Mary Marovich - Academia.edu (original) (raw)
Papers by Mary Marovich
Journal of Investigative Dermatology Symposium Proceedings, 2001
Virology, 2009
Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We expo... more Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We exposed both subsets to dengue virus (DV) in vitro and investigated their functional characteristics. High levels of DV replication in mDC were found to correlate with DC-SIGN expression. Production of inflammatory cytokines by mDC increased gradually after DV-infection, which was dependent on DV replication. Co-stimulatory markers were upregulated on mDC upon DV-infection. On the contrary, lower levels of DV-replication were observed in pDC, but the cytokine production in pDC was quicker and stronger. This cytokine response was not dependent on viral replication, but dependent on cell endosomal activity and TLR7, and could be also induced by purified DV genome RNA. These results clearly suggested functional differences between mDC and pDC in response to DV infection. Additionally, the TLR7-mediated recognition of DV RNA may be involved in pDC functional activation.
Vaccine, 2009
A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV ... more A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy ,☆,☆☆
JAMA, 2022
CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic di... more CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage. OBJECTIVE To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged Ն12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported. INTERVENTIONS Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156). MAIN OUTCOMES AND MEASURES The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log 10 copies/mL). RESULTS Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, −13.3% [95% CI, −26.3% to −0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19. CONCLUSIONS AND RELEVANCE Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days.
Science, 2014
Future HIV vaccine research should consider the balance between responses that favor protection a... more Future HIV vaccine research should consider the balance between responses that favor protection and those that lead to susceptibility to infection.
JAMA, 2021
IMPORTANCE Preventive interventions are needed to protect residents and staff of skilled nursing ... more IMPORTANCE Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. OBJECTIVE To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. INTERVENTIONS Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587). MAIN OUTCOMES AND MEASURES The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. RESULTS The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%; odds ratio, 0.43 [95% CI, 0.28-0.68]; P < .001; absolute risk difference, −6.6 [95% CI, −10.7 to −2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). CONCLUSIONS AND RELEVANCE Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy.
Truncated Hiv Envelope Proteins (Env), Methods and Compositions Related Thereto
AIDS (London, England), Jun 16, 2016
To evaluate differences in soluble inflammatory markers between chronically HIV-infected men and ... more To evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment. Soluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-naïve individuals (25 males and 35 females) with chronic HIV infection and 18 HIV-uninfected controls (9 males and 9 females) from Thailand. Following enrollment, participants began combination antiretroviral therapy (cART) and were evaluated for expression of these markers after 48 weeks. Plasma and CSF levels of 19 soluble biomarkers (IFN-γ, TNFα, TNF-RII, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFNα, I-FABP, and sCD14) were measured using either a multi-parameter or standard ELISA assay. Prior to cART, females with impaired cognition had elevated levels of neopterin and TNF-RII compared to females with normal cognition in both the plasma and CSF, however le...
Journal of Virology, 2005
ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infection... more ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infections and initiators of antiviral immune responses. Previous observations showed that DCs are activated by infection, presumably acquiring the capacity to promote cell-mediated immunity. However, separate evaluations of the maturation profiles of infected and uninfected bystander cells show that infection impairs the ability of DCs to upregulate cell surface expression of costimulatory, maturation, and major histocompatibility complex molecules, resulting in reduced T-cell stimulatory capacity. Infected DCs failed to respond to tumor necrosis factor alpha as an additional maturation stimulus and were apoptotic. Interleukin 10 (IL-10) was detected in supernatants from cultures of DV-infected DCs and cocultures of DCs and T cells. Taken together, these results constitute an immune evasion strategy used by DV that directly impairs antigen-presenting cell function by maturation blockade and indu...
Journal of Investigative Dermatology Symposium Proceedings, 2001
Virology, 2009
Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We expo... more Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We exposed both subsets to dengue virus (DV) in vitro and investigated their functional characteristics. High levels of DV replication in mDC were found to correlate with DC-SIGN expression. Production of inflammatory cytokines by mDC increased gradually after DV-infection, which was dependent on DV replication. Co-stimulatory markers were upregulated on mDC upon DV-infection. On the contrary, lower levels of DV-replication were observed in pDC, but the cytokine production in pDC was quicker and stronger. This cytokine response was not dependent on viral replication, but dependent on cell endosomal activity and TLR7, and could be also induced by purified DV genome RNA. These results clearly suggested functional differences between mDC and pDC in response to DV infection. Additionally, the TLR7-mediated recognition of DV RNA may be involved in pDC functional activation.
