scholarly journals Long-term protective immunity induced by an adjuvant-containing live-attenuated AIDS virus

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Tomotaka Okamura ◽  
Yuya Shimizu ◽  
Masamitsu N. Asaka ◽  
Tomohiro Kanuma ◽  
Yusuke Tsujimura ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Immune Responses ◽  
Protective Immunity ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Aids Virus ◽  
Cynomolgus Macaques ◽  
Cd8 Depletion

AbstractThe use of an adjuvant in vaccination is thought to be effective for enhancing immune responses to various pathogens. We genetically constructed a live attenuated simian human immunodeficiency virus (SHIV) to express the adjuvant molecule Ag85B (SHIV-Ag85B). SHIV-Ag85B could not be detected 4 weeks after injection in cynomolgus macaques, and strong SHIV-specific T cell responses were induced in these macaques. When the macaques in which SHIV-Ag85B had become undetectable were challenged with pathogenic SHIV89.6P at 37 weeks after SHIV-Ag85B had become undetectable, SHIV89.6P was not detected after the challenge. Eradication of SHIV89.6P was confirmed by adoptive transfer experiments and CD8-depletion studies. The SHIV-Ag85B-inoculated macaques showed enhancement of Gag-specific monofunctional and polyfunctional CD8+ T cells in the acute phase of the pathogenic SHIV challenge. The results suggest that SHIV-Ag85B elicited strong sterile immune responses against pathogenic SHIV and that it may lead to the development of a vaccine for AIDS virus infection.

scholarly journals Long-term sterile immunity induced by an adjuvant-containing live-attenuated AIDS virus

2020 ◽  
Author(s):  
Tomotaka Okamura ◽  
Yuya Shimizu ◽  
Tomohiro Kanuma ◽  
Yusuke Tsujimura ◽  
Masamitsu N Asaka ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cell Responses ◽  
Aids Epidemic ◽  
Immunodeficiency Virus ◽  
Aids Virus ◽  
Cynomolgus Macaques ◽  
Cd8 Depletion

AbstractAntigen 85B (Ag85B) is one of the most dominant proteins secreted from most mycobacterial species, and it induces Th1-type immune responses as an adjuvant. We genetically constructed a live attenuated simian human immunodeficiency virus to express the adjuvant molecule Ag85B (SHIV-Ag85B). SHIV-Ag85B could not be detected 4 weeks after injection in cynomolgus macaques, and strong SHIV-specific T cell responses were induced in these macaques. When these macaques in which SHIV-Ag85B had become undetectable were challenged with pathogenic SHIV89.6P at 37 weeks after SHIV-Ag85B became undetectable, SHIV89.6P could not be detected after the challenge. Eradication of SHIV89.6P was confirmed by adoptive transfer experiments and CD8-depletion studies. The SHIV-Ag85B-inoculated macaques showed enhancement of Gag-specific monofunctional and polyfunctional CD8+ T cells in the acute phase of pathogenic SHIV challenge. The results suggest that SHIV-Ag85B elicited strong sterile immune responses against pathogenic SHIV and that it may lead to the development of a vaccine for AIDS virus infection.ImportanceDevelopment of an effective HIV vaccine has been a major priority to control the worldwide AIDS epidemic. The moderately attenuated prototypic vaccine strain SIVmac239Δnef has been used in various studies; however, it does not provide sufficient effects to prevent infection. The use of adjuvant in vaccination is thought to be useful for enhancing the immune responses to various pathogens. In the present study, we constructed a live attenuated SHIV virus expressing adjuvant molecule Ag85B and assessed vaccine effects in cynomolgus macaques. The present study shows that live-attenuated SHIV expressing Ag85B elicits viral antigen-specific polyfunctional CD8+ T cell responses against pathogenic SHIV and provide the possibility of eradicating a pathogenic lentivirus from infected animals.

scholarly journals Dynamics of T-Cell Responses and Memory T Cells during Primary Simian Immunodeficiency Virus Infection in Cynomolgus Macaques

