286 results found
Donnelly L, Curran RM, Morrow RJ, et al., 2009, Stable lyophilised gel vehicles for vaginal administration of recombinant C-clade HIV-1 trimeric CN54gp140, RETROVIROLOGY, Vol: 6, ISSN: 1742-4690
Lewis DJ, Lacey CJ, Jeffs S, et al., 2009, Phase I safety and immunogenicity randomised controlled trial of a vaginal gp140 vaccine, RETROVIROLOGY, Vol: 6, ISSN: 1742-4690
Cranage M, Fraser C, Cope A, et al., 2009, Intravaginal administration of HIV-1ZM96 gp140 augments systemic and mucosal antibody responses following systemic priming with adjuvanted protein, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Buffa V, Stieh D, Mamhood N, et al., 2009, Cyanovirin-N potently inhibits human immunodeficiency virus type 1 infection in cellular and cervical explant models, JOURNAL OF GENERAL VIROLOGY, Vol: 90, Pages: 234-243, ISSN: 0022-1317
Siddiqui AA, King DF, Buffa V, et al., 2009, Evaluation of HIV-1 subtype B acute envelope-expressing infectious molecular clones, RETROVIROLOGY, Vol: 6, ISSN: 1742-4690
Cranage M, Fraser C, Cope A, et al., 2009, Intravaginal administration of HIV-1ZM96 gp140 augments systemic and mucosal antibody responses following systemic priming with adjuvanted protein., AIDS Vaccine 2009
Fletcher P, Harman S, Azijn H, et al., 2009, Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor, Vol: 53, Pages: 487-495, ISSN: 1098-6596
Buffa V, Stieh D, Mamhood N, et al., 2009, Cyanovirin-N potently inhibits human immunodeficiency virus type 1 infection in cellular and cervical explant models, Vol: 90, Pages: 234-243, ISSN: 0022-1317
Mann JF, Cranage MP, Shattock RJ, et al., 2008, Development of a Novel Transcytosis-Mediated HIV Envelope Vaccine Mucosal Delivery Modality, AIDS Vaccine 2008
Fischetti L, Shattock RJ, 2008, Monomac-1 as a Model to Study Antibody-Mediated HIV-1 Inhibition, AIDS Vaccine 2008 Conference, Publisher: MARY ANN LIEBERT INC, Pages: 48-48, ISSN: 0889-2229
Lisco A, Vanpouille C, Tchesnokov EP, et al., 2008, Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues., Cell Host Microbe, Vol: 4, Pages: 260-270
For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is one such drug. It is activated into a human herpesvirus (HHV) DNA polymerase inhibitor exclusively by HHV kinases and, thus, does not suppress other viruses. Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues, but not in HHV-free tissue or cell cultures. However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV activity. We hypothesized that such HIV suppression requires ACV phosphorylation by HHV kinases. Indeed, an ACV monophosphorylated prodrug bypasses the HHV requirement for HIV suppression. Furthermore, phosphorylated ACV directly inhibits HIV-1 reverse transcriptase (RT), terminating DNA chain elongation, and can trap RT at the termination site. These data suggest that ACV anti-HIV-1 activity may contribute to the response of HIV/HHV-coinfected patients to ACV treatment and could guide strategies for the development of new HIV-1 RT inhibitors.
Cranage M, Sharpe S, Herrera C, et al., 2008, Prevention of SIV rectal transmission and priming of T cell responses in macaques after local pre-exposure application of tenofovir gel, PLoS Medicine, Vol: 5, ISSN: 1549-1277
BACKGROUND: The rectum is particularly vulnerable to HIV transmission having only a single protective layer of columnar epithelium overlying tissue rich in activated lymphoid cells; thus, unprotected anal intercourse in both women and men carries a higher risk of infection than other sexual routes. In the absence of effective prophylactic vaccines, increasing attention is being given to the use of microbicides and preventative antiretroviral (ARV) drugs. To prevent mucosal transmission of HIV, a microbicide/ARV should ideally act locally at and near the virus portal of entry. As part of an integrated rectal microbicide development programme, we have evaluated rectal application of the nucleotide reverse transcriptase (RT) inhibitor tenofovir (PMPA, 9-[(R)-2-(phosphonomethoxy) propyl] adenine monohydrate), a drug licensed for therapeutic use, for protective efficacy against rectal challenge with simian immunodeficiency virus (SIV) in a well-established and standardised macaque model. METHODS AND FINDINGS: A total of 20 purpose-bred Indian rhesus macaques were used to evaluate the protective efficacy of topical tenofovir. Nine animals received 1% tenofovir gel per rectum up to 2 h prior to virus challenge, four macaques received placebo gel, and four macaques remained untreated. In addition, three macaques were given tenofovir gel 2 h after virus challenge. Following intrarectal instillation of 20 median rectal infectious doses (MID50) of a noncloned, virulent stock of SIVmac251/32H, all animals were analysed for virus infection, by virus isolation from peripheral blood mononuclear cells (PBMC), quantitative proviral DNA load in PBMC, plasma viral RNA (vRNA) load by sensitive quantitative competitive (qc) RT-PCR, and presence of SIV-specific serum antibodies by ELISA. We report here a significant protective effect (p = 0.003; Fisher exact probability test) wherein eight of nine macaques given tenofovir per rectum up to 2 h prior to virus challenge were protected from
