Research

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20 pages, 2519 KiB

Open AccessArticle

Induction of Tier 1 HIV Neutralizing Antibodies by Envelope Trimers Incorporated into a Replication Competent Vesicular Stomatitis Virus Vector

by C. Anika Bresk, Tamara Hofer, Sarah Wilmschen, Marina Krismer, Anja Beierfuß, Grégory Effantin, Winfried Weissenhorn, Michael J. Hogan, Andrea P. O. Jordan, Rebecca S. Gelman, David C. Montefiori, Hua-Xin Liao, Joern E. Schmitz, Barton F. Haynes, Dorothee von Laer and Janine Kimpel

Viruses 2019, 11(2), 159; https://doi.org/10.3390/v11020159 - 15 Feb 2019

Cited by 12 | Viewed by 5602

Abstract

A chimeric vesicular stomatitis virus with the glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, is a potent viral vaccine vector that overcomes several of the limitations of wild-type VSV. Here, we evaluated the potential of VSV-GP as an HIV vaccine vector. We introduced [...] Read more.

A chimeric vesicular stomatitis virus with the glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, is a potent viral vaccine vector that overcomes several of the limitations of wild-type VSV. Here, we evaluated the potential of VSV-GP as an HIV vaccine vector. We introduced genes for different variants of the HIV-1 envelope protein Env, i.e., secreted or membrane-anchored, intact or mutated furin cleavage site or different C-termini, into the genome of VSV-GP. We found that the addition of the Env antigen did not attenuate VSV-GP replication. All HIV-1 Env variants were expressed in VSV-GP infected cells and some were incorporated very efficiently into VSV-GP particles. Crucial epitopes for binding of broadly neutralizing antibodies against HIV-1 such as MPER (membrane-proximal external region), CD4 binding site, V1V2 and V3 loop were present on the surface of VSV-GP-Env particles. Binding of quaternary antibodies indicated a trimeric structure of VSV-GP incorporated Env. We detected high HIV-1 antibody titers in mice and showed that vectors expressing membrane-anchored Env elicited higher antibody titers than vectors that secreted Envs. In rabbits, Tier 1A HIV-1 neutralizing antibodies were detectable after prime immunization and titers further increased after boosting with a second immunization. Taken together, VSV-GP-Env is a promising vector vaccine against HIV-1 infection since this vector permits incorporation of native monomeric and/or trimeric HIV-1 Env into a viral membrane. Full article

(This article belongs to the Special Issue HIV Vaccines)

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23 pages, 3542 KiB

Open AccessArticle

Potent HIV-1-Specific CD8 T Cell Responses Induced in Mice after Priming with a Multiepitopic DNA-TMEP and Boosting with the HIV Vaccine MVA-B

by Beatriz Perdiguero, Suresh C. Raman, Cristina Sánchez-Corzo, Carlos Oscar S. Sorzano, José Ramón Valverde, Mariano Esteban and Carmen Elena Gómez

Viruses 2018, 10(8), 424; https://doi.org/10.3390/v10080424 - 13 Aug 2018

Cited by 9 | Viewed by 3656

Abstract

An effective vaccine against Human Immunodeficiency Virus (HIV) still remains the best solution to provide a sustainable control and/or eradication of the virus. We have previously generated the HIV-1 vaccine modified vaccinia virus Ankara (MVA)-B, which exhibited good immunogenicity profile in phase I [...] Read more.

An effective vaccine against Human Immunodeficiency Virus (HIV) still remains the best solution to provide a sustainable control and/or eradication of the virus. We have previously generated the HIV-1 vaccine modified vaccinia virus Ankara (MVA)-B, which exhibited good immunogenicity profile in phase I prophylactic and therapeutic clinical trials, but was unable to prevent viral rebound after antiretroviral (ART) removal. To potentiate the immunogenicity of MVA-B, here we described the design and immune responses elicited in mice by a new T cell multi-epitopic B (TMEP-B) immunogen, vectored by DNA, when administered in homologous or heterologous prime/boost regimens in combination with MVA-B. The TMEP-B protein contained conserved regions from Gag, Pol, and Nef proteins including multiple CD4 and CD8 T cell epitopes functionally associated with HIV control. Heterologous DNA-TMEP/MVA-B regimen induced higher HIV-1-specific CD8 T cell responses with broader epitope recognition and higher polyfunctional profile than the homologous DNA-TMEP/DNA-TMEP or the heterologous DNA-GPN/MVA-B combinations. Moreover, higher HIV-1-specific CD4 and Tfh immune responses were also detected using this regimen. After MVA-B boost, the magnitude of the anti-VACV CD8 T cell response was significantly compromised in DNA-TMEP-primed animals. Our results revealed the immunological potential of DNA-TMEP prime/MVA-B boost regimen and supported the application of these combined vectors in HIV-1 prevention and/or therapy. Full article

