scholarly journals Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection

2015 ◽  
Vol 112 (9) ◽  
pp. E992-E999 ◽  
Author(s):  
Timothy R. Fouts ◽  
Kenneth Bagley ◽  
Ilia J. Prado ◽  
Kathryn L. Bobb ◽  
Jennifer A. Schwartz ◽  
...  
Keyword(s):  
T Cell ◽  
Rhesus Macaque ◽  
Humoral Immunity ◽  
T Cell Responses ◽  
Hiv Vaccine ◽  
Single Chain ◽  
Hiv Vaccines ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cellular And Humoral Immunity

A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation.

scholarly journals Pseudovirion Particle Production by Live Poxvirus Human Immunodeficiency Virus Vaccine Vector Enhances Humoral and Cellular Immune Responses

2005 ◽  
Vol 79 (9) ◽  
pp. 5537-5547 ◽  
Author(s):  
Xuemin Chen ◽  
Michael T. Rock ◽  
Jason Hammonds ◽  
James Tartaglia ◽  
Ayumi Shintani ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Immune Responses ◽  
Particle Production ◽  
T Cell Responses ◽  
Particle Formation ◽  
Hiv Vaccine ◽  
Hiv Vaccines ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Live-vector-based human immunodeficiency virus (HIV) vaccines are an integral part of a number of HIV vaccine regimens currently under evaluation. Live vectors that carry an intact gag gene are capable of eliciting HIV pseudovirion particle formation from infected host cells. The impact of pseudovirion particle formation on the immune response generated by live HIV vaccine vectors has not been established. In this study, a canarypox HIV vaccine candidate vector expressing HIV gag and env genes, vCP205, was modified by the introduction of a glycine-to-alanine coding change in the N-terminal myristylation site of gag to create Myr− vCP205. This substitution effectively eliminated particle formation without altering the level of protein production. vCP205 and Myr− vCP205 were then directly compared for the ability to induce HIV-specific immune responses in mice. The particle-competent vector vCP205 elicited higher levels of CD8+ T-cell responses, as indicated by gamma interferon enzyme-linked immunospot (ELISPOT) assay and intracellular cytokine staining. Humoral responses to Gag and Env were also markedly higher from animals immunized with the particle-competent vector. Furthermore, HIV-specific CD4+ T-cell responses were greater among animals immunized with the particle-competent vector. Using a human dendritic cell model of antigen presentation in vitro, vCP205 generated greater ELISPOT responses than Myr− vCP205. These results demonstrate that pseudovirion particle production by live-vector HIV vaccines enhances HIV-specific cellular and humoral immune responses.

scholarly journals Evaluation of Recombinant Influenza Virus-Simian Immunodeficiency Virus Vaccines in Macaques

2009 ◽  
Vol 83 (15) ◽  
pp. 7619-7628 ◽  
Author(s):  
Amy Sexton ◽  
Robert De Rose ◽  
Jeanette C. Reece ◽  
Sheilajen Alcantara ◽  
Liyen Loh ◽  
...  
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Mucosal Immunity ◽  
Influenza A ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Hiv Vaccines ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT There is an urgent need for human immunodeficiency virus (HIV) vaccines that induce robust mucosal immunity. Influenza A viruses (both H1N1 and H3N2) were engineered to express simian immunodeficiency virus (SIV) CD8 T-cell epitopes and evaluated following administration to the respiratory tracts of 11 pigtail macaques. Influenza virus was readily detected from respiratory tract secretions, although the infections were asymptomatic. Animals seroconverted to influenza virus and generated CD8 and CD4 T-cell responses to influenza virus proteins. SIV-specific CD8 T-cell responses bearing the mucosal homing marker β7 integrin were induced by vaccination of naïve animals. Further, SIV-specific CD8 T-cell responses could be boosted by recombinant influenza virus-SIV vaccination of animals with already-established SIV infection. Sequential vaccination with influenza virus-SIV recombinants of different subtypes (H1N1 followed by H3N2 or vice versa) produced only a limited boost in immunity, probably reflecting T-cell immunity to conserved internal proteins of influenza A virus. SIV challenge of macaques vaccinated with an influenza virus expressing a single SIV CD8 T cell resulted in a large anamnestic recall CD8 T-cell response, but immune escape rapidly ensued and there was no impact on chronic SIV viremia. Although our results suggest that influenza virus-HIV vaccines hold promise for the induction of mucosal immunity to HIV, broader antigen cover will be needed to limit cytotoxic T-lymphocyte escape.

