Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8+and CD4+Cell Responses

AbstractMultiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV. In this study, an alternative replication-defective flavivirus vector, RepliVax (RV), was evaluated for the delivery of HIV-1 immunogens. Recombinant RV-HIV viruses were engineered to stably express clade C virus Gag and Env (gp120TM) proteins and propagated in Vero helper cells. RV-based vectors enabled efficient expression and correct maturation of Gag and gp120TM proteins, were apathogenic in a sensitive suckling mouse neurovirulence test, and were similar in immunogenicity to recombinant poxvirus NYVAC-HIV vectors in homologous or heterologous prime-boost combinations in mice. In a pilot NHP study, immunogenicity of RV-HIV viruses used as a prime or boost for DNA or NYVAC candidates was compared to a DNA prime/NYVAC boost benchmark scheme when administered together with adjuvanted gp120 protein. Similar neutralizing antibody titers, binding IgG titers measured against a broad panel of Env and Gag antigens, and ADCC responses were observed in the groups throughout the course of the study, and T cell responses were elicited. The entire data demonstrate that RV vectors have the potential as novel HIV-1 vaccine components for use in combination with other promising candidates to develop new effective vaccination strategies.

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HIV-1 clade C infection and progressive disruption in the relationship between cortisol, DHEAS and CD4 cell numbers: A two-year follow-up study

Clinica Chimica Acta ◽

10.1016/j.cca.2009.06.032 ◽

2009 ◽

Vol 409 (1-2) ◽

pp. 4-10 ◽

Cited By ~ 18

Author(s):

Seetharamaiah Chittiprol ◽

Adarsh M. Kumar ◽

K. Taranath Shetty ◽

H. Ravi Kumar ◽

P. Satishchandra ◽

...

Keyword(s):

Cell Numbers ◽

Follow Up Study ◽

Clade C ◽

Cd4 Cell ◽

The Relationship ◽

Hiv 1

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HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+ Gag-Specific CD4+ T Cells in Chronic Clade C HIV-1 Infection

Journal of Virology ◽

10.1128/jvi.02477-16 ◽

2017 ◽

Vol 91 (7) ◽

Cited By ~ 10

Author(s):

Faatima Laher ◽

Srinika Ranasinghe ◽

Filippos Porichis ◽

Nikoshia Mewalal ◽

Karyn Pretorius ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Single Class ◽

Cell Responses ◽

Clade C ◽

Hiv Controllers ◽

Hiv 1

ABSTRACT Immune control of viral infections is heavily dependent on helper CD4+ T cell function. However, the understanding of the contribution of HIV-specific CD4+ T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4+ T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4+ T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4+ T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4+ T cells in HIV controllers than progressors (P = 0.0001), and these expanded Gag-specific CD4+ T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control (r = −0.5, P = 0.02). These data identify an association between HIV-specific CD4+ T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4+ T cell responses in natural infections. IMPORTANCE Increasing evidence suggests that virus-specific CD4+ T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4+ T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV infections worldwide. Understanding the contribution of HIV-specific CD4+ T cell responses in clade C infection is particularly important for developing vaccines that would be efficacious in sub-Saharan Africa, where clade C infection is dominant. Here, we employed MHC class II tetramers designed to immunodominant Gag epitopes and used them to characterize CD4+ T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4+ T cell responses targeting an immunodominant DRB1*11-Gag41 complex and HIV control, highlighting the important contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infections.

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TLR-9 agonist and CD40-targeting vaccination induces HIV-1 envelope-specific B cells with a diversified immunoglobulin repertoire in humanized mice

PLoS Pathogens ◽

10.1371/journal.ppat.1009025 ◽

2020 ◽

Vol 16 (11) ◽

pp. e1009025

Author(s):

Véronique Godot ◽

Colas Tcherakian ◽

Laurine Gil ◽

Iñaki Cervera-Marzal ◽

Guangming Li ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Humanized Mice ◽

Hematopoietic Stem ◽

Cell Responses ◽

Clade C ◽

Specific Igg ◽

B Cell Responses ◽

Hiv 1 ◽

Human B Cell

The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to efficiently transition from IgM B cells to IgG B cells. Here, we found that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mice. We further dissected hu-B cell responses directed against the HIV-1 Env protein elicited by targeting Env gp140 clade C to the CD40 receptor of antigen-presenting cells. The anti-CD40.Env gp140 vaccine was injected with CpG-B in a homologous prime/boost regimen or as a boost of a NYVAC-KC pox vector encoding Env gp140 clade C. Both regimens elicited Env-specific IgG-switched memory hu-B cells at a greater magnitude in hu-mice primed with NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific hu-B cells to express polyclonal IgG1 and IgG3 isotypes and a broad Ig VH/VL repertoire, with predominant VH3 family gene usage. These cells exhibited a higher rate of somatic hypermutation than the non-specific IgG+ hu-B-cell counterpart. Both vaccine regimens induced splenic GC-like structures containing hu-B and hu-Tfh-like cells expressing PD-1 and BCL-6. We confirmed in this model that circulating ICOS+ memory hu-Tfh cells correlated with the magnitude of gp140-specific B-cell responses. Finally, the NYVAC-KC heterologous prime led to a more diverse clonal expansion of specific hu-B cells. Thus, this study shows that CD40-targeted vaccination induces human IgG production in hu-mice and provides insights for the development of a CD40-targeting vaccine to prevent HIV-1 infection in humans.