Journal of Virology, 2008
Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million in... more Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of DC-SIGN ( DC - s pecific i ntercellular adhesion molecule-3- g rabbing n onintegrin) and requires Fc gamma receptor IIa (FcγRIIa). Mature DC exhibited ADE, whereas immature DC, expressing higher levels of DC-SIGN and similar FcγRIIa levels, did not undergo ADE. ADE results in increased intracellular de novo DV protein s...
Vaccine, 2009
A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV ... more A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy ,☆,☆☆
Journal of Virology, 2005
ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infection... more ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infections and initiators of antiviral immune responses. Previous observations showed that DCs are activated by infection, presumably acquiring the capacity to promote cell-mediated immunity. However, separate evaluations of the maturation profiles of infected and uninfected bystander cells show that infection impairs the ability of DCs to upregulate cell surface expression of costimulatory, maturation, and major histocompatibility complex molecules, resulting in reduced T-cell stimulatory capacity. Infected DCs failed to respond to tumor necrosis factor alpha as an additional maturation stimulus and were apoptotic. Interleukin 10 (IL-10) was detected in supernatants from cultures of DV-infected DCs and cocultures of DCs and T cells. Taken together, these results constitute an immune evasion strategy used by DV that directly impairs antigen-presenting cell function by maturation blockade and indu...
Journal of Virology, 2008
Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million in... more Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of DC-SIGN ( DC - s pecific i ntercellular adhesion molecule-3- g rabbing n onintegrin) and requires Fc gamma receptor IIa (FcγRIIa). Mature DC exhibited ADE, whereas immature DC, expressing higher levels of DC-SIGN and similar FcγRIIa levels, did not undergo ADE. ADE results in increased intracellular de novo DV protein s...
Journal of Virological Methods, 2006
The mechanisms underlying the pathogenesis of dengue hemorrhagic fever (DHF) remain poorly unders... more The mechanisms underlying the pathogenesis of dengue hemorrhagic fever (DHF) remain poorly understood, but a clear correlation appears to exist between dengue viral load and disease severity. While antibody-dependent enhancement and T-cell-mediated pathogenesis theories suggest an immunopathologic basis for the development of severe disease, intriguing evidence suggest a role for viral strain differences. Consistent genetic differences exist in the envelope glycoproteins of dengue 2 strains associated with DHF epidemics (Asian genotype) and dengue 2 strains only associated with DF (American genotype). It has also been established that dengue virus infection can be mediated by Civ type lectins DC-SIGN and L-SIGN. DC-SIGN is found on dendritic cells, a presumed target in human infection. L-SIGN is found on liver sinusoidal endothelial cells. Such cells have been shown to tolerize naïve T cells. To avoid the pitfalls associated with current measures of infection and neutralization, we developed an assay that uses cells expressing these relevant lectin receptors and low-passage viral isolates that yields results within 24 hours. Using this assay, we examined whether Asian and American genotype dengue 2 viruses exhibit differences in utilization of these two receptors. Our results showed that American strains infect DC-SIGN bearing cells to a greater extent than LSIGN bearing cells while Asian strains preferentially infect L-SIGN bearing cells. A single mutation in the envelope glycoprotein of an American strain at E390 from aspartic acid (American) to asparagine converted the C-type lectin binding phenotype from an American strain to an Asian strain by the observation that the E390 amino acid (aa) in the Asian strain is also asparagine. Furthermore, Asian and American strains differed in their sensitivity to antibody neutralization. The neutralizing capacity of mAbs 3H5 and 4G2 for Asian virus was significantly decreased when infection was measured in L-SIGN bearing cells compared to DC-SIGN bearing cells. We also found that serum from Venezuelan DF patients had much greater neutralizing capacity for Asian virus in LSIGN cells than serum from patients who progressed to DHF. Further, the magnitude of neutralization of L-SIGN-mediated Asian virus infection was inversely associated with disease severity. Taken together, our studies suggest that differences in receptor utilization and neutralization sensitivity between Asian and American dengue 2 strains may contribute to our understanding of the role that viral strain differences play in dengue pathogenesis.