Haynes BF, Shattock RJ, 2008, Critical issues in mucosal immunity for HIV-1 vaccine development, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 122, Pages: 3-9, ISSN: 0091-6749
Mesquita PMM, Wilson SS, Manlow P, et al., 2008, Candidate microbicide PPCM blocks human immunodeficiency virus type 1 infection in cell and tissue cultures and prevents genital herpes in a murine model, JOURNAL OF VIROLOGY, Vol: 82, Pages: 6576-6584, ISSN: 0022-538X
van de Wijgert J, Shattock RJ, 2008, Vaginal microbicides: the importance of effective distribution, retention and coating of the mucosa, AIDS, Vol: 22, Pages: 1231-1232, ISSN: 0269-9370
Fichorova RN, Richardson-Harman N, Alfano M, et al., 2008, Biological and technical variables affecting immunoassay recovery of cytokines from human serum and simulated vaginal fluid: a multicenter study., Anal Chem, Vol: 80, Pages: 4741-4751
The increase of proinflammatory cytokines in vaginal secretions may serve as a surrogate marker of unwanted inflammatory reaction to microbicide products topically applied for the prevention of sexually transmitted diseases, including HIV-1. Interleukin (IL)-1beta and IL-6 have been proposed as indicators of inflammation and increased risk of HIV-1 transmission; however, the lack of information regarding detection platforms optimal for vaginal fluids and interlaboratory variation limit their use for microbicide evaluation and other clinical applications. This study examines fluid matrix variants relevant to vaginal sampling techniques and proposes a model for interlaboratory comparisons across current cytokine detection technologies. IL-1beta and IL-6 standards were measured by 12 laboratories in four countries, using 14 immunoassays and four detection platforms based on absorbance, chemiluminescence, electrochemiluminescence, and fluorescence. International reference preparations of cytokines with defined biological activity were spiked into (1) a defined medium simulating the composition of human vaginal fluid at pH 4.5 and 7.2, (2) physiologic salt solutions (phosphate-buffered saline and saline) commonly used for vaginal lavage sampling in clinical studies of cytokines, and (3) human blood serum. Assays were assessed for reproducibility, linearity, accuracy, and significantly detectable fold difference in cytokine level. Factors with significant impact on cytokine recovery were determined by Kruskal-Wallis analysis of variance with Dunn's multiple comparison test and multiple regression models. All assays showed acceptable intra-assay reproducibility; however, most were associated with significant interlaboratory variation. The smallest reliably detectable cytokine differences ( P < 0.05) derived from pooled interlaboratory data varied from 1.5- to 26-fold depending on assay, cytokine, and matrix type. IL-6 but not IL-1beta determinations were lower in both s
Shattock RJ, Haynes BF, Pulendran B, et al., 2008, Improving defences at the portal of HIV entry: mucosal and innate immunity - A summary report from a global HIV vaccine enterprise working group, PLOS MEDICINE, Vol: 5, Pages: 537-541, ISSN: 1549-1277
Harman SJ, Shattock RJ, 2008, Characterisation of small molecule entry inhibitors in human cervical and penile tissue models, Microbicides 2008
Fletcher PS, Shattock RJ, 2008, PRO-2000, an antimicrobial gel for the potential prevention of HIV infection, CURRENT OPINION IN INVESTIGATIONAL DRUGS, Vol: 9, Pages: 189-200, ISSN: 1472-4472
Fletcher PS, Harman SJ, Boothe AR, et al., 2008, Preclinical evaluation of lime juice as a topical microbicide candidate, RETROVIROLOGY, Vol: 5, ISSN: 1742-4690
Fletcher PS, Harman SJ, Boothe AR, et al., 2008, Preclinical evaluation of lime juice as a topical microbicide candidate, Vol: 5, ISSN: 1742-4690
Klasse PJ, Shattock R, Moore JP, 2008, Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission., Annu Rev Med, Vol: 59, Pages: 455-471, ISSN: 0066-4219
The development of a vaginal (and perhaps a rectal) microbicide would be of major benefit for slowing the global spread of human immunodeficiency virus type 1 (HIV-1). A microbicide is a gel or related device that, when inserted vaginally or rectally, acts to prevent infection of a woman or a man by HIV-1 during sexual intercourse. A practical microbicide must be not only effective, safe, and user-friendly but also economically affordable in the developing world. To date, the performance of microbicide candidates in efficacy trials has been disappointing, but next-generation concepts now in or approaching clinical trials offer improved prospects for efficacy. The most plausible approaches involve topical application of antiretroviral agents with specific activity against HIV-1, compounds similar to drugs used to treat HIV-1 infection. How these inhibitors are applied may also be critical, with sustained-release formulations and vaginal ring delivery systems now becoming a high priority.
