scholarly journals Antiviral Antibodies Are Necessary for Control of Simian Immunodeficiency Virus Replication

2007 ◽  
Vol 81 (10) ◽  
pp. 5024-5035 ◽  
Author(s):  
Christopher J. Miller ◽  
Meritxell Genescà ◽  
Kristina Abel ◽  
David Montefiori ◽  
Donald Forthal ◽  
...  

ABSTRACT To better define the role of B cells in the control of pathogenic simian immunodeficiency virus (SIV) replication, six rhesus monkeys were depleted of B cells by intravenous infusion of rituximab (anti-CD20) 28 days and 7 days before intravaginal SIVmac239 inoculation and every 21 days thereafter until AIDS developed. Although the blood and tissues were similarly depleted of B cells, anti-SIV immunoglobulin G (IgG) antibody responses were completely blocked in only three of the six animals. In all six animals, levels of viral RNA (vRNA) in plasma peaked at 2 weeks and declined by 4 weeks postinoculation (PI). However, the three animals prevented from making an anti-SIV antibody response had significantly higher plasma vRNA levels through 12 weeks PI (P = 0.012). The remaining three B-cell-depleted animals made moderate anti-SIV IgG antibody responses, maintained moderate plasma SIV loads, and showed an expected rate of disease progression, surviving to 24 weeks PI without developing AIDS. In contrast, all three of the B-cell-depleted animals prevented from making anti-SIV IgG responses developed AIDS by 16 weeks PI (P = 0.0001). These observations indicate that antiviral antibody responses are critical in maintaining effective control of SIV replication at early time points postinfection.

2003 ◽  
Vol 77 (20) ◽  
pp. 11125-11138 ◽  
Author(s):  
Henry E. Neuman de Vegvar ◽  
Rama Rao Amara ◽  
Lawrence Steinman ◽  
Paul J. Utz ◽  
Harriet L. Robinson ◽  
...  

ABSTRACT We developed antigen microarrays to profile the breadth, strength, and kinetics of epitope-specific antiviral antibody responses in vaccine trials with a simian-human immunodeficiency virus (SHIV) model for human immunodeficiency virus (HIV) infection. These arrays contained 430 distinct proteins and overlapping peptides spanning the SHIV proteome. In macaques vaccinated with three different DNA and/or recombinant modified vaccinia virus Ankara (rMVA) vaccines encoding Gag-Pol or Gag-Pol-Env, these arrays distinguished vaccinated from challenged macaques, identified three novel viral epitopes, and predicted survival. Following viral challenge, anti-SHIV antibody responses ultimately converged to target eight immunodominant B-cell regions in Env regardless of vaccine regimen, host histocompatibility type, and divergent T-cell specificities. After challenge, responses to nonimmunodominant epitopes were transient, while responses to dominant epitopes were gained. These data suggest that the functional diversity of anti-SHIV B-cell responses is highly limited in the presence of persisting antigen.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3025-3025
Author(s):  
Heather A. Wasserstrom ◽  
Charlotte Cunningham-Rundles ◽  
Lony C.L. Lim ◽  
Nadia T. Guerrero ◽  
Megan H. Wissert ◽  
...  