2007 ◽  
Vol 81 (24) ◽  
pp. 13456-13468 ◽  
Author(s):  
Ingrid Karlsson ◽  
Benoît Malleret ◽  
Patricia Brochard ◽  
Benoît Delache ◽  
Julien Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Peripheral Blood ◽  
Primary Infection ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Cynomolgus Macaques ◽  
Cellular Immune

ABSTRACT Cellular immune responses make an important contribution to both the control of human immunodeficiency virus (HIV) replication and disease progression. We used a pathogenic model of SIVmac251 infection of cynomolgus macaques to longitudinally evaluate cellular immune responses in association with various rates of disease progression. We found an inverse relationship between plasma viral load and the simian immunodeficiency virus (SIV)-specific T cells responses in peripheral blood and lymph nodes. SIV-specific T-cell responses in peripheral blood were transient during primary infection, with the highest responses detected around 3 months after infection. There was also a transient increase of central memory CD8+ T cells in peripheral blood during primary infection, and effector memory T-cell counts in peripheral lymph nodes were increased. This study emphasizes the importance of the early virus-specific immune responses in the outcome of HIV/SIV disease and provides details about the changes of virus-specific immune responses over time.

scholarly journals Utility of Human Immunodeficiency Virus Type 1 Envelope as a T-Cell Immunogen

2007 ◽  
Vol 81 (23) ◽  
pp. 13125-13134 ◽  
Author(s):  
Viv Peut ◽  
Stephen J. Kent
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Viral Escape ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV)-specific CD8 T lymphocytes are important for the control of viremia, but the relative utility of responses to the various HIV proteins is controversial. Immune responses that force escape mutations that exact a significant fitness cost from the mutating virus would help slow progression to AIDS. The HIV envelope (Env) protein is subject to both humoral and cellular immune responses, suggesting that multiple rounds of mutation are needed to facilitate viral escape. The Gag protein, however, has recently been shown to elicit a more effective CD8 T-cell immune response in humans. We studied 30 pigtail macaques for their CD8 T-lymphocyte responses to HIV-1 Env and simian immunodeficiency virus (SIV) Gag following prime/boost vaccination and intrarectal challenge with simian-human immunodeficiency virus SHIVmn229. Eight CD8 Env-specific T-cell epitopes were identified and mapped in 10 animals. Animals that generated Env-specific CD8 T-cell responses had equivalent viral loads and only a modest advantage in retention of peripheral CD4 T lymphocytes compared to those animals without responses to Env. This contrasts with animals that generated CD8 T-cell responses to SIV Gag in the same trial, demonstrating superior control of viral load and a larger advantage in retention of peripheral CD4 T cells than Gag nonresponders. Mutational escape was common in Env but, in contrast to mutations in Gag, did not result in the rapid emergence of dominant escape motifs, suggesting modest selective pressure from Env-specific T cells. These results suggest that Env may have limited utility as a CD8 T-cell immunogen.

scholarly journals Aviremia 10 Years Postdiscontinuation of Antiretroviral Therapy Initiated During Primary Human Immunodeficiency Virus-1 Infection and Association With Gag-Specific T-Cell Responses

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Sabine Kinloch-de Loes ◽  
Lucy Dorrell ◽  
Hongbing Yang ◽  
Gareth A. D. Hardy ◽  
Sabine Yerly ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Viral Reservoir ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Drug Free ◽  
Human Immunodeficiency Virus 1

Abstract Combination antiretroviral therapy during primary human immunodeficiency virus-1 infection may enable long-term drug-free virological control in rare individuals. We describe a female who maintained aviremia and a normal CD4+/CD8+ T cell ratio for 10 years after stopping therapy, despite a persistent viral reservoir. Cellular immune responses may have contributed to this outcome.

scholarly journals Viral Suppression and Immune Restoration in the Gastrointestinal Mucosa of Human Immunodeficiency Virus Type 1-Infected Patients Initiating Therapy during Primary or Chronic Infection

