Elias Haddad - Academia.edu (original) (raw)
Papers by Elias Haddad
Nature Immunology, Oct 31, 2022
time after vaccination) variables on the variance in the transcriptomic data (Fig. 1c). Age (14%)... more time after vaccination) variables on the variance in the transcriptomic data (Fig. 1c). Age (14%), time points (9%) and vaccine (9%) explained only a small fraction of the variance observed in the transcriptomic data; over 62% of the variance between samples remained unexplained by any of the recorded clinical and experimental variables.
Current Hiv/aids Reports, Feb 1, 2008
Generation of memory T cells, which mediate immunity against microbes and cancers, relies, for op... more Generation of memory T cells, which mediate immunity against microbes and cancers, relies, for optimal activity, on the interactions of multiple cell types that are highly regulated through the expression of soluble factors and negative and positive receptors. Their disruption will lead to aberrant immune responses, which can result in the invasion of the host by foreign pathogens. In chronic viral infections including HIV and hepatitis C virus, persistence of antigen and lack of CD4 help (HIV) disrupt memory T-cell function and induce defects in memory T-cell responses, which have been defined as T-cell exhaustion. In this review, we examine the molecular mechanisms involved in such T-cell dysfunction. Better understanding of these mechanisms will assist in the development of novel therapies to prevent the immune damage mediated by HIV infection.
PLOS Neglected Tropical Diseases
Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increa... more Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine respon...
Frontiers in Immunology
Despite numerous clinically available vaccines and therapeutics, aged patients remain at increase... more Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of TH2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased TH2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function an...
Biomedicines, Jan 3, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
ABSTRACTBackgroundBetter understanding of the association between characteristics of patients hos... more ABSTRACTBackgroundBetter understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management.MethodsImmunophenotypingAssessment in aCOVID-19Cohort (IMPACC) is a prospective, observational study of 1,164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed.FindingsThe median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering ...
Vaccines are among the most cost-effective public health interventions for preventing infection-i... more Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern ‘omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines, including those targeting seasonal influenza, yellow fever, and hepatitis B. These data are made available to the broader scientific community through the ImmuneSpace data portal and analysis engine leveraging the NIH/NIAID ImmPort repository1,2. However, a barrier to progress in this area is that comparative analyses have been limited by the distributed nature of some data, potential batch effe...
The Journal of Heart and Lung Transplantation, 2018
Of the 21 patients acquiring HCV infection, 8 completed a course of DAAs and achieved a sustained... more Of the 21 patients acquiring HCV infection, 8 completed a course of DAAs and achieved a sustained virologic response at 12 weeks after end of treatment (SVR12), and 1 died 4-months post-HT. Data on ICUS derived maximal intimal thickness (MIT) was available in 6 patients at 6-months and 2 patients at 1-year (see Table). At 6-months, 1 of 6 patients (16.7%) showed severe intimal hyperplasia (defined as MIT> 0.5 mm). At 1-year, 2 patients had follow-up ICUS, and did not have progression to severe intimal hyperplasia. By the time of this presentation, we expect to have 6-months ICUS data in 20 patients, and 1-year follow-up ICUS data in 13 patients; 14 are expected to have achieved SVR12. Conclusion: Though short-term risk of severe CAV may be acceptable in presence of acquired HCV infection treated with current DAAs, we intend to analyze and report incident and progression of CAV, using ICUS-guidance, from a larger sample size.
PLoS Pathogens, 2013
The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between c... more The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 59 triphosphate (59ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 59pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes-hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN) signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 59pppRNA, and not by IFNa-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 59pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 59pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 59pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.