scholarly journals HLA-I Associated Adaptation Dampens CD8 T-Cell Responses in HIV Ad5-Vectored Vaccine Recipients

2019 ◽  
Vol 220 (10) ◽  
pp. 1620-1628 ◽  
Author(s):  
Sushma Boppana ◽  
Sarah Sterrett ◽  
Jacob Files ◽  
Kai Qin ◽  
Andrew Fiore-Gartland ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Hiv Vaccine ◽  
Viral Control ◽  
Cell Responses ◽  
Efficacy Trials ◽  
Immunodeficiency Virus ◽  
Vectored Vaccine

Abstract HLA-I–associated human immunodeficiency virus (HIV) adaptation is known to negatively affect disease progression and CD8 T-cell responses. We aimed to assess how HLA-I–associated adaptation affects HIV vaccine–induced CD8 T-cell responses in 2 past vaccine efficacy trials. We found that vaccine-encoded adapted epitopes were less immunogenic than vaccine-encoded nonadapted epitopes, and adapted epitope-specific responses were less polyfunctional than nonadapted epitope-specific responses. Along those lines, vaccine recipients with higher HLA-I adaptation to the Gag vaccine insert mounted less polyfunctional CD8 T-cell responses at the protein level. Breadth of response, which correlated with viral control in recipients who became infected, is also dampened by HLA-I adaptation. These findings suggest that HLA-I–associated adaptation is an important consideration for strategies aiming to induce robust CD8 T-cell responses.

scholarly journals Central Role of Reverting Mutations in HLA Associations with Human Immunodeficiency Virus Set Point

2008 ◽  
Vol 82 (17) ◽  
pp. 8548-8559 ◽  
Author(s):  
Philippa C. Matthews ◽  
Andrew Prendergast ◽  
Alasdair Leslie ◽  
Hayley Crawford ◽  
Rebecca Payne ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Cell Responses ◽  
Hiv Vaccine ◽  
Viral Fitness ◽  
Strongly Correlated ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Selection Of

ABSTRACT Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8+ T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert posttransmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = −0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = −0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.

scholarly journals Cellular and humoral immunity to SARS-CoV-2 infection in multiple sclerosis patients on ocrelizumab and other disease-modifying therapies: a multi-ethnic observational study

2022 ◽  
Author(s):  
Ilya Kister ◽  
Yury Patskovsky ◽  
Ryan Curtin ◽  
Jinglan Pei ◽  
Katherine Perdomo ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Humoral Immunity ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cell Responses ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Cellular And Humoral Immunity ◽  
Multiple Sclerosis Patients

Objective: To determine the impact of MS disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to SARS-CoV-2 infection. Methods: MS patients aged 18-60 were evaluated for anti-nucleocapsid and anti-Spike RBD antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture ELISA; and IL-2 and IFNγ ; ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. Results: Between 1/6/2021 and 7/21/2021, 389 MS patients were recruited (mean age 40.3 years; 74% female; 62% non-White). Most common DMTs were ocrelizumab (OCR) - 40%; natalizumab - 17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. 177 patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, 47 - asymptomatic. Antibody responses were markedly attenuated in OCR compared to other groups (p≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p=0.03), increased in natalizumab (p<0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r=0.45, p=0.0002) and non-OCR (r=0.64, p<0.0001). Immune responses did not differ by race/ethnicity. COVID-19 clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. Interpretation: DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and non-disabled group of MS patients.

scholarly journals A Novel Immunogen Selectively Eliciting CD8+ T Cells but Not CD4+ T Cells Targeting Immunodeficiency Virus Antigens

2020 ◽  
Vol 94 (8) ◽  
Author(s):  
Hiroshi Ishii ◽  
Kazutaka Terahara ◽  
Takushi Nomura ◽  
Akiko Takeda ◽  
Midori Okazaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
T Cell Responses ◽  
Hiv Vaccine ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cell Induction ◽  
Immunogen Design ◽  
Anti Hiv