2006 ◽  
Vol 80 (16) ◽  
pp. 8236-8247 ◽  
Author(s):  
Moraima Guadalupe ◽  
Sumathi Sankaran ◽  
Michael D. George ◽  
Elizabeth Reay ◽  
David Verhoeven ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Microarray Analysis ◽  
Dna Microarray ◽  
Peripheral Blood ◽  
Viral Suppression ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11α, αEβ7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.

scholarly journals Cell-mediated immune responses in healthy children with a history of subclinical infection with Japanese encephalitis virus: analysis of CD4+ and CD8+ T cell target specificities by intracellular delivery of viral proteins using the human immunodeficiency virus Tat protein transduction domain

2004 ◽  
Vol 85 (2) ◽  
pp. 471-482 ◽  
Author(s):  
Priti Kumar ◽  
Venkatramana D. Krishna ◽  
Paramadevanapalli Sulochana ◽  
Gejjehalli Nirmala ◽  
Maganti Haridattatreya ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Encephalitis Virus ◽  
Structural Proteins ◽  
Healthy Children ◽  
Immunodeficiency Virus

Japanese encephalitis virus (JEV), a single-stranded positive-sense RNA virus of the family Flaviviridae, is the major cause of paediatric encephalitis in Asia. The high incidence of subclinical infections in Japanese encephalitis-endemic areas and subsequent evasion of encephalitis points to the development of immune responses against JEV. Humoral responses play a central role in protection against JEV; however, cell-mediated immune responses contributing to this end are not fully understood. The structural envelope (E) protein, the major inducer of neutralizing antibodies, is a poor target for T cells in natural JEV infections. The extent to which JEV non-structural proteins are targeted by T cells in subclinically infected healthy children would help to elucidate the role of cell-mediated immunity in protection against JEV as well as other flaviviral infections. The property of the Tat peptide of Human immunodeficiency virus to transduce proteins across cell membranes, facilitating intracellular protein delivery following exogenous addition to cultured cells, prompted us to express the four largest proteins of JEV, comprising 71 % of the JEV genome coding sequence, as Tat fusions for enumerating the frequencies of virus-specific CD4+ and CD8+ T cells in JEV-immune donors. At least two epitopes recognized by distinct HLA alleles were found on each of the non-structural proteins, with dominant antiviral Th1 T cell responses to the NS3 protein in nearly 96 % of the cohort. The data presented here show that non-structural proteins are frequently targeted by T cells in natural JEV infections and may be efficacious supplements for the predominantly antibody-eliciting E-based JEV vaccines.

scholarly journals Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

2015 ◽  
Vol 89 (7) ◽  
pp. 3542-3556 ◽  
Author(s):  
Timothée Bruel ◽  
Chiraz Hamimi ◽  
Nathalie Dereuddre-Bosquet ◽  
Antonio Cosma ◽  
So Youn Shin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Cell Responses ◽  
Cell Depletion ◽  
Viral Control ◽  
Cell Responses ◽  
Cynomolgus Macaques ◽  
Hiv 1

ABSTRACTThe spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8+T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8+T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8+T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8+T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8+T cells that lacked efficient SIV suppression capacityex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4+T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8+cell depletion and inducible SIV replication from its CD4+T cellsin vitro. Altogether, our results suggest that CD8+T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control.IMPORTANCESpontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8+T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8+T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8+cells induced a rise in the viral load. However, viremia was correlated with CD4+T-cell activation subsequent to CD8+cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8+T cells. Our results suggest that CD8+T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.

scholarly journals Induction of Potent CD8+ T-Cell Responses by Novel Biodegradable Nanoparticles Carrying Human Immunodeficiency Virus Type 1 gp120