Arthritis Care & Research, 2014
ObjectiveLow‐dose aspirin prevents platelet aggregation by suppressing thromboxane A2 (TXA2) synt... more ObjectiveLow‐dose aspirin prevents platelet aggregation by suppressing thromboxane A2 (TXA2) synthesis. However, in some individuals TXA2 suppression by aspirin is impaired, indicating suboptimal inhibition of platelet cyclooxygenase 1 (COX‐1) by aspirin. Because patients with systemic lupus erythematosus (SLE) have increased risk of thrombotic events, many receive aspirin; however, the efficacy of aspirin in SLE has not been determined. We examined the hypothesis that aspirin response is impaired in SLE.MethodsWe assessed the effect of aspirin by measuring concentrations of the stable metabolite of TXA2, serum thromboxane B2 (sTXB2), before and after treatment with daily aspirin (81 mg) for 7 days in 34 patients with SLE and 36 control subjects. The inability to suppress sTXB2 synthesis to <10 ng/ml represents suboptimal inhibition of platelet COX‐1 by aspirin.ResultsAspirin almost completely suppressed sTXB2 in control subjects to median 1.5 ng/ml (interquartile range [IQR] 0.8...
The impact of endemic infections on protective immunity is critical to inform vaccination strateg... more The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence ofSchistosoma mansoniinfection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that nega...
Vaccines & Vaccination Open Access, 2017
Objective: To evaluate in non-immunocompromised adults not vaccinated against HBV (Hepatitis B vi... more Objective: To evaluate in non-immunocompromised adults not vaccinated against HBV (Hepatitis B virus), the response rate to vaccination according to standard protocol (SP) (0, 1, 6 months) and response rate in non-responders subjected to two protocols. Materials And Methods: 192 employees in a Hospital located in Beirut, average age of 44.3, not previously vaccinated, non-immunocompromised, are vaccinated by Engerix B 20 mcg/1ml according to the SP. Non-responders to this protocol are divided into two subgroups. The first one receives a single booster dose 4 months after the end of the SP, and those who remains unresponsive receives a double booster dose 2 years later. The second one receives only one double booster dose 2 years after the SP. Results: The rate of positive immune response after vaccination using the SP is 145/192 (75.5%). 28 non-responder's individuals receives 4 months later a booster dose; the positive response rate is 9/28 (32.14%). The 19 non-responders individual R1 receives a double booster at 2 years with a positive response rate of7/18 (36.84%). The positive response in this subgroup is 57.14%. Non-responders formed by 19 individuals, are boosted after 2 years. Their positive response rate is 63.16%. 19/192 (9.9%) of the individuals do not respond to any protocols. Female gender and advanced age are two factors that diminish the response to vaccination. Conclusion: A booster dose at 2 years gives a better immunity than a simple reminder at 4 months, and is similar to the protocol using a booster at 4 months followed by a second one after 2 years.
ABSTRACTNK-cell resistance to transduction is a major technical hurdle for developing NK-cell imm... more ABSTRACTNK-cell resistance to transduction is a major technical hurdle for developing NK-cell immunotherapy. By using Baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) encoding eGFP, we obtained a transduction rate of 23.0±6.6% in freshly-isolated NK-cells (FI-NK) and 83.4±10.1% in NK-cells obtained from the NK-cell Activation and Expansion System (NKAES), even at low MOI, with a sustained transgene expression for at least 21 days. BaEV-LVs outperformed Vesicular Stomatitis Virus type-G (VSV-G)-, RD114-and Measles Virus (MV)-pseudotyped LVs (p<0.001). mRNA expression of both BaEV receptors, ASCT1 and ASCT2, was detected in FI-NK and NKAES, with much higher expression in NKAES. Transduction with BaEV-LVs encoding for CAR-CD22 resulted in robust CAR-expression on 44.2%±14.2% of NKAES cells, which allowed the specific killing of the NK-resistant pre-B-ALL-RS4;11 cell line. Using a larger vector, encoding a dual CD19/CD22-CAR separated by T2A, we were able to transduce and re...
