scholarly journals Immune Failure in the Absence of Profound CD4+ T-Lymphocyte Depletion in Simian Immunodeficiency Virus-Infected Rapid Progressor Macaques

2004 ◽  
Vol 78 (1) ◽  
pp. 275-284 ◽  
Author(s):  
Vanessa M. Hirsch ◽  
Sampa Santra ◽  
Simoy Goldstein ◽  
Ronald Plishka ◽  
Alicia Buckler-White ◽  
...  
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Specific Antibody ◽  
Hepatitis A Virus ◽  
Antibody Responses ◽  
Lymphoid Tissues ◽  
Humoral Immune ◽  
Immunodeficiency Virus ◽  
Immune Defect

ABSTRACT A fraction of simian immunodeficiency virus (SIV)-infected macaques develop rapidly progressive disease in the apparent absence of detectable SIV-specific antibody responses. To characterize the immunopathogenesis of this syndrome, we studied viral load, CD4+ T-lymphocyte numbers as well as cellular and humoral immune responses to SIV and other exogenous antigens in four SIVsm-infected rhesus macaques that progressed to AIDS 9 to 16 weeks postinoculation. Each of these animals exhibited high levels of viremia but showed relatively preserved CD4 T lymphocytes in blood and lymphoid tissues at the time of death. Transient SIV-specific antibody responses and cytotoxic T-lymphocyte responses were observed at 2 to 4 weeks postinoculation. Two of the macaques that were immunized sequentially with tetanus toxoid and hepatitis A virus failed to develop antibody to either antigen. These studies show that the SIV-infected rapid progressor macaques initially mounted an appropriate but transient cellular and humoral immune response. The subsequent immune defect in these animals appeared to be global, affecting both cellular and humoral immunity to SIV as well as immune responses against unrelated antigens. The lack of CD4 depletion and loss of humoral and cellular immune responses suggest that their immune defect may be due to an early loss in T helper function.

scholarly journals Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Sudhir Pai Kasturi ◽  
Pamela A. Kozlowski ◽  
Helder I. Nakaya ◽  
Matheus C. Burger ◽  
Pedro Russo ◽  
...  
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Specific Antibody ◽  
Protective Immunity ◽  
Low Dose ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Toll Like Receptor ◽  
Immunodeficiency Virus ◽  
Vaginal Secretions

ABSTRACT Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NP-adjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5α restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Env-specific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV). IMPORTANCE The results of the RV144 HIV vaccine trial, which demonstrated a rapid waning of protective immunity with time, have underscored the need to develop strategies to enhance the durability of protective immune responses. Our recent work in mice has highlighted the capacity of nanoparticle-encapsulated TLR ligands (NP) to induce potent and durable antibody responses that last a lifetime in mice. In the present study, we evaluated the ability of these NP adjuvants to promote robust and durable protective immune responses against SIV in nonhuman primates. Our results demonstrate that immunization of rhesus macaques with NP adjuvants mixed with soluble SIV Env or a virus-like particle form of Env (VLP) induces potent and durable Env-specific antibody responses in the serum and in vaginal secretions. These responses were superior to those induced by alum adjuvant, and they resulted in enhanced protection against a low-dose intravaginal challenge with a heterologous strain of SIV in animals with TRIM5a restrictive alleles. These results highlight the potential for such NP TLR L adjuvants in promoting robust and durable antibody responses against HIV in the next generation of HIV immunogens currently being developed.

scholarly journals Induction of Mucosal Protection against Primary, Heterologous Simian Immunodeficiency Virus by a DNA Vaccine

2002 ◽  
Vol 76 (7) ◽  
pp. 3309-3317 ◽  
Author(s):  
Deborah Heydenburg Fuller ◽  
Premeela A. Rajakumar ◽  
Lawrence A. Wilson ◽  
Anita M. Trichel ◽  
James T. Fuller ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Dna Vaccine ◽  
Dna Sequences ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Effective Vaccine ◽  
Lymphoid Tissues ◽  
Mucosal Protection ◽  
Mucosal Transmission ◽  
Immunodeficiency Virus

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.

scholarly journals Impaired Cellular Immunity to SARS-CoV-2 in Severe COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Ling Ni ◽  
Meng-Li Cheng ◽  
Yu Feng ◽  
Hui Zhao ◽  
Jingyuan Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cellular Immunity ◽  
Specific Antibody ◽  
Peripheral Blood ◽  
Neutralizing Antibodies ◽  
Acute Infection ◽  
Peripheral Blood Lymphocytes ◽  
Antibody Responses ◽  
Humoral Immune

