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11.
Kristina K. Peachman Nicos Karasavvas Agnes-Laurence Chenine Robert McLinden Supachai Rerks-Ngarm Kaewkungwal Jaranit Sorachai Nitayaphan Punnee Pitisuttithum Sodsai Tovanabutra Susan Zolla-Pazner Nelson L. Michael Jerome H. Kim Carl R. Alving Mangala Rao 《PloS one》2015,10(12)
Background
The gut mucosal homing integrin receptor α4β7 present on activated CD4+ T cells interacts with the HIV-1 gp120 second variable loop (V2). Case control analysis of the RV144 phase III vaccine trial demonstrated that plasma IgG binding antibodies specific to scaffolded proteins expressing the first and second variable regions (V1V2) of HIV envelope protein gp120 containing the α4β7 binding motif correlated inversely with risk of infection. Subsequently antibodies to the V3 region were also shown to correlate with protection. The integrin receptor α4β7 was shown to interact with the LDI/V motif on V2 loop but recent studies suggest that additional regions of V2 loop could interact with the α4β7. Thus, there may be several regions on the V2 and possibly V3 loops that may be involved in this binding. Using a cell line, that constitutively expressed α4β7 receptors but lacked CD4, we examined the contribution of V2 and V3 loops and the ability of V2 peptide-, V2 integrin-, V3-specific monoclonal antibodies (mAbs), and purified IgG from RV144 vaccinees to block the V2/V3-α4β7 interaction.Results
We demonstrate that α4β7 on RPMI8866 cells bound specifically to its natural ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) as well as to cyclic-V2 and cyclic-V3 peptides. This binding was inhibited by anti-α4β7-specific monoclonal antibody (mAb) ACT-1, mAbs specific to either V2 or V3 loops, and by purified primary virions or infectious molecular clones expressing envelopes from acute or chronic subtypes A, C, and CRF01_AE viruses. Plasma from HIV-1 infected Thai individuals as well as purified IgG from uninfected RV144 vaccinees inhibited (0–50%) the binding of V2 and V3 peptides to α4β7.Conclusion
Our results indicate that in addition to the tripeptide LDI/V motif, other regions of the V2 and V3 loops of gp120 were involved in binding to α4β7 receptors and this interaction was blocked by anti-V2 peptide, anti-V2 integrin, and anti-V3 antibodies. The ability of purified IgG from some of the uninfected RV144 vaccinees to inhibit α4β7 raises the hypothesis that anti-V2 and anti-V3 antibodies may play a role in blocking the gp120-α4β7 interaction after vaccination and thus prevent HIV-1 acquisition. 相似文献12.
Heather A. Prentice Philip K. Ehrenberg Karen M. Baldwin Aviva Geretz Charla Andrews Sorachai Nitayaphan Supachai Rerks-Ngarm Jaranit Kaewkungwal Punnee Pitisuttithum Robert J. O’Connell Merlin L. Robb Jerome H. Kim Nelson L. Michael Rasmi Thomas 《Immunogenetics》2014,66(5):299-310
RV144 is the first phase 3 HIV vaccine clinical trial to demonstrate efficacy. This study consisted of more than 8,000 individuals in each arm of the trial, representing the four major regions of Thailand. Human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptor (KIR) genes, as well as 96 genome-wide ancestry informative markers (AIMs) were genotyped in 450 placebo HIV-1-uninfected individuals to identify the immunogenetic diversity and population structure of this cohort. High-resolution genotyping identified the common HLA alleles as A*02:03, A*02:07, A*11:01, A*24:02, A*24:07, A*33:03, B*13:01, B*15:02, B*18:01, B*40:01, B*44:03, B*46:01, B*58:01, C*01:02, C*03:02, C*03:04, C*07:01, C*07:02, C*07:04, and C*08:01. The most frequent three-loci haplotype was B*46:01-C*01:02-A*02:07. Framework genes KIR2DL4, 3DL2, and 3DL3 were present in all samples, and KIR2DL1, 2DL3, 3DL1, 2DS4, and 2DP1 occurred at frequencies greater than 90 %. The combined HLA and KIR profile suggests admixture with neighboring Asian populations. Principal component and correspondence analyses comparing the RV144 samples to the phase 3 International HapMap Project (HapMap3) populations using AIMs corroborated these findings. Structure analyses identified a distinct profile in the Thai population that did not match the Asian or other HapMap3 samples. This shows genetic variability unique to Thais in RV144, making it essential to take into account population stratification while performing genetic association studies. The overall analyses from all three genetic markers indicate that the RV144 samples are representative of the Thai population. This will inform subsequent host genetic analyses in the RV144 cohort and provide insight for future genetic association studies in the Thai population. 相似文献
13.