Journal of Neuroimmune Pharmacology, 2018
Despite the success of combination anti-retroviral therapy (cART), around 50% of HIV-infected ind... more Despite the success of combination anti-retroviral therapy (cART), around 50% of HIV-infected individuals still display a variety of neuropathological and neurocognitive sequelae known as NeuroHIV. Current research suggests these effects are mediated by long-term changes in CNS function in response to chronic infection and inflammation, and not solely due to active viral replication. In the post-cART era, drug abuse is a major risk-factor for the development of NeuroHIV, and increases extracellular dopamine in the CNS. Our lab has previously shown that dopamine can increase HIV infection of primary human macrophages and increase the production of inflammatory cytokines, suggesting that elevated dopamine could enhance the development of HIV-associated neuropathology. However, the precise mechanism(s) by which elevated dopamine could exacerbate NeuroHIV, particularly in chronically-infected, virally suppressed individuals remain unclear. To determine the connection between dopaminergic alterations and HIV-associated neuroinflammation, we have examined the impact of dopamine exposure on macrophages from healthy and virally suppressed, chronically infected HIV patients. Our data show that dopamine treatment of human macrophages isolated from healthy and cART-treated donors promotes production of inflammatory mediators including IL-1β, IL-6, IL-18, CCL2, CXCL8, CXCL9, and CXCL10. Furthermore, in healthy individuals, dopamine-mediated modulation of specific cytokines is correlated with macrophage expression of dopamine-receptor transcripts, particularly DRD5, the most highly-expressed dopamine-receptor subtype. Overall, these data will provide more understanding of the role of dopamine in the development of NeuroHIV, and may suggest new molecules or pathways that can be useful as therapeutic targets during HIV infection.
Biomarkers in medicine, Oct 1, 2017
Proceedings of the National Academy of Sciences, 2010
Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the... more Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the persistence of long-lived, latently infected resting memory CD4 + T cells. We now show that HIV-1 latency can be established in resting CD4 + T cells infected with HIV-1 after exposure to ligands for CCR7 (CCL19), CXCR3 (CXCL9 and CXCL10), and CCR6 (CCL20) but not in unactivated CD4 + T cells. The mechanism did not involve cell activation or significant changes in gene expression, but was associated with rapid dephosphorylation of cofilin and changes in filamentous actin. Incubation with chemokine before infection led to efficient HIV-1 nuclear localization and integration and this was inhibited by the actin stabilizer jasplakinolide. We propose a unique pathway for establishment of latency by direct HIV-1 infection of resting CD4 + T cells during normal chemokine-directed recirculation of CD4 + T cells between blood and tissue.
Nature Medicine, 2006
In the version of the article initially published, the key in Figure 4a,b identifying the bars in... more In the version of the article initially published, the key in Figure 4a,b identifying the bars in the histograms is incorrect. The white bar should be identified as peptide and the black bar should be identified as peptide + anti-PD-L1. The error has been corrected in the HTML and PDF versions of the article.
The Journal of Immunology
Despite numerous clinically available vaccines and therapeutics, aged patients remain at increase... more Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity and mortality. Furthermore, the aged patient population has suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mouse models. Aged mice had altered cellular responses, including decreased IFNγ secretion and increased TNFα secretion as compared to young mice. Aged mice had significantly decreased binding and neutralizing antibodies in their serum compared to their young counterparts. Co-immunization with the plasmid-encoded molecular adjuvant adenosine deaminase-1 (pADA) enhanced cellular responses and expanded the breadth and affinity of humoral responses in aged mice. pADA co-delivery also altered the gene expression profiles of lymph node lymphocytes in aged animals. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a stro...
![Research paper thumbnail of Circulating CXCR5[superscript +]CXCR3[superscript +]PD-1[superscript lo] Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth](https://a.academia-assets.com/images/blank-paper.jpg)
](HIV-‐1-‐specific broadly-‐neutralizing antibodies (bnAbs) typically develop in individuals wit... more HIV-‐1-‐specific broadly-‐neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-‐level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-‐ level viremia may be important for designing bnAb-‐inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-‐1 controllers was associated with a relative enrichment of circulating CXCR5+ CXCR3+ PD-‐1Lo CD4 T cells. These CXCR3+ PD-‐1Lo Tfh-‐like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-‐21 and support B cells. In addition, these CXCR3+ PD-‐1Lo Tfh-‐like cells contained higher proportions of stem cell-‐like memory T cells, and upon antigenic stimulation differentiated into PD-‐1Hi Tfh-‐like cells in a Notch-‐dependent manner. Together, these data suggest that CXCR5+ CXCR3+ PD-‐1Lo cells represent a dendritic cell-‐ primed precursor cell population for PD-‐1Hi Tfh-‐like cells that may contribute to the generation of bnAbs in the absence of high-‐level viremia.