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Faculty Opinions recommendation of An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1100117.793495233 ◽

2014 ◽

Author(s):

Angus Dalgleish

Keyword(s):

T Cell ◽

T Cell Responses ◽

Vaccine Regimen ◽

Cell Responses ◽

Clade C ◽

Boost Vaccine ◽

Hiv 1

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An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses

Journal of Experimental Medicine ◽

10.1084/jem.20071331 ◽

2008 ◽

Vol 205 (1) ◽

pp. 63-77 ◽

Cited By ~ 217

Author(s):

Alexandre Harari ◽

Pierre-Alexandre Bart ◽

Wolfgang Stöhr ◽

Gonzalo Tapia ◽

Miguel Garcia ◽

...

Keyword(s):

T Cell ◽

Mononuclear Cells ◽

Recombinant Dna ◽

T Cell Responses ◽

Interferon Γ ◽

Vaccine Regimen ◽

Cell Responses ◽

Clade C ◽

Boost Vaccine ◽

Hiv 1

The EuroVacc 02 phase I trial has evaluated the safety and immunogenicity of a prime-boost regimen comprising recombinant DNA and the poxvirus vector NYVAC, both expressing a common immunogen consisting of Env, Gag, Pol, and Nef polypeptide domain from human immunodeficiency virus (HIV)-1 clade C isolate, CN54. 40 volunteers were randomized to receive DNA C or nothing on day 0 and at week 4, followed by NYVAC C at weeks 20 and 24. The primary immunogenicity endpoints were measured at weeks 26 and 28 by the quantification of T cell responses using the interferon γ enzyme-linked immunospot assay. Our results indicate that the DNA C plus NYVAC C vaccine regimen was highly immunogenic, as indicated by the detection of T cell responses in 90% of vaccinees and was superior to responses induced by NYVAC C alone (33% of responders). The vaccine-induced T cell responses were (a) vigorous in the case of the env response (mean 480 spot-forming units/106 mononuclear cells at weeks 26/28), (b) polyfunctional for both CD4 and CD8 T cell responses, (c) broad (the average number of epitopes was 4.2 per responder), and (d) durable (T cell responses were present in 70% of vaccinees at week 72). The vaccine-induced T cell responses were strongest and most frequently directed against Env (91% of vaccines), but smaller responses against Gag-Pol-Nef were also observed in 48% of vaccinees. These results support the development of the poxvirus platform in the HIV vaccine field and the further clinical development of the DNA C plus NYVAC C vaccine regimen.

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A DNA-Based Candidate HIV Vaccine Delivered viaIn VivoElectroporation Induces CD4 Responses toward the α4β7-Binding V2 Loop of HIV gp120 in Healthy Volunteers

Clinical and Vaccine Immunology ◽

10.1128/cvi.00327-12 ◽

2012 ◽

Vol 19 (9) ◽

pp. 1557-1559 ◽

Cited By ~ 26

Author(s):

Jakub Kopycinski ◽

Hannah Cheeseman ◽

Ambreen Ashraf ◽

Dilbinder Gill ◽

Peter Hayes ◽

...

Keyword(s):

Healthy Volunteers ◽

Dna Vaccine ◽

Hiv Vaccine ◽

Vaccine Regimen ◽

Cell Responses ◽

Clade C ◽

Vectored Vaccine ◽

Hiv Gp120 ◽

Hiv 1

ABSTRACTAdministration of a clade C/B′ candidate HIV-1 DNA vaccine, ADVAX, byin vivoelectroporation (EP) was safe and more immunogenic than intramuscular administration without EP. The breadth and specificity of T-cell responses to full-length Env were mapped. Responses to multiple Env regions were induced, with most focusing on V3/C4 and V2 regions, including the α4β7 integrin-binding domain. The breadth of responses induced by this DNA vaccine regimen was comparable to that of viral-vectored vaccine regimens.

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Amplification of T-cell responses in DNA-based immunization with HIV-1 Nef by coinjection with a GM-CSF expression vector

Immunology Letters ◽

10.1016/s0165-2478(97)88025-x ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 294-295

Author(s):

C Svanholm

Keyword(s):

T Cell ◽

Expression Vector ◽

T Cell Responses ◽

Gm Csf ◽

Cell Responses ◽

Hiv 1

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Faculty Opinions recommendation of A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717972955.793495235 ◽

2014 ◽

Author(s):

Angus Dalgleish

Keyword(s):

T Cell ◽

Dendritic Cell ◽

T Cell Responses ◽

Cell Responses ◽

Hiv 1 ◽

Dendritic Cell Based Vaccine

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Polyfunctional CD8+ T-Cell Response to Autologous Peptides from Protease and Reverse Transcriptase of HIV-1 Clade B

Current HIV Research ◽

10.2174/1570162x17666191017105910 ◽

2019 ◽

Vol 17 (5) ◽

pp. 350-359

Author(s):

Liliana Acevedo-Saenz ◽

Federico Perdomo-Celis ◽

Carlos J. Montoya ◽

Paula A. Velilla

Keyword(s):

T Cell ◽

Reverse Transcriptase ◽

Cellular Response ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Effective Vaccine ◽

Cell Responses ◽

Clade B ◽

Hiv 1

Background: : The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective:: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods:: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results:: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion:: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

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