Abstract Introduction : Splenectomized patients are thought to have poor antibody responses to polyvalent non-conjugate pneumococcal vaccination. Recent studies found that these patients have decreased circulating CD27+ (memory) B cells, suggesting the possibility of a specific defect in splenectomized patients’ humoral immunity. In this study we sought to verify this reduction and ascertain whether it correlates with inadequate antibody production. Thus, we enumerated peripheral blood CD27+ B cells in splenectomized patients and non-splenectomized controls, administered a polyvalent non-conjugate pneumococcal vaccine, and compared their IgG antibody titers to all 23 serotypes before and 4 to 6 weeks after immunization. Participants : 31 participants were enrolled: 21 splenectomized patients (6 male, 15 female; age: 10–80 years, mean: 47.3) and 10 non-splenectomized controls (2 male, 8 female; age: 26–64 years, mean: 37.5). Indications for splenectomy included ITP (17), spherocytosis (2), hemolytic anemia (1), and thrombocytopenia-absent radii syndrome (1). No patients received pneumococcal vaccination within 2 years, or IVIG, Rituxan or immunosuppressive therapy within 6 months of enrollment. Time since splenectomy ranged from 6 months to 50 years (mean: 12.5). 17 patients received at least one prior pneumococcal immunization, from 3 to 22 years previously (mean: 8.0). No controls formerly received a pneumococcal vaccination. Results : B Cell Enumeration: Compared to the 10 controls, the 21 splenectomized patients had a greater percentage of circulating B cells (patients: 12.05% ± 7.61; controls: 7.99% ± 2.92; ρ = 0.042), but a significantly reduced CD27+ B cell component (patients: 12.38% ± 8.48; controls: 40.46% ± 18.68; ρ = 0.001). This reduction was not specific to either of the CD27+ B cell populations (IgM+IgD+CD27+: patients: 31.64% ± 19.72; controls: 44.58% ± 16.01; ρ = 0.081. IgM−IgD−CD27+: patients: 52.05 ± 23.71; controls: 48.08% ± 13.89; ρ = 0.628.) Antibody Analysis: Antibody responses to pneumococcal vaccination did not differ significantly between splenectomized patients and non-splenectomized controls. 9 of 13 splenectomized patients and 9 of 10 controls achieved protection to immunization (χ2 = 1.433; ρ = 0.339), defined as a post-vaccination IgG titer ≥ 1.3 μg/ml or a post:pre-vaccination titer ratio ≥ 4, in at least 70% of the serotypes tested (~16 of 23 serotypes). When comparing the mean number of serotypes to which each cohort achieved protection, splenectomized patients and controls mounted statistically similar responses, at 17 and 20 serotypes, respectively (ρ = 0.134). Furthermore, the geometric means of each cohort’s post-vaccination IgG titers did not differ significantly in 22 of the 23 serotypes. Conclusion : Splenectomized patients had a significant reduction in their circulating CD27+ B cells. This decrease did not correlate with an impaired antibody response to (re-)immunization with a polyvalent non-conjugate pneumococcal vaccine however, as splenectomized patients and non-splenectomized controls achieved comparable protection and produced similar IgG responses to vaccination. For ITP patients and others who have undergone splenectomy, our data indicates that a pneumococcal vaccine can be effectively administered after splenectomy, if needed.


2004 ◽  
Vol 78 (3) ◽  
pp. 1525-1539 ◽  
Author(s):  
Kelly Stefano Cole ◽  
Jonathan D. Steckbeck ◽  
Jennifer L. Rowles ◽  
Ronald C. Desrosiers ◽  
Ronald C. Montelaro

ABSTRACT One mechanism of immune evasion utilized by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelope glycoproteins is the presence of a dense carbohydrate shield. Accumulating evidence from in vitro and in vivo experiments suggests that alterations in N-linked glycosylation of SIV gp120 can enhance host humoral immune responses that may be involved in immune control. The present study was designed to determine the ability of glycosylation mutant viruses to redirect antibody responses to shielded envelope epitopes. The influence of glycosylation on the maturation and specificity of antibody responses elicited by glycosylation mutant viruses containing mutations of specific N-linked sites in and near the V1 and V2 regions of SIVmac239 gp120 was determined. Results from these studies demonstrated a remarkably similar maturation of antibody responses to native, fully glycosylated envelope proteins. However, analyses of antibodies to defined envelope domains revealed that mutation of glycosylation sites in V1 resulted in increased antibody recognition to epitopes in V1. In addition, we demonstrated for the first time that mutation of glycosylation sites in V1 resulted in a redirection of antibody responses to the V3 loop. Taken together, these results demonstrate that N-linked glycosylation is a determinant of SIV envelope B-cell immunogenicity in addition to in vitro antigenicity. In addition, our results demonstrate that the absence of N-linked carbohydrates at specific sites can influence the exposure of epitopes quite distant in the linear sequence.