ABSTRACT Optimization of immunogen is crucial for induction of effective T-cell responses in the development of a human immunodeficiency virus (HIV) vaccine. Conventional T-cell-based vaccines have been designed to induce virus-specific CD4+ T as well as CD8+ T cells. However, it has been indicated that induction of HIV-specific CD4+ T cells, preferential targets for HIV infection, by vaccination may be detrimental and accelerate viral replication after HIV exposure. In the present study, we present a novel immunogen to selectively induce CD8+ T cells but not CD4+ T cells targeting viral antigens. The immunogen, CaV11, was constructed by tandem connection of overlapping 11-mer peptides spanning simian immunodeficiency virus (SIV) Gag capsid (CA) and Vif. Prime-boost immunization with DNA and Sendai virus (SeV) vectors expressing CaV11 efficiently induced Gag/Vif-specific CD8+ T-cell responses with inefficient Gag/Vif-specific CD4+ T-cell induction in rhesus macaques (n = 6). None of the macaques exhibited the enhancement of acute viral replication after an intravenous high-dose SIV challenge, which was observed in those immunized with DNA and SeV expressing the whole Gag protein in our previous study. Set point viral control postinfection was associated with SeV-specific CD4+ T-cell responses postimmunization, suggesting contribution of SeV-specific helper responses to effective Gag/Vif-specific CD8+ T-cell induction by vaccination. This immunogen design could be a promising method for selective induction of effective anti-HIV CD8+ T-cell responses. IMPORTANCE Induction of effective CD8+ T-cell responses is an important HIV vaccine strategy. Several promising vaccine delivery tools have been developed, and immunogen optimization is now crucial for effective T-cell induction. Conventional immunogens have been designed to induce virus-specific CD4+ T cells as well as CD8+ T cells, but induction of virus-specific CD4+ T cells that are preferential targets for HIV infection could enhance acute HIV proliferation. Here, we designed a novel immunogen to induce HIV-specific CD8+ T cells without HIV-specific CD4+ T-cell induction but with non-HIV antigen-specific CD4+ T-cell help. Our analysis in a macaque AIDS model showed that our immunogen can efficiently elicit effective CD8+ T but not CD4+ T cells targeting viral antigens, resulting in no enhancement of acute viral replication after virus exposure. This immunogen design, also applicable for other currently developed immunogens, could be a promising method for selective induction of effective anti-HIV CD8+ T-cell responses.

scholarly journals Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive elderly

2021 ◽  
Author(s):  
Addi Romero Olmedo ◽  
Axel Schulz ◽  
Svenja Hochstäter ◽  
Dennis DasGupta ◽  
Iiris Virta ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Humoral Immunity ◽  
Specific Antibody ◽  
T Cell Responses ◽  
The Elderly ◽  
Cell Responses ◽  
Cellular And Humoral Immunity

Abstract Herein, we compared SARS-CoV-2-specific antibody and T-cell responses to two doses of BNT162b2 mRNA in 51 vaccinees > 80 years old and 46 (20–53 years old) controls. The responses of the elderly were much lower and 10% non-responders were identified. Importantly, in four of them, a third vaccination raised the immune response to levels seen in responders after two vaccinations, thus implying that non-response is not fateful even in the elderly.

scholarly journals Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy

2019 ◽  
Vol 11 (519) ◽  
pp. eaav1800 ◽  
Author(s):  
Venkateswarlu Chamcha ◽  
Pradeep B. J. Reddy ◽  
Sunil Kannanganat ◽  
Courtney Wilkins ◽  
Sailaja Gangadhara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Efficacy ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Hiv Vaccine ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv Acquisition

Activated CD4 T cells are a major target of HIV infection. Results from the STEP HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced interferon γ (IFNγ+) CD4 T cells [T helper 1 (TH1) cells] rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal TH1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. After intravaginal or intrarectal simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV) challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific TH1 cells but not in animals that had higher frequencies of TH1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer TH1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine–induced TH1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.

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