Immunity, Oct 1, 2013
The vast majority of currently licensed human vaccines work on the basis of long-term protective ... more The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4 + T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1 + CXCR5 + CD4 + T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV + individuals. Immunity Tfh Cells Correlate with HIV Antibodies
Nature Immunology, Oct 31, 2022
time after vaccination) variables on the variance in the transcriptomic data (Fig. 1c). Age (14%)... more time after vaccination) variables on the variance in the transcriptomic data (Fig. 1c). Age (14%), time points (9%) and vaccine (9%) explained only a small fraction of the variance observed in the transcriptomic data; over 62% of the variance between samples remained unexplained by any of the recorded clinical and experimental variables.
Current Hiv/aids Reports, Feb 1, 2008
Generation of memory T cells, which mediate immunity against microbes and cancers, relies, for op... more Generation of memory T cells, which mediate immunity against microbes and cancers, relies, for optimal activity, on the interactions of multiple cell types that are highly regulated through the expression of soluble factors and negative and positive receptors. Their disruption will lead to aberrant immune responses, which can result in the invasion of the host by foreign pathogens. In chronic viral infections including HIV and hepatitis C virus, persistence of antigen and lack of CD4 help (HIV) disrupt memory T-cell function and induce defects in memory T-cell responses, which have been defined as T-cell exhaustion. In this review, we examine the molecular mechanisms involved in such T-cell dysfunction. Better understanding of these mechanisms will assist in the development of novel therapies to prevent the immune damage mediated by HIV infection.
PLOS Neglected Tropical Diseases
Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increa... more Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine respon...
Frontiers in Immunology
Despite numerous clinically available vaccines and therapeutics, aged patients remain at increase... more Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of TH2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased TH2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function an...
Biomedicines, Jan 3, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
ABSTRACTBackgroundBetter understanding of the association between characteristics of patients hos... more ABSTRACTBackgroundBetter understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management.MethodsImmunophenotypingAssessment in aCOVID-19Cohort (IMPACC) is a prospective, observational study of 1,164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed.FindingsThe median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering ...
Vaccines are among the most cost-effective public health interventions for preventing infection-i... more Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern ‘omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines, including those targeting seasonal influenza, yellow fever, and hepatitis B. These data are made available to the broader scientific community through the ImmuneSpace data portal and analysis engine leveraging the NIH/NIAID ImmPort repository1,2. However, a barrier to progress in this area is that comparative analyses have been limited by the distributed nature of some data, potential batch effe...
The Journal of Heart and Lung Transplantation, 2018
Of the 21 patients acquiring HCV infection, 8 completed a course of DAAs and achieved a sustained... more Of the 21 patients acquiring HCV infection, 8 completed a course of DAAs and achieved a sustained virologic response at 12 weeks after end of treatment (SVR12), and 1 died 4-months post-HT. Data on ICUS derived maximal intimal thickness (MIT) was available in 6 patients at 6-months and 2 patients at 1-year (see Table). At 6-months, 1 of 6 patients (16.7%) showed severe intimal hyperplasia (defined as MIT> 0.5 mm). At 1-year, 2 patients had follow-up ICUS, and did not have progression to severe intimal hyperplasia. By the time of this presentation, we expect to have 6-months ICUS data in 20 patients, and 1-year follow-up ICUS data in 13 patients; 14 are expected to have achieved SVR12. Conclusion: Though short-term risk of severe CAV may be acceptable in presence of acquired HCV infection treated with current DAAs, we intend to analyze and report incident and progression of CAV, using ICUS-guidance, from a larger sample size.
PLoS Pathogens, 2013
The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between c... more The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 59 triphosphate (59ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 59pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes-hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN) signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 59pppRNA, and not by IFNa-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 59pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 59pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 59pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.