(This article belongs to the Special Issue HIV Vaccines)

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14 pages, 11641 KiB

Open AccessArticle

Gp120 V5 Is Targeted by the First Wave of Sequential Neutralizing Antibodies in SHIV_SF162P3N-Infected Rhesus Macaques

by Manxue Jia, Hong Lu, Xiang-Peng Kong, Cecilia Cheng-Mayer and Xueling Wu

Viruses 2018, 10(5), 262; https://doi.org/10.3390/v10050262 - 16 May 2018

Cited by 2 | Viewed by 2843

Abstract

Simian-human immunodeficiency virus (SHIV) infection provides a relevant animal model to study HIV-1 neutralization breadth. With previously identified SHIV_SF162P3N infected rhesus macaques that did or did not develop neutralization breadth, we characterized the transmitted/founder viruses and initial autologous/homologous neutralizing antibodies in these [...] Read more.

Simian-human immunodeficiency virus (SHIV) infection provides a relevant animal model to study HIV-1 neutralization breadth. With previously identified SHIV_SF162P3N infected rhesus macaques that did or did not develop neutralization breadth, we characterized the transmitted/founder viruses and initial autologous/homologous neutralizing antibodies in these animals. The plasma viral load and blood CD4 count did not distinguish macaques with and without breadth, and only one tested homologous envelope clone revealed a trend for macaques with breadth to favor an early homologous response. In two macaques with breadth, GB40 and FF69, infected with uncloned SHIV_SF162P3N, multiple viral variants were transmitted, and the transmitted variants were not equal in neutralization sensitivity. The targets of initial autologous neutralizing antibodies, arising between 10 and 20 weeks post infection, were mapped to N462 glycan and G460a in gp120 V5 in GB40 and FF69, respectively. Although it is unclear whether these targets are related to later neutralization breadth development, the G460a target but not N462 glycan appeared more common in macaques with breadth than those without. Longitudinal plasmas revealed 2–3 sequential waves of neutralizing antibodies in macaques with breadth, implicating that 3 sequential envelope variants, if not more, may be required for the broadening of HIV-1 neutralizing antibodies. Full article

(This article belongs to the Special Issue HIV Vaccines)

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2959 KiB

Open AccessArticle

Immune Modulation of NYVAC-Based HIV Vaccines by Combined Deletion of Viral Genes that Act on Several Signalling Pathways

by Carmen Elena Gómez, Beatriz Perdiguero, Cristina Sánchez-Corzo, Carlos Oscar S. Sorzano and Mariano Esteban

Viruses 2018, 10(1), 7; https://doi.org/10.3390/v10010007 - 27 Dec 2017

Cited by 6 | Viewed by 3709

Abstract

An HIV-1 vaccine continues to be a major target to halt the AIDS pandemic. The limited efficacy of the RV144 phase III clinical trial with the canarypox virus-based vector ALVAC and a gp120 protein component led to the conclusion that improved immune responses [...] Read more.

An HIV-1 vaccine continues to be a major target to halt the AIDS pandemic. The limited efficacy of the RV144 phase III clinical trial with the canarypox virus-based vector ALVAC and a gp120 protein component led to the conclusion that improved immune responses to HIV antigens are needed for a more effective vaccine. In non-human primates, the New York vaccinia virus (NYVAC) poxvirus vector has a broader immunogenicity profile than ALVAC and has been tested in clinical trials. We therefore analysed the HIV immune advantage of NYVAC after removing viral genes that act on several signalling pathways (Toll-like receptors—TLR—interferon, cytokines/chemokines), as well as genes of unknown immune function. We generated a series of NYVAC deletion mutants and studied immune behaviour (T and B cell) to HIV antigens and to the NYVAC vector in mice. Our results showed that combined deletion of selected vaccinia virus (VACV) genes is a valuable strategy for improving the immunogenicity of NYVAC-based vaccine candidates. These immune responses were differentially modulated, positive or negative, depending on the combination of gene deletions. The deletions also led to enhanced antigen- or vector-specific cellular and humoral responses. These findings will facilitate the development of optimal NYVAC-based vaccines for HIV and other diseases. Full article

(This article belongs to the Special Issue HIV Vaccines)

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Review

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15 pages, 2144 KiB

Open AccessReview

Structural Basis for Epitopes in the gp120 Cluster A Region that Invokes Potent Effector Cell Activity

by William D. Tolbert, Rebekah T. Sherburn, Verna Van and Marzena Pazgier

Viruses 2019, 11(1), 69; https://doi.org/10.3390/v11010069 - 16 Jan 2019

Cited by 19 | Viewed by 4539

Abstract

While a number of therapeutic options to control the progression of human immunodeficiency virus (HIV-1) now exist, a broadly effective preventive vaccine is still not available. Through detailed structural analysis of antibodies able to induce potent effector cell activity, a number of Env [...] Read more.