The high infection rate and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) make it a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, and most convalescent individuals have been shown to develop both cellular and humoral immune responses. However, virus-specific adaptive immune responses in severe patients during acute phase have not been thoroughly studied. Here, we found that in a group of COVID-19 patients with acute respiratory distress syndrome (ARDS) during hospitalization, most of them mounted SARS-CoV-2-specific antibody responses, including neutralizing antibodies. However, compared to healthy controls, the percentages and absolute numbers of both NK cells and CD8+ T cells were significantly reduced, with decreased IFNγ expression in CD4+ T cells in peripheral blood from severe patients. Most notably, their peripheral blood lymphocytes failed in producing IFNγ against viral proteins. Thus, severe COVID-19 patients at acute infection stage developed SARS-CoV-2-specific antibody responses but were impaired in cellular immunity, which emphasizes on the role of cellular immunity in COVID-19.

scholarly journals Rapid Virus Dissemination in Infant Macaques after Oral Simian Immunodeficiency Virus Exposure in the Presence of Local Innate Immune Responses

2006 ◽  
Vol 80 (13) ◽  
pp. 6357-6367 ◽  
Author(s):  
Kristina Abel ◽  
Bapi Pahar ◽  
Koen K. A. Van Rompay ◽  
Linda Fritts ◽  
Clarissa Sin ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Virus Replication ◽  
Proinflammatory Cytokines ◽  
Innate Immune ◽  
Lymphoid Tissues ◽  
Innate Immune Responses ◽  
Virus Dissemination ◽  
Immunodeficiency Virus

ABSTRACT A vaccine to protect human immunodeficiency virus (HIV)-exposed infants is an important goal in the global fight against the HIV pandemic. Two major challenges in pediatric HIV vaccine design are the competence of the neonatal/infant immune system in comparison to the adult immune system and the frequent exposure to HIV via breast-feeding. Based on the hypothesis that an effective vaccine needs to elicit antiviral immune responses directly at the site of virus entry, the pattern of virus dissemination in relation to host immune responses was determined in mucosal and lymphoid tissues of infant macaques at 1 week after multiple oral exposures to simian immunodeficiency virus (SIV). The results show that SIV disseminates systemically by 1 week. Infant macaques can respond rapidly to virus challenge and mount strong innate immune responses. However, despite systemic infection, these responses are most pronounced in tissues close to the viral entry site, with the tonsil being the primary site of virus replication and induction of immune responses. Thus, distinct anatomic compartments are characterized by unique cytokine gene expression patterns. Importantly, the early response at mucosal entry sites is dominated by the induction of proinflammatory cytokines, while cytokines with direct antiviral activity, alpha/beta interferons, are only minimally induced. In contrast, both antiviral and proinflammatory cytokines are induced in lymphoid tissues. Thus, although infant macaques can respond quickly to oral viral challenge, the locally elicited immune responses at mucosal entry sites are likely to favor immune activation and thereby virus replication and are insufficient to limit virus replication and dissemination.

scholarly journals Lymphatic Dissemination of Simian Immunodeficiency Virus after Penile Inoculation

2016 ◽  
Vol 90 (8) ◽  
pp. 4093-4104 ◽  
Author(s):  
Zhong-Min Ma ◽  
Joseph Dutra ◽  
Linda Fritts ◽  
Christopher J. Miller
Keyword(s):  
Immune Responses ◽  
Lymph Nodes ◽  
Simian Immunodeficiency Virus ◽  
Virus Replication ◽  
Target Cells ◽  
Lymphoid Tissues ◽  
Inguinal Lymph Nodes ◽  
Mucosal Surfaces ◽  
Immunodeficiency Virus ◽  
Rna Levels

ABSTRACTThe human immunodeficiency virus (HIV) is primarily transmitted by heterosexual contact, and approximately equal numbers of men and women worldwide are infected with the virus. Understanding the biology of HIV acquisition and dissemination in men exposed to the virus by insertive penile intercourse is likely to help with the rational design of vaccines that can limit or prevent HIV transmission. To characterize the target cells and dissemination pathways involved in establishing systemic simian immunodeficiency virus (SIV) infection, we necropsied male rhesus macaques at 1, 3, 7, and 14 days after penile SIV inoculation and quantified the levels of unspliced SIV RNA and spliced SIV RNA in tissue lysates and the number of SIV RNA-positive cells in tissue sections. We found that penile (glans, foreskin, coronal sulcus) T cells and, to a lesser extent, macrophages and dendritic cells are primary targets of infection and that SIV rapidly reaches the regional lymph nodes. At 7 days after inoculation, SIV had disseminated to the blood, systemic lymph nodes, and mucosal lymphoid tissues. Further, at 7 days postinoculation (p.i.), spliced SIV RNA levels were the highest in the genital lymph nodes, indicating that this is the site where the infection is initially amplified. By 14 days p.i., spliced SIV RNA levels were high in all tissues, but they were the highest in the gastrointestinal tract, indicating that the primary site of virus replication had shifted from the genital lymph nodes to the gut. The stepwise pattern of virus replication and dissemination described here suggests that vaccine-elicited immune responses in the genital lymph nodes could help prevent infection after penile SIV challenge.IMPORTANCETo be the most effective, vaccines should produce antiviral immune responses in the anatomic sites of virus replication. Thus, understanding the path taken by HIV from the mucosal surfaces, which are the site of virus exposure, to the deeper tissues where the virus replicates will provide insight into where AIDS vaccines should produce immunity to be the most effective. In this study, we determined that, by day 7 after penile inoculation, SIV has moved first to the inguinal lymph nodes and replicates to high levels. Although the virus is widely disseminated to other tissues by day 7, replication is largely limited to the inguinal lymph nodes. The step-by-step movement of SIV from penile mucosal surfaces to the draining lymph nodes may allow an HIV vaccine that produces immunity in these lymph nodes to block HIV from establishing an infection in an exposed person.