Journal of Investigative Dermatology Symposium Proceedings, 2001
Virology, 2009
Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We expo... more Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We exposed both subsets to dengue virus (DV) in vitro and investigated their functional characteristics. High levels of DV replication in mDC were found to correlate with DC-SIGN expression. Production of inflammatory cytokines by mDC increased gradually after DV-infection, which was dependent on DV replication. Co-stimulatory markers were upregulated on mDC upon DV-infection. On the contrary, lower levels of DV-replication were observed in pDC, but the cytokine production in pDC was quicker and stronger. This cytokine response was not dependent on viral replication, but dependent on cell endosomal activity and TLR7, and could be also induced by purified DV genome RNA. These results clearly suggested functional differences between mDC and pDC in response to DV infection. Additionally, the TLR7-mediated recognition of DV RNA may be involved in pDC functional activation.
Vaccine, 2009
A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV ... more A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy ,☆,☆☆
JAMA, 2022
CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic di... more CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage. OBJECTIVE To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged Ն12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported. INTERVENTIONS Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156). MAIN OUTCOMES AND MEASURES The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log 10 copies/mL). RESULTS Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, −13.3% [95% CI, −26.3% to −0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19. CONCLUSIONS AND RELEVANCE Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days.
Science, 2014
Future HIV vaccine research should consider the balance between responses that favor protection a... more Future HIV vaccine research should consider the balance between responses that favor protection and those that lead to susceptibility to infection.
JAMA, 2021
IMPORTANCE Preventive interventions are needed to protect residents and staff of skilled nursing ... more IMPORTANCE Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. OBJECTIVE To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. INTERVENTIONS Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587). MAIN OUTCOMES AND MEASURES The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. RESULTS The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%; odds ratio, 0.43 [95% CI, 0.28-0.68]; P < .001; absolute risk difference, −6.6 [95% CI, −10.7 to −2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). CONCLUSIONS AND RELEVANCE Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy.
Truncated Hiv Envelope Proteins (Env), Methods and Compositions Related Thereto
AIDS (London, England), Jun 16, 2016
To evaluate differences in soluble inflammatory markers between chronically HIV-infected men and ... more To evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment. Soluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-naïve individuals (25 males and 35 females) with chronic HIV infection and 18 HIV-uninfected controls (9 males and 9 females) from Thailand. Following enrollment, participants began combination antiretroviral therapy (cART) and were evaluated for expression of these markers after 48 weeks. Plasma and CSF levels of 19 soluble biomarkers (IFN-γ, TNFα, TNF-RII, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFNα, I-FABP, and sCD14) were measured using either a multi-parameter or standard ELISA assay. Prior to cART, females with impaired cognition had elevated levels of neopterin and TNF-RII compared to females with normal cognition in both the plasma and CSF, however le...
Journal of Virology, 2005
ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infection... more ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infections and initiators of antiviral immune responses. Previous observations showed that DCs are activated by infection, presumably acquiring the capacity to promote cell-mediated immunity. However, separate evaluations of the maturation profiles of infected and uninfected bystander cells show that infection impairs the ability of DCs to upregulate cell surface expression of costimulatory, maturation, and major histocompatibility complex molecules, resulting in reduced T-cell stimulatory capacity. Infected DCs failed to respond to tumor necrosis factor alpha as an additional maturation stimulus and were apoptotic. Interleukin 10 (IL-10) was detected in supernatants from cultures of DV-infected DCs and cocultures of DCs and T cells. Taken together, these results constitute an immune evasion strategy used by DV that directly impairs antigen-presenting cell function by maturation blockade and indu...
Journal of Investigative Dermatology Symposium Proceedings, 2001
Virology, 2009
Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We expo... more Myeloid and plasmacytoid dendritic cells (mDC and pDC) are naturally distinctive subsets. We exposed both subsets to dengue virus (DV) in vitro and investigated their functional characteristics. High levels of DV replication in mDC were found to correlate with DC-SIGN expression. Production of inflammatory cytokines by mDC increased gradually after DV-infection, which was dependent on DV replication. Co-stimulatory markers were upregulated on mDC upon DV-infection. On the contrary, lower levels of DV-replication were observed in pDC, but the cytokine production in pDC was quicker and stronger. This cytokine response was not dependent on viral replication, but dependent on cell endosomal activity and TLR7, and could be also induced by purified DV genome RNA. These results clearly suggested functional differences between mDC and pDC in response to DV infection. Additionally, the TLR7-mediated recognition of DV RNA may be involved in pDC functional activation.