Loyprasert S Thavarungkul P Asawatreratanakul P Wongkittisuksa B Limsakul C Kanatharana P 《Biosensors & bioelectronics》2008,24(1):78-86
A label-free immunosensor based on a modified gold electrode incorporated with silver (Ag) nanoparticles (NPs) to enhance the capacitive response to microcystin-LR (MCLR) has been developed. Anti-microcystin-LR (anti-MCLR) was immobilized on silver nanoparticles bound to a self-assembled thiourea monolayer. Interaction of anti-MCLR and MCLR were directly detected by capacitance measurement. Under optimum conditions, MCLR could be determined with a detection limit of 7.0pgl(-1) and linearity between 10pgl(-1) and 1mugl(-1). The immobilized anti-MCLR on self-assembled thiourea monolayer incorporated with silver nanoparticles was stable and good reproducibility of the signal could be obtained up to 43 times with an R.S.D. of 2.1%. Comparing to the modified electrode without silver nanoparticles it gave 1.7-fold higher sensitivity and lower limit of detection. The developed immunosensor was applied to analyze MCLR in water samples and the results were in good agreement with those obtained by high-performance liquid chromatography (HPLC) (P<0.05). 相似文献
14.
HIV-1 Vaccine-Induced C1 and V2 Env-Specific Antibodies Synergize for Increased Antiviral Activities
Justin Pollara Mattia Bonsignori M. Anthony Moody Pinghuang Liu S. Munir Alam Kwan-Ki Hwang Thaddeus C. Gurley Daniel M. Kozink Lawrence C. Armand Dawn J. Marshall John F. Whitesides Jaranit Kaewkungwal Sorachai Nitayaphan Punnee Pitisuttithum Supachai Rerks-Ngarm Merlin L. Robb Robert J. O'Connell Jerome H. Kim Nelson L. Michael David C. Montefiori Georgia D. Tomaras Hua-Xin Liao Barton F. Haynes Guido Ferrari 《Journal of virology》2014,88(14):7715-7726
15.
Pinghuang Liu Nicole L. Yates Xiaoying Shen Mattia Bonsignori M. Anthony Moody Hua-Xin Liao Youyi Fong S. Munir Alam R. Glenn Overman Thomas Denny Guido Ferrari Christina Ochsenbauer John C. Kappes Victoria R. Polonis Punnee Pitisuttithum Jaranit Kaewkungwal Sorachai Nitayaphan Supachai Rerks-Ngarm David C. Montefiori Peter Gilbert Nelson L. Michael Jerome H. Kim Barton F. Haynes Georgia D. Tomaras 《Journal of virology》2013,87(14):7828-7836
The detailed examination of the antibody repertoire from RV144 provides a unique template for understanding potentially protective antibody functions. Some potential immune correlates of protection were untested in the correlates analyses due to inherent assay limitations, as well as the need to keep the correlates analysis focused on a limited number of endpoints to achieve statistical power. In an RV144 pilot study, we determined that RV144 vaccination elicited antibodies that could bind infectious virions (including the vaccine strains HIV-1 CM244 and HIV-1 MN and an HIV-1 strain expressing transmitted/founder Env, B.WITO.c). Among vaccinees with the highest IgG binding antibody profile, the majority (78%) captured the infectious vaccine strain virus (CM244), while a smaller proportion of vaccinees (26%) captured HIV-1 transmitted/founder Env virus. We demonstrated that vaccine-elicited HIV-1 gp120 antibodies of multiple specificities (V3, V2, conformational C1, and gp120 conformational) mediated capture of infectious virions. Although capture of infectious HIV-1 correlated with other humoral immune responses, the extent of variation between these humoral responses and virion capture indicates that virion capture antibodies occupy unique immunological space. 相似文献
16.