Arthritis Care & Research, 2014
ObjectiveLow‐dose aspirin prevents platelet aggregation by suppressing thromboxane A2 (TXA2) synt... more ObjectiveLow‐dose aspirin prevents platelet aggregation by suppressing thromboxane A2 (TXA2) synthesis. However, in some individuals TXA2 suppression by aspirin is impaired, indicating suboptimal inhibition of platelet cyclooxygenase 1 (COX‐1) by aspirin. Because patients with systemic lupus erythematosus (SLE) have increased risk of thrombotic events, many receive aspirin; however, the efficacy of aspirin in SLE has not been determined. We examined the hypothesis that aspirin response is impaired in SLE.MethodsWe assessed the effect of aspirin by measuring concentrations of the stable metabolite of TXA2, serum thromboxane B2 (sTXB2), before and after treatment with daily aspirin (81 mg) for 7 days in 34 patients with SLE and 36 control subjects. The inability to suppress sTXB2 synthesis to <10 ng/ml represents suboptimal inhibition of platelet COX‐1 by aspirin.ResultsAspirin almost completely suppressed sTXB2 in control subjects to median 1.5 ng/ml (interquartile range [IQR] 0.8...
The impact of endemic infections on protective immunity is critical to inform vaccination strateg... more The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence ofSchistosoma mansoniinfection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that nega...
Vaccines & Vaccination Open Access, 2017
Objective: To evaluate in non-immunocompromised adults not vaccinated against HBV (Hepatitis B vi... more Objective: To evaluate in non-immunocompromised adults not vaccinated against HBV (Hepatitis B virus), the response rate to vaccination according to standard protocol (SP) (0, 1, 6 months) and response rate in non-responders subjected to two protocols. Materials And Methods: 192 employees in a Hospital located in Beirut, average age of 44.3, not previously vaccinated, non-immunocompromised, are vaccinated by Engerix B 20 mcg/1ml according to the SP. Non-responders to this protocol are divided into two subgroups. The first one receives a single booster dose 4 months after the end of the SP, and those who remains unresponsive receives a double booster dose 2 years later. The second one receives only one double booster dose 2 years after the SP. Results: The rate of positive immune response after vaccination using the SP is 145/192 (75.5%). 28 non-responder's individuals receives 4 months later a booster dose; the positive response rate is 9/28 (32.14%). The 19 non-responders individual R1 receives a double booster at 2 years with a positive response rate of7/18 (36.84%). The positive response in this subgroup is 57.14%. Non-responders formed by 19 individuals, are boosted after 2 years. Their positive response rate is 63.16%. 19/192 (9.9%) of the individuals do not respond to any protocols. Female gender and advanced age are two factors that diminish the response to vaccination. Conclusion: A booster dose at 2 years gives a better immunity than a simple reminder at 4 months, and is similar to the protocol using a booster at 4 months followed by a second one after 2 years.
ABSTRACTNK-cell resistance to transduction is a major technical hurdle for developing NK-cell imm... more ABSTRACTNK-cell resistance to transduction is a major technical hurdle for developing NK-cell immunotherapy. By using Baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) encoding eGFP, we obtained a transduction rate of 23.0±6.6% in freshly-isolated NK-cells (FI-NK) and 83.4±10.1% in NK-cells obtained from the NK-cell Activation and Expansion System (NKAES), even at low MOI, with a sustained transgene expression for at least 21 days. BaEV-LVs outperformed Vesicular Stomatitis Virus type-G (VSV-G)-, RD114-and Measles Virus (MV)-pseudotyped LVs (p<0.001). mRNA expression of both BaEV receptors, ASCT1 and ASCT2, was detected in FI-NK and NKAES, with much higher expression in NKAES. Transduction with BaEV-LVs encoding for CAR-CD22 resulted in robust CAR-expression on 44.2%±14.2% of NKAES cells, which allowed the specific killing of the NK-resistant pre-B-ALL-RS4;11 cell line. Using a larger vector, encoding a dual CD19/CD22-CAR separated by T2A, we were able to transduce and re...