Fletcher PS, Shattock RJ, 2008, PRO-2000, an antimicrobial gel for the potential prevention of HIV infection, Vol: 9, Pages: 189-200, ISSN: 1472-4472
Arias MA, Jaramillo G, Lopez YP, et al., 2007, Mycobacterium tuberculosis antigens specifically modulate CCR2 and MCP-1/CCL2 on lymphoid cells from human pulmonary hilar lymph nodes, JOURNAL OF IMMUNOLOGY, Vol: 179, Pages: 8381-8391, ISSN: 0022-1767
van de Wijgert JHHM, Shattock RJ, 2007, Vaginal microbicides: moving ahead after an unexpected setback, AIDS, Vol: 21, Pages: 2369-2376, ISSN: 0269-9370
Hu Q, Mahmood N, Shattock RJ, 2007, High-mannose-specific deglycosylation of HIV-1 gp120 induced by resistance to cyanovirin-N and the impact on antibody neutralization, VIROLOGY, Vol: 368, Pages: 145-154, ISSN: 0042-6822
Tao J, Hu Q, Yang J, et al., 2007, In vitro anti-HIV and -HSV activity and safety of sodium rutin sulfate as a microbicide candidate., Antiviral Res, Vol: 75, Pages: 227-233, ISSN: 0166-3542
Sodium rutin sulfate (SRS) is a sulfated rutin modified from the natural flavonol glycoside rutin. Here, we investigated its in vitro anti-HIV and -HSV activities and its cytotoxic profile. Fifty percent inhibitory concentration (IC(50)) values of SRS against HIV-1 X4 virus IIIB, HIV-1 R5 isolates Ada-M and Ba-L were 2.3+/-0.2, 4.5+/-2.0 and 8.5+/-3.8 microM with a selectivity index (SI) of 563, 575 and 329, respectively. Its IC(50) against primary R5 HIV-1 isolate from Yunnan province in China was 13.1+/-5.5 microM, with a SI of 197. In contrast, unsulfated rutin had no activity against any of the HIV-1 isolates tested. Further study indicated that SRS blocked viral entry and virus-cell fusion likely through interacting with the HIV-1 envelope glycoprotein. SRS also demonstrated some activity against human herpes simplex virus (HSV) with an IC(50) of 88.3+/-0.1 microM and a SI of 30. The 50% cytotoxicity concentration (CC(50)) of SRS was >3.0 mM, as determined in human genital ME180, HeLa and primary human foreskin fibroblast cells. Minimum inhibitory concentration of SRS for vaginal lactobacilli was >3.0 mM. These results collectively indicate that SRS represents a novel candidate for anti-HIV-1/HSV microbicide development.
Madan RP, Mesquita PMM, Cheshenko N, et al., 2007, Molecular umbrellas: a novel class of candidate topical microbicides to prevent human immunodeficiency virus and herpes simplex virus infections, JOURNAL OF VIROLOGY, Vol: 81, Pages: 7636-7646, ISSN: 0022-538X
Grivel J-C, Elliott J, Lisco A, et al., 2007, HIV-1 pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with CCR5-and CXCR4-tropic HIV-1, AIDS, Vol: 21, Pages: 1263-1272, ISSN: 0269-9370
McFadden K, Cocklin S, Gopi H, et al., 2007, A recombinant allosteric lectin antagonist of HIV-1 envelope gp120 interactions., Proteins, Vol: 67, Pages: 617-629
The first, critical stage of HIV-1 infection is fusion of viral and host cellular membranes initiated by a viral envelope glycoprotein gp120. We evaluated the potential to form a chimeric protein entry inhibitor that combines the action of two gp120-targeting molecules, an allosteric peptide inhibitor 12p1 and a higher affinity carbohydrate-binding protein cyanovirin (CVN). In initial mixing experiments, we demonstrated that the inhibitors do not interfere with each other and instead show functional synergy in inhibiting viral cell infection. Based on this, we created a chimera, termed L5, with 12p1 fused to the C-terminal domain of CVN through a linker of five penta-peptide repeats. L5 revealed the same broad specificity as CVN for gp120 from a variety of clades and tropisms. By comparison to CVN, the L5 chimera exhibited substantially increased inhibition of gp120 binding to receptor CD4, coreceptor surrogate mAb 17b and gp120 antibody F105. These binding inhibition effects by the chimera reflected both the high affinity of the CVN domain and the allosteric action of the 12p1 domain. The results open up the possibility to form high potency chimeras, as well as noncovalent mixtures, as leads for HIV-1 envelope antagonism that can overcome potency limits and potential virus mutational resistance for either 12p1 or CVN alone.
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