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Search Results: 1 - 10 of 149785 matches for " Douglas F. Nixon "
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Tenofovir treatment augments anti-viral immunity against drug-resistant SIV challenge in chronically infected rhesus macaques
Karin J Metzner, James M Binley, Agegnehu Gettie, Preston Marx, Douglas F Nixon, Ruth I Connor
Retrovirology , 2006, DOI: 10.1186/1742-4690-3-97
Abstract: Replication of SIVmac055 was detected in untreated macaques infected with SIVmac239Δnef, and in tenofovir-treated, na?ve control macaques. The majority of macaques infected with SIVmac055 experienced high levels of plasma viremia, rapid CD4+ T cell loss and clinical disease progression. By comparison, macaques infected with SIVmac239Δnef and treated with tenofovir showed no evidence of replicating SIVmac055 in plasma using allele-specific real-time PCR assays with a limit of sensitivity of 50 SIV RNA copies/ml plasma. These animals remained clinically healthy with stable CD4+ T cell counts during three years of follow-up. Both the tenofovir-treated and untreated macaques infected with SIVmac239Δnef had antibody responses to SIV gp130 and p27 antigens and SIV-specific CD8+ T cell responses prior to SIVmac055 challenge, but only those animals receiving concurrent treatment with tenofovir resisted infection with SIVmac055.These results support the concept that anti-viral immunity acts synergistically with ART to augment drug efficacy by suppressing replication of viral variants with reduced drug sensitivity. Treatment strategies that seek to combine immunotherapeutic intervention as an adjunct to antiretroviral drugs may therefore confer added benefit by controlling replication of HIV-1, and reducing the likelihood of treatment failure due to the emergence of drug-resistant virus, thereby preserving treatment options.Initiation of antiretroviral therapy (ART) in patients with HIV-1 infection can rapidly reduce plasma viremia, bolster immune responses, and improve clinical outcome [1-3]. Despite significant progress in the clinical management of HIV-1 infection, the therapeutic efficacy of ART is often undermined by incomplete suppression of virus replication and the emergence of drug-resistant HIV-1 [4]. Drug-resistant strains of HIV-1 harbor mutations that can negatively impact viral fitness, but these viruses gain a replicative advantage in the presence of drug and c
Decay Kinetics of HIV-1 Specific T Cell Responses in Vertically HIV-1 Exposed Seronegative Infants
Sara J. Holditch,Esper G. Kallas,Michael G. Rosenberg,Douglas F. Nixon
Frontiers in Immunology , 2012, DOI: 10.3389/fimmu.2011.00094
Abstract: Objective: The majority of infants born, in developed countries, to HIV-1 positive women are exposed to the HIV-1 virus in utero or peri/post-partum, but are born uninfected. We, and others, have previously shown HIV-1 specific T cell responses in HIV-1 exposed seronegative (HESN) neonates/infants. Our objective in this study was to examine the rate of decay in their HIV-1 specific T cell response over time from birth. Design: Cross-sectional and longitudinal studies of HIV-1 specific T cell responses in HESN infants were performed. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from 18 HIV-1 DNA PCR negative infants born to HIV-1 infected mothers receiving care at the Jacobi Medical Center, Bronx, NY, USA. PBMC were examined for T cell responses to HIV-1 antigens by interferon-gamma (IFN-γ) ELISPOT. Results: PBMC from 15 HESN neonates/infants were analyzed. We observed a decay of HIV-1 specific T cell responses from birth at a rate of ?0.599 spot forming unit/106 cells per day, with a median half-life decay rate of 21.38 weeks (13.39–115.8). Conclusion: Our results support the dynamic nature of T cell immunity in the context of a developing immune system. The disparate rate of decay with studies of adults placed on antiretroviral drugs suggests that antigen specific T cell responses are driven by the natural rate of decay of the T cell sub-populations themselves.
Nucleoside Analogue Reverse Transcriptase Inhibitors Differentially Inhibit Human LINE-1 Retrotransposition
R. Brad Jones, Keith E. Garrison, Jessica C. Wong, Erick H. Duan, Douglas F. Nixon, Mario A. Ostrowski
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001547
Abstract: Background Intact LINE-1 elements are the only retrotransposons encoded by the human genome known to be capable of autonomous replication. Numerous cases of genetic disease have been traced to gene disruptions caused by LINE-1 retrotransposition events in germ-line cells. In addition, genomic instability resulting from LINE-1 retrotransposition in somatic cells has been proposed as a contributing factor to oncogenesis and to cancer progression. LINE-1 element activity may also play a role in normal physiology. Methods and Principal Findings Using an in vitro LINE-1 retrotransposition reporter assay, we evaluated the abilities of several antiretroviral compounds to inhibit LINE-1 retrotransposition. The nucleoside analogue reverse transcriptase inhibitors (nRTIs): stavudine, zidovudine, tenofovir disoproxil fumarate, and lamivudine all inhibited LINE-1 retrotransposition with varying degrees of potencies, while the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine showed no effect. Conclusions/Significance Our data demonstrates the ability for nRTIs to suppress LINE-1 retrotransposition. This is immediately applicable to studies aimed at examining potential roles for LINE-1 retrotransposition in physiological processes. In addition, our data raises novel safety considerations for nRTIs based on their potential to disrupt physiological processes involving LINE-1 retrotransposition.