Kalpana Dommaraju Gustavo Kijak Jonathan M. Carlson Brendan B. Larsen Sodsai Tovanabutra Dan E. Geraghty Wenjie Deng Brandon S. Maust Paul T. Edlefsen Eric Sanders-Buell Silvia Ratto-Kim Mark S. deSouza Supachai Rerks-Ngarm Sorachai Nitayaphan Punnee Pitisuttihum Jaranit Kaewkungwal Robert J. O'Connell Merlin L. Robb Nelson L. Michael James I. Mullins Jerome H. Kim Morgane Rolland 《PloS one》2014,9(10)
The modest protection afforded by the RV144 vaccine offers an opportunity to evaluate its mechanisms of protection. Differences between HIV-1 breakthrough viruses from vaccine and placebo recipients can be attributed to the RV144 vaccine as this was a randomized and double-blinded trial. CD8 and CD4 T cell epitope repertoires were predicted in HIV-1 proteomes from 110 RV144 participants. Predicted Gag epitope repertoires were smaller in vaccine than in placebo recipients (p = 0.019). After comparing participant-derived epitopes to corresponding epitopes in the RV144 vaccine, the proportion of epitopes that could be matched differed depending on the protein conservation (only 36% of epitopes in Env vs 84–91% in Gag/Pol/Nef for CD8 predicted epitopes) or on vaccine insert subtype (55% against CRF01_AE vs 7% against subtype B). To compare predicted epitopes to the vaccine, we analyzed predicted binding affinity and evolutionary distance measurements. Comparisons between the vaccine and placebo arm did not reveal robust evidence for a T cell driven sieve effect, although some differences were noted in Env-V2 (0.022≤p-value≤0.231). The paucity of CD8 T cell responses identified following RV144 vaccination, with no evidence for V2 specificity, considered together both with the association of decreased infection risk in RV 144 participants with V-specific antibody responses and a V2 sieve effect, lead us to hypothesize that this sieve effect was not T cell specific. Overall, our results did not reveal a strong differential impact of vaccine-induced T cell responses among breakthrough infections in RV144 participants. 相似文献
17.
Pitisuttithum P Rerks-Ngarm S Bussaratid V Dhitavat J Maekanantawat W Pungpak S Suntharasamai P Vanijanonta S Nitayapan S Kaewkungwal J Benenson M Morgan P O'Connell RJ Berenberg J Gurunathan S Francis DP Paris R Chiu J Stablein D Michael NL Excler JL Robb ML Kim JH 《PloS one》2011,6(12):e27837
Background
A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand.Methodology/Principal Findings
Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p<0.001) and were more frequent after ALVAC-HIV than AIDSVAX B/E vaccination. Systemic reactions were more frequent in vaccine than placebo recipients (77.2% vs. 59.8%, p<0.001). Local and systemic reactions were mostly mild to moderate, resolving within 3 days.Conclusions/Significance
The ALVAC-HIV and AIDSVAX B/E vaccine regimen was found to be safe, well tolerated and suitable for potential large-scale use in Thailand.Trial Registration
ClinicalTrials.gov NCT00223080相似文献18.
Mattia Bonsignori Justin Pollara M. Anthony Moody Michael D. Alpert Xi Chen Kwan-Ki Hwang Peter B. Gilbert Ying Huang Thaddeus C. Gurley Daniel M. Kozink Dawn J. Marshall John F. Whitesides Chun-Yen Tsao Jaranit Kaewkungwal Sorachai Nitayaphan Punnee Pitisuttithum Supachai Rerks-Ngarm Jerome H. Kim Nelson L. Michael Georgia D. Tomaras David C. Montefiori George K. Lewis Anthony DeVico David T. Evans Guido Ferrari Hua-Xin Liao Barton F. Haynes 《Journal of virology》2012,86(21):11521-11532
The ALVAC-HIV/AIDSVAX-B/E RV144 vaccine trial showed an estimated efficacy of 31%. RV144 secondary immune correlate analysis demonstrated that the combination of low plasma anti-HIV-1 Env IgA antibodies and high levels of antibody-dependent cellular cytotoxicity (ADCC) inversely correlate with infection risk. One hypothesis is that the observed protection in RV144 is partially due to ADCC-mediating antibodies. We found that the majority (73 to 90%) of a representative group of vaccinees displayed plasma ADCC activity, usually (96.2%) blocked by competition with the C1 region-specific A32 Fab fragment. Using memory B-cell cultures and antigen-specific B-cell sorting, we isolated 23 ADCC-mediating nonclonally related antibodies from 6 vaccine recipients. These antibodies targeted A32-blockable conformational epitopes (n = 19), a non-A32-blockable conformational epitope (n = 1), and the gp120 Env variable loops (n = 3). Fourteen antibodies mediated cross-clade target cell killing. ADCC-mediating antibodies displayed modest levels of V-heavy (VH) chain somatic mutation (0.5 to 1.5%) and also displayed a disproportionate usage of VH1 family genes (74%), a phenomenon recently described for CD4-binding site broadly neutralizing antibodies (bNAbs). Maximal ADCC activity of VH1 antibodies correlated with mutation frequency. The polyclonality and low mutation frequency of these VH1 antibodies reveal fundamental differences in the regulation and maturation of these ADCC-mediating responses compared to VH1 bNAbs. 相似文献
19.