2007 ◽  
Vol 81 (18) ◽  
pp. 10009-10016 ◽  
Author(s):  
Xin Wang ◽  
Tomofumi Uto ◽  
Takami Akagi ◽  
Mitsuru Akashi ◽  
Masanori Baba
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Memory T Cells ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The mainstream of recent anti-AIDS vaccines is a prime/boost approach with multiple doses of the target DNA of human immunodeficiency virus type 1 (HIV-1) and recombinant viral vectors. In this study, we have attempted to construct an efficient protein-based vaccine using biodegradable poly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs), which are capable of inducing potent cellular immunity. A significant expansion of CD8+ T cells specific to the major histocompatibility complex class I-restricted gp120 epitope was observed in mice intranasally immunized once with gp120-carrying NPs but not with gp120 alone or gp120 together with the B-subunit of cholera toxin. Both the gp120-encapsulating and -immobilizing forms of NPs could induce antigen-specific spleen CD8+ T cells having a functional profile of cytotoxic T lymphocytes. Long-lived memory CD8+ T cells could also be elicited. Although a substantial decay in the effector memory T cells was observed over time in the immunized mice, the central memory T cells remained relatively constant from day 30 to day 238 after immunization. Furthermore, the memory CD8+ T cells rapidly expanded with boosting with the same immunogen. In addition, γ-PGA NPs were found to be a much stronger inducer of antigen-specific CD8+ T-cell responses than nonbiodegradable polystyrene NPs. Thus, γ-PGA NPs carrying various HIV-1 antigens may have great potential as a novel priming and/or boosting tool in current vaccination regimens for the induction of cellular immune responses.

scholarly journals Reduction of Retrovirus-Induced Immunosuppression by In Vivo Modulation of T Cells during Acute Infection

2004 ◽  
Vol 78 (21) ◽  
pp. 11641-11647 ◽  
Author(s):  
Hong He ◽  
Ronald J. Messer ◽  
Shimon Sakaguchi ◽  
Guojun Yang ◽  
Shelly J. Robertson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Acute Infection ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Responses ◽  
Th1 Immune Responses ◽  
Necrosis Factor

ABSTRACT Chronic infection with Friend retrovirus is associated with suppressed antitumor immune responses. In the present study we investigated whether modulation of T-cell responses during acute infection would restore antitumor immunity in persistently infected mice. T-cell modulation was done by treatments with DTA-1 anti- glucocorticoid-induced tumor necrosis factor receptor monoclonal antibodies. The DTA-1 monoclonal antibody is nondepleting and delivers costimulatory signals that both enhance the activation of effector T cells and inhibit suppression by regulatory T cells. DTA-1 therapy produced faster Th1 immune responses, significant reductions in both acute virus loads and pathology and, most importantly, long-term improvement of CD8+ T-cell-mediated antitumor responses.

scholarly journals Initial B-Cell Responses to Transmitted Human Immunodeficiency Virus Type 1: Virion-Binding Immunoglobulin M (IgM) and IgG Antibodies Followed by Plasma Anti-gp41 Antibodies with Ineffective Control of Initial Viremia

2008 ◽  
Vol 82 (24) ◽  
pp. 12449-12463 ◽  
Author(s):  
Georgia D. Tomaras ◽  
Nicole L. Yates ◽  
Pinghuang Liu ◽  
Li Qin ◽  
Genevieve G. Fouda ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
B Cell ◽  
Human Immunodeficiency Virus Type ◽  
Igg Antibodies ◽  
Plasma Virus ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1) exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus), but, to date, this period has been logistically difficult to analyze. To probe B-cell responses immediately following HIV-1 transmission, we have determined envelope-specific antibody responses to autologous and consensus Envs in plasma donors from the United States for whom frequent plasma samples were available at time points immediately before, during, and after HIV-1 plasma viral load (VL) ramp-up in acute infection, and we have modeled the antibody effect on the kinetics of plasma viremia. The first detectable B-cell response was in the form of immune complexes 8 days after plasma virus detection, whereas the first free plasma anti-HIV-1 antibody was to gp41 and appeared 13 days after the appearance of plasma virus. In contrast, envelope gp120-specific antibodies were delayed an additional 14 days. Mathematical modeling of the earliest viral dynamics was performed to determine the impact of antibody on HIV replication in vivo as assessed by plasma VL. Including the initial anti-gp41 immunoglobulin G (IgG), IgM, or both responses in the model did not significantly impact the early dynamics of plasma VL. These results demonstrate that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.

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