Differential Expression of CD96 Surface Molecule Represents CD8+ T Cells with Dissimilar Effector Function during HIV-1 Infection
Emily M. Eriksson, Chris E. Keh, Steven G. Deeks, Jeffrey N. Martin, Frederick M. Hecht, Douglas F. Nixon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051696
Abstract: During HIV-1 infection, immune dysregulation and aberrant lymphocyte functions are well-established characteristics. Cell surface molecules are important for immunological functions and changes in expression can affect lymphocyte effector functions, thereby contributing to pathogenesis and disease progression. In this study we have focused on CD96, a member of the IgG superfamily receptors that have generated increasing recent interest due to their adhesive and co-stimulatory functions in addition to immunoregulatory capacity. CD96 is expressed by both T and NK cells. Although the function of CD96 is not completely elucidated, it has been shown to have adhesive functions and enhance cytotoxicity. Interestingly, CD96 may also have inhibitory functions due to its immunoreceptor tyrosine-based inhibitory motif (ITIM). The clinical significance of CD96 is still comparatively limited although it has been associated with chronic Hepatitis B infection and disease progression. CD96 has not previously been studied in the context of HIV-1 infection, but due to its potential importance in immune regulation and relevance to chronic disease, we examined CD96 expression in relation to HIV-1 pathogenesis. In a cross-sectional analysis, we investigated the CD8+ T cell expression of CD96 in cohorts of untreated HIV-1 infected adults with high viral loads (non-controllers) and low viral loads (“elite” controllers). We demonstrated that elite controllers have significantly higher CD96 mean fluorescence intensity on CD8+ T cells compared to HIV-1 non-controllers and CD96 expression was positively associated with CD4+ T cell counts. Functional assessment showed that CD8+ T cells lacking CD96 expression represented a population that produced both perforin and IFN-γ following stimulation. Furthermore, CD96 expression on CD8+ T cells was decreased in presence of lipopolysaccharide in vitro. Overall, these findings indicate that down-regulation of CD96 is an important aspect of HIV-1 pathogenesis and differential expression is related to cell effector functions and HIV-1 disease course.
Sequential Broadening of CTL Responses in Early HIV-1 Infection Is Associated with Viral Escape
Annika C. Karlsson, Astrid K.N. Iversen, Joan M. Chapman, Tulio de Oliveira, Gerald Spotts, Andrew J. McMichael, Miles P. Davenport, Frederick M. Hecht, Douglas F. Nixon
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000225
Abstract: Background Antigen-specific CTL responses are thought to play a central role in containment of HIV-1 infection, but no consistent correlation has been found between the magnitude and/or breadth of response and viral load changes during disease progression. Methods and Findings We undertook a detailed investigation of longitudinal CTL responses and HIV-1 evolution beginning with primary infection in 11 untreated HLA-A2 positive individuals. A subset of patients developed broad responses, which selected for consensus B epitope variants in Gag, Pol, and Nef, suggesting CTL-induced adaptation of HIV-1 at the population level. The patients who developed viral escape mutations and broad autologous CTL responses over time had a significantly higher increase in viral load during the first year of infection compared to those who did not develop viral escape mutations. Conclusions A continuous dynamic development of CTL responses was associated with viral escape from temporarily effective immune responses. Our results suggest that broad CTL responses often represent footprints left by viral CTL escape rather than effective immune control, and help explain earlier findings that fail to show an association between breadth of CTL responses and viral load. Our results also demonstrate that CTL pressures help to maintain certain elements of consensus viral sequence, which likely represent viral escape from common HLA-restricted CTL responses. The ability of HIV to evolve to escape CTL responses restricted by a common HLA type highlights the challenges posed to development of an effective CTL-based vaccine.
Association of Differentiation State of CD4+ T Cells and Disease Progression in HIV-1 Perinatally Infected Children
Elizabeth R. Sharp, Christian B. Willberg, Peter J. Kuebler, Jacob Abadi, Glenn J. Fennelly, Joanna Dobroszycki, Andrew A. Wiznia, Michael G. Rosenberg, Douglas F. Nixon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029154
Abstract: Background In the USA, most HIV-1 infected children are on antiretroviral drug regimens, with many individuals surviving through adolescence and into adulthood. The course of HIV-1 infection in these children is variable, and understudied. Methodology/Principal Findings We determined whether qualitative differences in immune cell subsets could explain a slower disease course in long term survivors with no evidence of immune suppression (LTS-NS; CD4%≥25%) compared to those with severe immune suppression (LTS-SS; CD4%≤15%). Subjects in the LTS-NS group had significantly higher frequencies of na?ve (CCR7+CD45RA+) and central memory (CCR7+CD45RA?) CD4+ T cells compared to LTS-SS subjects (p = 0.0005 and <0.0001, respectively). Subjects in the rapid progressing group had significantly higher levels of CD4+ TEMRA (CCR7?CD45RA+) cells compared to slow progressing subjects (p<0.0001). Conclusions/Significance Rapid disease progression in vertical infection is associated with significantly higher levels of CD4+ TEMRA (CCR7?CD45RA+) cells.