Patrick Sagaki Vipa Thanachartwet Varunee Desakorn Duangjai Sahassananda Supat Chamnanchanunt Wirongrong Chierakul Punnee Pitisuttithum Prajej Ruangkanchanasetr 《PloS one》2013,8(8)
Plasmodium falciparum is a major cause of severe malaria in Southeast Asia, however, there is limited information regarding clinical factors associated with the severity of falciparum malaria from this region. We performed a retrospective case-control study to compare clinical factors and outcomes between patients with severe and non-severe malaria, and to identify clinical factors associated with the requirement for intensive care unit (ICU) admission of patients with severe falciparum malaria among hospitalized adults in Southeast Asia. A total of 255 patients with falciparum malaria in the Hospital for Tropical Diseases in Bangkok, Thailand between 2006 and 2012 were included. We identified 104 patients with severe malaria (cases) and 151 patients with non-severe malaria (controls). Patients with falciparum malaria with following clinical and laboratory characteristics on admission (1) referrals, (2) no prior history of malaria, (3) body temperature of >38.5°C, (4) white blood cell counts >10×109/µL, (5) presence of schizonts in peripheral blood smears, and (6) albumin concentrations of <3.5 g/dL, were more likely to develop severe malaria (P<0.05). Among patients with severe malaria, patients who met ≥3 of the 2010 WHO criteria had sensitivity of 79.2% and specificity of 81.8% for requiring ICU admission. Multivariate analysis identified the following as independent associated factors for severe malaria requiring ICU admission; (1) ethnicity of Thai [odds ratio (OR) = 3.601, 95% confidence interval (CI) = 1.011–12.822] or Myanmar [OR = 3.610, 95% CI = 1.138–11.445]; (2) referrals [OR = 3.571, 95% CI = 1.306–9.762]; (3) no prior history of malaria [OR = 5.887, 95% CI = 1.354–25.594]; and (4) albumin concentrations of <3.5 g/dL [OR = 7.200, 95% CI = 1.802–28.759]. Our findings are important for the clinical management of patients with malaria because it can help early identification of patients that could develop severe malaria and require ICU admission. Early identification and the timely initiation of appropriate treatments may well improve the outcomes and reduce the mortality of these patients. 相似文献
20.
Silvia Ratto-Kim Mark S. de Souza Jeffrey R. Currier Nicos Karasavvas John Sidney Morgane Rolland Anais Valencia-Micolta Sirinan Madnote Alessandro Sette Sorachai Nitayaphan Punnee Pitisuttuthum Jaranit Kaewkungwal Supachai Rerks-Ngarm Robert O’Connell Nelson Michael Merlin L. Robb Mary Marovich Jerome H. Kim 《PloS one》2015,10(2)
We performed fine epitope mapping of the CD4+ responses in the ALVAC-HIV-AIDSVAX B/E prime-boost regimen in the Thai Phase III trial (RV144). Non-transformed Env-specific T cell lines established from RV144 vaccinees were used to determine the fine epitope mapping of the V2 and C1 responses and the HLA class II restriction. Data showed that there are two CD4+ epitopes contained within the V2 loop: one encompassing the α4β7 integrin binding site (AA179-181) and the other nested between two previously described genetic sieve signatures (AA169, AA181). There was no correlation between the frequencies of CD4+ fine epitope responses and binding antibody. 相似文献