Dynamic immune responses maintain cytotoxic T lymphocyte epitope mutations in transmitted simian immunodeficiency virus variants

2005 ◽  
Vol 6 (3) ◽  
pp. 247-252 ◽  
Author(s):  
Dan H Barouch ◽  
Jennifer Powers ◽  
Diana M Truitt ◽  
Michael G Kishko ◽  
Janelle C Arthur ◽  
...  
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Immunodeficiency Virus

scholarly journals Common Themes of Antibody Maturation to Simian Immunodeficiency Virus, Simian-Human Immunodeficiency Virus, and Human Immunodeficiency Virus Type 1 Infections

1998 ◽  
Vol 72 (10) ◽  
pp. 7852-7859 ◽  
Author(s):  
Kelly Stefano Cole ◽  
Michael Murphey-Corb ◽  
Opendra Narayan ◽  
Sanjay V. Joag ◽  
George M. Shaw ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Infection ◽  
Simian Immunodeficiency Virus ◽  
Specific Antibody ◽  
Antibody Responses ◽  
Antibody Maturation ◽  
Immunodeficiency Virus ◽  
Virus Specific Antibody ◽  
Hiv 1

ABSTRACT Characterization of virus-specific immune responses to human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) is important to understanding the early virus-host interactions that may determine the course of virus infection and disease. Using a comprehensive panel of serological assays, we have previously demonstrated a complex and lengthy maturation of virus-specific antibody responses elicited by attenuated strains of SIV that was closely associated with the development of protective immunity. In the present study, we expand these analyses to address several questions regarding the nature of the virus-specific antibody responses to pathogenic SIV, SIV/HIV-1 (SHIV), and HIV-1 infections. The results demonstrate for the first time a common theme of antibody maturation to SIV, SHIV, and HIV-1 infections that is characterized by ongoing changes in antibody titer, conformational dependence, and antibody avidity during the first 6 to 10 months following virus infection. We demonstrate that this gradual evolution of virus-specific antibody responses is independent of the levels of virus replication and the pathogenicity of the infection viral strain. While the serological assays used in these studies were useful in discriminating between protective and nonprotective antibody responses during evaluation of vaccine efficacy with attenuated SIV, these same assays do not distinguish the clinical outcome of infection in pathogenic SIV, SHIV, or HIV-1 infections. These results likely reflect differences in the immune mechanisms involved in mediating protection from virus challenge compared to those that control an established viral infection, and they suggest that additional characteristics of both humoral and cellular responses evolve during this early immune maturation.

scholarly journals Multiclade Human Immunodeficiency Virus Type 1 Envelope Immunogens Elicit Broad Cellular and Humoral Immunity in Rhesus Monkeys

2005 ◽  
Vol 79 (5) ◽  
pp. 2956-2963 ◽  
Author(s):  
Michael S. Seaman ◽  
Ling Xu ◽  
Kristin Beaudry ◽  
Kristi L. Martin ◽  
Margaret H. Beddall ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
T Lymphocyte ◽  
Rhesus Monkeys ◽  
Antibody Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The development of a human immunodeficiency virus type 1 (HIV-1) vaccine that elicits potent cellular and humoral immune responses recognizing divergent strains of HIV-1 will be critical for combating the global AIDS epidemic. The present studies were initiated to examine the magnitude and breadth of envelope (Env)-specific T-lymphocyte and antibody responses generated by vaccines containing either a single or multiple genetically distant HIV-1 Env immunogens. Rhesus monkeys were immunized with DNA prime-recombinant adenovirus boost vaccines encoding a Gag-Pol-Nef polyprotein in combination with either a single Env or a mixture of clade-A, clade-B, and clade-C Envs. Monkeys receiving the multiclade Env immunization developed robust immune responses to all vaccine antigens and, importantly, a greater breadth of Env recognition than monkeys immunized with vaccines including a single Env immunogen. All groups of vaccinated monkeys demonstrated equivalent immune protection following challenge with the pathogenic simian-human immunodeficiency virus 89.6P. These data suggest that a multicomponent vaccine encoding Env proteins from multiple clades of HIV-1 can generate broad Env-specific T-lymphocyte and antibody responses without antigenic interference. This study demonstrates that it is possible to generate protective immune responses by vaccination with genetically diverse isolates of HIV-1.

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