A Decreased Frequency of Regulatory T Cells in Patients with Common Variable Immunodeficiency
Karina M. Melo, Karina I. Carvalho, Fernanda R. Bruno, Lishomwa C. Ndhlovu, Wassim M. Ballan, Douglas F. Nixon, Esper G. Kallas, Beatriz T. Costa-Carvalho
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006269
Abstract: Introduction Common variable immunodeficiency disorder (CVID) is a heterogeneous syndrome, characterized by deficient antibody production and recurrent bacterial infections in addition abnormalities in T cells. CD4+CD25high regulatory T cells (Treg) are essential modulators of immune responses, including down-modulation of immune response to pathogens, allergens, cancer cells and self-antigens. Objective In this study we set out to investigate the frequency of Treg cells in CVID patients and correlate with their immune activation status. Materials and Methods Sixteen patients (6 males and 10 females) with CVID who had been treated with regular intravenous immunoglobulin and 14 controls were enrolled. Quantitative analyses of peripheral blood mononuclear cells (PBMC) were performed by multiparametric flow cytometry using the following cell markers: CD38, HLA-DR, CCR5 (immune activation); CD4, CD25, FOXP3, CD127, and OX40 (Treg cells); Ki-67 and IFN-γ (intracellular cytokine). Results A significantly lower proportion of CD4+CD25highFOXP3 T cells was observed in CVID patients compared with healthy controls (P<0.05). In addition to a higher proportion of CD8+ T cells from CVID patients expressing the activation markers, CD38+ and HLA-DR+ (P<0.05), we observed no significant correlation between Tregs and immune activation. Conclusion Our results demonstrate that a reduction in Treg cells could have impaired immune function in CVID patients.
Immunodominance of HIV-1 Specific CD8+ T-Cell Responses Is Related to Disease Progression Rate in Vertically Infected Adolescents
Elizabeth R. Sharp, Christian B. Willberg, Peter J. Kuebler, Jacob Abadi, Glenn J. Fennelly, Joanna Dobroszycki, Andrew A. Wiznia, Michael G. Rosenberg, Douglas F. Nixon
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021135
Abstract: Background HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. Methodology/Principal Findings In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of na?ve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. Conclusions/Significance Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions.
Age-Related Expansion of Tim-3 Expressing T Cells in Vertically HIV-1 Infected Children
Ravi Tandon, Maria T. M. Giret, Devi SenGupta, Vanessa A. York, Andrew A. Wiznia, Michael G. Rosenberg, Esper G. Kallas, Lishomwa C. Ndhlovu, Douglas F. Nixon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045733
Abstract: As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an “immune exhaustion”, with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28?CD57+CD8+ T cells between the groups. However, the frequency of Tim-3+CD8+ and Tim-3+CD4+ exhausted T cells, but not PD-1+ T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1+CD8+ T cells were directly associated with T cell immune activation in children. The frequency of Tim-3+CD8+ T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age-related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion.
Human Endogenous Retrovirus K106 (HERV-K106) Was Infectious after the Emergence of Anatomically Modern Humans
Aashish R. Jha,Douglas F. Nixon,Michael G. Rosenberg,Jeffrey N. Martin,Steven G. Deeks,Richard R. Hudson,Keith E. Garrison,Satish K. Pillai
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020234
Abstract: HERV-K113 and HERV-K115 have been considered to be among the youngest HERVs because they are the only known full-length proviruses that are insertionally polymorphic and maintain the open reading frames of their coding genes. However, recent data suggest that HERV-K113 is at least 800,000 years old, and HERV-K115 even older. A systematic study of HERV-K HML2 members to identify HERVs that may have infected the human genome in the more recent evolutionary past is lacking. Therefore, we sought to determine how recently HERVs were exogenous and infectious by examining sequence variation in the long terminal repeat (LTR) regions of all full-length HERV-K loci. We used the traditional method of inter-LTR comparison to analyze all full length HERV-Ks and determined that two insertions, HERV-K106 and HERV-K116 have no differences between their 5′ and 3′ LTR sequences, suggesting that these insertions were endogenized in the recent evolutionary past. Among these insertions with no sequence differences between their LTR regions, HERV-K106 had the most intact viral sequence structure. Coalescent analysis of HERV-K106 3′ LTR sequences representing 51 ethnically diverse individuals suggests that HERV-K106 integrated into the human germ line approximately 150,000 years ago, after the emergence of anatomically modern humans.
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