Journal of Virology, 2008
Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million in... more Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of DC-SIGN ( DC - s pecific i ntercellular adhesion molecule-3- g rabbing n onintegrin) and requires Fc gamma receptor IIa (FcγRIIa). Mature DC exhibited ADE, whereas immature DC, expressing higher levels of DC-SIGN and similar FcγRIIa levels, did not undergo ADE. ADE results in increased intracellular de novo DV protein s...
Vaccine, 2009
A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV ... more A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy ,☆,☆☆
Journal of Virology, 2005
ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infection... more ABSTRACTDendritic cells (DCs) play a central role as major targets of dengue virus (DV) infections and initiators of antiviral immune responses. Previous observations showed that DCs are activated by infection, presumably acquiring the capacity to promote cell-mediated immunity. However, separate evaluations of the maturation profiles of infected and uninfected bystander cells show that infection impairs the ability of DCs to upregulate cell surface expression of costimulatory, maturation, and major histocompatibility complex molecules, resulting in reduced T-cell stimulatory capacity. Infected DCs failed to respond to tumor necrosis factor alpha as an additional maturation stimulus and were apoptotic. Interleukin 10 (IL-10) was detected in supernatants from cultures of DV-infected DCs and cocultures of DCs and T cells. Taken together, these results constitute an immune evasion strategy used by DV that directly impairs antigen-presenting cell function by maturation blockade and indu...
Journal of Virology, 2008
Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million in... more Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of DC-SIGN ( DC - s pecific i ntercellular adhesion molecule-3- g rabbing n onintegrin) and requires Fc gamma receptor IIa (FcγRIIa). Mature DC exhibited ADE, whereas immature DC, expressing higher levels of DC-SIGN and similar FcγRIIa levels, did not undergo ADE. ADE results in increased intracellular de novo DV protein s...
Journal of Virological Methods, 2006
The mechanisms underlying the pathogenesis of dengue hemorrhagic fever (DHF) remain poorly unders... more The mechanisms underlying the pathogenesis of dengue hemorrhagic fever (DHF) remain poorly understood, but a clear correlation appears to exist between dengue viral load and disease severity. While antibody-dependent enhancement and T-cell-mediated pathogenesis theories suggest an immunopathologic basis for the development of severe disease, intriguing evidence suggest a role for viral strain differences. Consistent genetic differences exist in the envelope glycoproteins of dengue 2 strains associated with DHF epidemics (Asian genotype) and dengue 2 strains only associated with DF (American genotype). It has also been established that dengue virus infection can be mediated by Civ type lectins DC-SIGN and L-SIGN. DC-SIGN is found on dendritic cells, a presumed target in human infection. L-SIGN is found on liver sinusoidal endothelial cells. Such cells have been shown to tolerize naïve T cells. To avoid the pitfalls associated with current measures of infection and neutralization, we developed an assay that uses cells expressing these relevant lectin receptors and low-passage viral isolates that yields results within 24 hours. Using this assay, we examined whether Asian and American genotype dengue 2 viruses exhibit differences in utilization of these two receptors. Our results showed that American strains infect DC-SIGN bearing cells to a greater extent than LSIGN bearing cells while Asian strains preferentially infect L-SIGN bearing cells. A single mutation in the envelope glycoprotein of an American strain at E390 from aspartic acid (American) to asparagine converted the C-type lectin binding phenotype from an American strain to an Asian strain by the observation that the E390 amino acid (aa) in the Asian strain is also asparagine. Furthermore, Asian and American strains differed in their sensitivity to antibody neutralization. The neutralizing capacity of mAbs 3H5 and 4G2 for Asian virus was significantly decreased when infection was measured in L-SIGN bearing cells compared to DC-SIGN bearing cells. We also found that serum from Venezuelan DF patients had much greater neutralizing capacity for Asian virus in LSIGN cells than serum from patients who progressed to DHF. Further, the magnitude of neutralization of L-SIGN-mediated Asian virus infection was inversely associated with disease severity. Taken together, our studies suggest that differences in receptor utilization and neutralization sensitivity between Asian and American dengue 2 strains may contribute to our understanding of the role that viral strain differences play in dengue pathogenesis.