide trial design such as applicator use testing and real time feedback, improving education to participants about how trials answer their research questions, and improving transparency and clarity about study procedures. Participants also gave feedback on an innovative trial design with a non-randomised arm. Identifying HIV prevention products for women requires better understanding of the lives of women asked to join these trials, and application of that understanding to microbicide trial design. This study has demonstrated that participants and research teams can work collaboratively to design clinical trials that meet needs of both the research and of participants.
Topics: Administration, Intravaginal; Adult; Aged; Anti-HIV Agents; Anti-Infective Agents; Fear; Female; HIV Infections; Humans; Middle Aged; Patient Acceptance of Health Care; Patient Compliance; Randomized Controlled Trials as Topic; Research Design; South Africa; Tanzania; Young Adult
PubMed: 33411782
DOI: 10.1371/journal.pone.0244652 -
Lancet (London, England) Feb 2009
Topics: Anti-Infective Agents; Biomarkers; Clinical Trials as Topic; Female; Humans; Patient Compliance; Reproducibility of Results; Vaginal Diseases
PubMed: 19249629
DOI: 10.1016/S0140-6736(09)60437-2 -
Journal of Virology Sep 2019Over 2 million people are infected with HIV-1 annually. Approximately half of these new infections occur in women residing in low-income countries, where their access to...
Over 2 million people are infected with HIV-1 annually. Approximately half of these new infections occur in women residing in low-income countries, where their access to and control over HIV-1 preventative measures are often limited, indicating that female-controlled prevention options for HIV-1 are urgently needed. Microbicides that can be topically applied to the vaginal tract in advance of sexual activity represent a promising female-controlled prevention option for HIV-1. We have previously described the development of an HIV-1-specific microbicide using the surface or S-layer recombinant protein display capabilities of the nonpathogenic, freshwater bacterium Recombinant bacteria were created that displayed proteins that interfere with the HIV-1 attachment and entry process and that were able to provide significant protection of TZM-bl cells from infection with HIV-1 pseudovirus. These studies have been expanded to investigate if these recombinant bacteria are able to maintain efficacy with replication-competent HIV-1 and both TZM-bl cells and human peripheral blood mononuclear cells (PBMCs). In addition, we utilized the humanized bone marrow-liver-thymus (BLT) mouse model to determine if vaginal application of recombinant at the time of HIV-1 infection could provide protection from HIV-1 infection. Recombinant bacteria expressing Griffithsin, GB virus C E2 protein, elafin, α-1-antitrypsin, indolicidin, and the fusion inhibitor T-1249 were able to protect 40 to 75% of the BLT mice from vaginal infection with HIV-1, with bacteria expressing Griffithsin being the most effective. Taken together, these data suggest that a -based microbicide could be a safe and effective method for HIV-1 prevention. Human immunodeficiency virus (HIV) disproportionally infects young women in sub-Saharan Africa. Current HIV-1 prevention options have had limited success among women, suggesting that alternative, female-controlled prevention options need to be developed. Microbicides that can be applied to the vaginal tract are a promising prevention option. In this study, we describe the testing of 15 potential candidates for inhibition of HIV-1 infection in a humanized mouse model of HIV-1 infection. Four of these candidates were able to provide significant protection from vaginal infection with HIV-1, with the most successful candidate protecting 75% of the mice from infection. This study describes the preclinical testing of a new strategy that could be a safe and effective option for HIV-1 prevention in women.
Topics: Administration, Topical; Animals; Anti-HIV Agents; Anti-Infective Agents; Anti-Retroviral Agents; Bone Marrow; Caulobacter crescentus; Female; HEK293 Cells; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Liver; Mice; Vagina
PubMed: 31243127
DOI: 10.1128/JVI.00614-19 -
Antiviral Research Dec 2010
Topics: Administration, Intravaginal; Anti-Infective Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Female; Humans; Pregnancy
PubMed: 21109062
DOI: 10.1016/j.antiviral.2010.09.004 -
AIDS (London, England) Sep 2013To provide researchers, product sponsors, drug regulators, and funding organizations with a convenient reference regarding regulatory guidance for microbicide... (Review)
Review
OBJECTIVE
To provide researchers, product sponsors, drug regulators, and funding organizations with a convenient reference regarding regulatory guidance for microbicide development and licensure.
METHODS
WHO and other leading agencies in the microbicide field sponsored a series of technical consultations over the past decade that engaged a wide range of international experts in regional settings of primary relevance for microbicide development, testing, and eventual use. This article summarizes the results of those consultations against the ever-changing background of HIV prevention.
RESULTS
These efforts have significantly clarified the scientific basis for developing regulatory guidance for microbicide development and licensure.
CONCLUSION
The technical consultations organised by WHO and others have substantially expanded regulatory perspectives about the development and testing of topical microbicides for preventing the sexual transmission of HIV and other STIs.
Topics: Administration, Topical; Anti-Infective Agents; Chemoprevention; Drug Approval; Drug Discovery; HIV Infections; Humans
PubMed: 23612007
DOI: 10.1097/QAD.0b013e32836239b4 -
Sexually Transmitted Diseases Jan 2007The objective of this article is to study the effect of PC-815, a novel combination microbicide containing carrageenan and the nonnucleoside reverse transcriptase...
OBJECTIVE
The objective of this article is to study the effect of PC-815, a novel combination microbicide containing carrageenan and the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150, in blocking HIV-1 and HIV-2 infections in vitro as compared with Carraguard alone.
GOAL
The goal of this study was to develop a combination microbicide that is more efficacious than Carraguard against HIV-1 and HIV-2.
STUDY DESIGN
The microtiter syncytial assay was used to evaluate: 1) the antiviral and virucidal activity of MIV-150 against HIV-1MN; 2) the additive effect of MIV-150 when combined with carrageenan; and 3) a possible interference of seminal fluid in the antiviral activity of these compounds.
RESULTS
MIV-150 effectively inactivated free virus. Combination of MIV-150 and Carraguard demonstrated an additive antiviral effect. Seminal fluid had no effect on the antiviral activity of MIV-150 or Carraguard. The average concentration that blocks 50% of infection (EC50) for PC-815 was approximately 10 times stronger than Carraguard for the different clinical isolates used in the study.
CONCLUSION
Theoretically, PC-815 is likely to be a more efficacious microbicide than Carraguard.
Topics: Anti-Infective Agents; Carrageenan; Chondrus; Drug Therapy, Combination; HIV Infections; HIV-1; HIV-2; Humans; Male; Microbial Sensitivity Tests; Phytotherapy; Pyridines; Reverse Transcriptase Inhibitors; Semen; Urea
PubMed: 16924181
DOI: 10.1097/01.olq.0000223287.46097.4b