2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Daniela Frasca ◽  
Maria Romero ◽  
Denisse Garcia ◽  
Alain Diaz ◽  
Bonnie B. Blomberg

Abstract Background Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. Methods Splenic B cells and the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs), were isolated from the spleens of young and old mice and left unstimulated. The RNA was collected to measure the expression of markers associated with intrinsic inflammation and autoimmune antibody production by qPCR. B cells and B cell subsets were also stimulated with CpG and supernatants collected after 7 days to measure autoimmune IgG secretion by ELISA. Metabolic measures (oxygen consumption rate, extracellular acidification rate and glucose uptake) were performed using a Seahorse XFp extracellular flux analyzer. Results Results have identified the subset of ABCs, whose frequencies and numbers increase with age and represent the most pro-inflammatory B cell subset, as the cell type mainly if not exclusively responsible for the expression of inflammatory markers and for the secretion of autoimmune antibodies in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic, as compared to those from young mice and to the subset of FO B cells, a feature needed not only to support their higher expression of RNA for inflammatory markers but also their higher autoimmune antibody secretion. Conclusions These results identify a relationship between intrinsic inflammation, metabolism and autoimmune B cells and suggest possible ways to understand cellular mechanisms that lead to the generation of pathogenic B cells, that are hyper-inflammatory and hyper-metabolic, and secrete IgG antibodies with autoimmune specificities.


2002 ◽  
Vol 76 (7) ◽  
pp. 3309-3317 ◽  
Author(s):  
Deborah Heydenburg Fuller ◽  
Premeela A. Rajakumar ◽  
Lawrence A. Wilson ◽  
Anita M. Trichel ◽  
James T. Fuller ◽  
...  

ABSTRACT An effective vaccine against human immunodeficiency virus (HIV) should protect against mucosal transmission of genetically divergent isolates. As a safe alternative to live attenuated vaccines, the immunogenicity and protective efficacy of a DNA vaccine containing simian immunodeficiency virus (SIV) strain 17E-Fr (SIV/17E-Fr) gag-pol-env was analyzed in rhesus macaques. Significant levels of cytotoxic T lymphocytes (CTL), but low to undetectable serum antibody responses, were observed following multiple immunizations. SIV-specific mucosal antibodies and CTL were also detected in rectal washes and gut-associated lymphoid tissues, respectively. Vaccinated and naive control monkeys were challenged intrarectally with SIV strain DeltaB670 (SIV/DeltaB670), a primary isolate whose env is 15% dissimilar to that of the vaccine strain. Four of seven vaccinees were protected from infection as determined by the inability to identify viral RNA or DNA sequences in the peripheral blood and the absence of anamnestic antibody responses postchallenge. This is the first report of mucosal protection against a primary pathogenic, heterologous isolate of SIV by using a commercially viable vaccine approach. These results support further development of a DNA vaccine for protection against HIV.


2009 ◽  
Vol 90 (10) ◽  
pp. 2513-2518 ◽  
Author(s):  
Christine S. Siegismund ◽  
Oliver Hohn ◽  
Reinhard Kurth ◽  
Stephen Norley

As a prelude to primate studies, the immunogenicity of wild-type and codon-optimized versions of simian immunodeficiency virus (SIV)agm Gag DNA, with and without co-administered granulocyte–macrophage colony-stimulating factor (GM-CSF) DNA, was directly compared in two strains of mice. Gag-specific T cells in the splenocytes of BALB/c and C57BL/6 mice immunized by gene gun were quantified by ELISpot using panels of overlapping synthetic peptides (15mers) spanning the entire capsid proteins of SIVagm, SIVmac and human immunodeficiency virus type 1. Specific antibodies were measured by ELISA. Codon optimization was shown to significantly increase the immune response to the DNA immunogens, reducing the amount of DNA necessary to induce cellular and antibody responses by one and two orders of magnitude, respectively. Co-administration of murine GM-CSF DNA was necessary for the induction of high level T- and B-cell responses. Finally, it was possible to identify both known and novel T-cell epitopes in the Gag proteins of the three viruses.


Immunology ◽  
2018 ◽  
Vol 155 (4) ◽  
pp. 458-466
Author(s):  
Mitra Bhattacharyya ◽  
James B. Whitney ◽  
Michael Seaman ◽  
Dan H. Barouch ◽  
Pablo Penaloza-MacMaster

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