Journal of Neuroimmune Pharmacology, 2018
Despite the success of combination anti-retroviral therapy (cART), around 50% of HIV-infected ind... more Despite the success of combination anti-retroviral therapy (cART), around 50% of HIV-infected individuals still display a variety of neuropathological and neurocognitive sequelae known as NeuroHIV. Current research suggests these effects are mediated by long-term changes in CNS function in response to chronic infection and inflammation, and not solely due to active viral replication. In the post-cART era, drug abuse is a major risk-factor for the development of NeuroHIV, and increases extracellular dopamine in the CNS. Our lab has previously shown that dopamine can increase HIV infection of primary human macrophages and increase the production of inflammatory cytokines, suggesting that elevated dopamine could enhance the development of HIV-associated neuropathology. However, the precise mechanism(s) by which elevated dopamine could exacerbate NeuroHIV, particularly in chronically-infected, virally suppressed individuals remain unclear. To determine the connection between dopaminergic alterations and HIV-associated neuroinflammation, we have examined the impact of dopamine exposure on macrophages from healthy and virally suppressed, chronically infected HIV patients. Our data show that dopamine treatment of human macrophages isolated from healthy and cART-treated donors promotes production of inflammatory mediators including IL-1β, IL-6, IL-18, CCL2, CXCL8, CXCL9, and CXCL10. Furthermore, in healthy individuals, dopamine-mediated modulation of specific cytokines is correlated with macrophage expression of dopamine-receptor transcripts, particularly DRD5, the most highly-expressed dopamine-receptor subtype. Overall, these data will provide more understanding of the role of dopamine in the development of NeuroHIV, and may suggest new molecules or pathways that can be useful as therapeutic targets during HIV infection.
Biomarkers in medicine, Oct 1, 2017
Proceedings of the National Academy of Sciences, 2010
Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the... more Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the persistence of long-lived, latently infected resting memory CD4 + T cells. We now show that HIV-1 latency can be established in resting CD4 + T cells infected with HIV-1 after exposure to ligands for CCR7 (CCL19), CXCR3 (CXCL9 and CXCL10), and CCR6 (CCL20) but not in unactivated CD4 + T cells. The mechanism did not involve cell activation or significant changes in gene expression, but was associated with rapid dephosphorylation of cofilin and changes in filamentous actin. Incubation with chemokine before infection led to efficient HIV-1 nuclear localization and integration and this was inhibited by the actin stabilizer jasplakinolide. We propose a unique pathway for establishment of latency by direct HIV-1 infection of resting CD4 + T cells during normal chemokine-directed recirculation of CD4 + T cells between blood and tissue.
Nature Medicine, 2006
In the version of the article initially published, the key in Figure 4a,b identifying the bars in... more In the version of the article initially published, the key in Figure 4a,b identifying the bars in the histograms is incorrect. The white bar should be identified as peptide and the black bar should be identified as peptide + anti-PD-L1. The error has been corrected in the HTML and PDF versions of the article.
The Journal of Immunology
Despite numerous clinically available vaccines and therapeutics, aged patients remain at increase... more Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity and mortality. Furthermore, the aged patient population has suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mouse models. Aged mice had altered cellular responses, including decreased IFNγ secretion and increased TNFα secretion as compared to young mice. Aged mice had significantly decreased binding and neutralizing antibodies in their serum compared to their young counterparts. Co-immunization with the plasmid-encoded molecular adjuvant adenosine deaminase-1 (pADA) enhanced cellular responses and expanded the breadth and affinity of humoral responses in aged mice. pADA co-delivery also altered the gene expression profiles of lymph node lymphocytes in aged animals. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a stro...
HIV-‐1-‐specific broadly-‐neutralizing antibodies (bnAbs) typically develop in individuals wit... more HIV-‐1-‐specific broadly-‐neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-‐level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-‐ level viremia may be important for designing bnAb-‐inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-‐1 controllers was associated with a relative enrichment of circulating CXCR5+ CXCR3+ PD-‐1Lo CD4 T cells. These CXCR3+ PD-‐1Lo Tfh-‐like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-‐21 and support B cells. In addition, these CXCR3+ PD-‐1Lo Tfh-‐like cells contained higher proportions of stem cell-‐like memory T cells, and upon antigenic stimulation differentiated into PD-‐1Hi Tfh-‐like cells in a Notch-‐dependent manner. Together, these data suggest that CXCR5+ CXCR3+ PD-‐1Lo cells represent a dendritic cell-‐ primed precursor cell population for PD-‐1Hi Tfh-‐like cells that may contribute to the generation of bnAbs in the absence of high-‐level viremia.
Immunity, Oct 1, 2013
The vast majority of currently licensed human vaccines work on the basis of long-term protective ... more The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4 + T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1 + CXCR5 + CD4 + T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV + individuals. Immunity Tfh Cells Correlate with HIV Antibodies