While a number of therapeutic options to control the progression of human immunodeficiency virus (HIV-1) now exist, a broadly effective preventive vaccine is still not available. Through detailed structural analysis of antibodies able to induce potent effector cell activity, a number of Env epitopes have been identified which have the potential to be considered vaccine candidates. These antibodies mainly target the gp120 Cluster A region which is only exposed upon viral binding to the target cell with epitopes becoming available for antibody binding during viral entry and fusion and, therefore, after the effective window for neutralizing antibody activity. This review will discuss recent advances in the structural characterization of these important targets with a special focus on epitopes that are involved in Fc-mediated effector function without direct viral neutralizing activities. Full article

(This article belongs to the Special Issue HIV Vaccines)

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19 pages, 693 KiB

Open AccessReview

Harnessing T Follicular Helper Cell Responses for HIV Vaccine Development

by Julia Niessl and Daniel E. Kaufmann

Viruses 2018, 10(6), 336; https://doi.org/10.3390/v10060336 - 19 Jun 2018

Cited by 5 | Viewed by 7502

Abstract

Passive administration of broadly neutralizing antibodies (bNAbs) capable of recognizing a broad range of viral strains to non-human primates has led to protection from infection with chimeric SIV/HIV virus (SHIV). This data suggests that generating protective antibody responses could be an effective strategy [...] Read more.

Passive administration of broadly neutralizing antibodies (bNAbs) capable of recognizing a broad range of viral strains to non-human primates has led to protection from infection with chimeric SIV/HIV virus (SHIV). This data suggests that generating protective antibody responses could be an effective strategy for an HIV vaccine. However, classic vaccine approaches have failed so far to induce such protective antibodies in HIV vaccine trials. HIV-specific bNAbs identified in natural infection show high levels of somatic hypermutations, demonstrating that they underwent extensive affinity maturation. It is likely that to gain ability to recognize diverse viral strains, vaccine-induced humoral responses will also require complex, iterative maturation. T follicular helper cells (Tfh) are a specialized CD4+ T cell subset that provides help to B cells in the germinal center for the generation of high-affinity and long-lasting humoral responses. It is therefore probable that the quality and quantity of Tfh responses upon vaccination will impact development of bNAbs. Here, we review studies that advanced our understanding of Tfh differentiation, function and regulation. We discuss correlates of Tfh responses and bNAb development in natural HIV infection. Finally, we highlight recent strategies to optimize Tfh responses upon vaccination and their impact on prophylactic HIV vaccine research. Full article

(This article belongs to the Special Issue HIV Vaccines)

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13 pages, 922 KiB

Open AccessReview

Neutralizing Antibody-Based Prevention of Cell-Associated HIV-1 Infection

by Matthew S Parsons, Roger Le Grand and Stephen J Kent

Viruses 2018, 10(6), 333; https://doi.org/10.3390/v10060333 - 18 Jun 2018

Cited by 7 | Viewed by 4307

Abstract

Improved vaccine-mediated protection against HIV-1 requires a thorough understanding of the mode of HIV-1 transmission and how various immune responses control transmission. Cell-associated HIV-1 is infectious and contributes to HIV-1 transmission in humans. Non-human primate models of cell-associated SIV infection demonstrate that cell-associated [...] Read more.

Improved vaccine-mediated protection against HIV-1 requires a thorough understanding of the mode of HIV-1 transmission and how various immune responses control transmission. Cell-associated HIV-1 is infectious and contributes to HIV-1 transmission in humans. Non-human primate models of cell-associated SIV infection demonstrate that cell-associated SIV is more infectious than cell-free SIV. In a recently described chimeric simian–human immunodeficiency virus (SHIV) macaque model, it was demonstrated that an occult infection with cell-associated SHIV can be established that evades passive protection with a broadly neutralizing antibody (bnAb). Indeed, considerable in vitro data shows that bnAbs have less efficacy against cell-associated HIV-1 than cell-free HIV-1. Optimizing the protective capacity of immune responses such as bnAbs against cell-associated infections may be needed to maximize their protective efficacy. Full article

(This article belongs to the Special Issue HIV Vaccines)

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13 pages, 488 KiB

Open AccessReview

Natural Immunity to HIV: A Template for Vaccine Strategies

by Lyvia Fourcade, Johanne Poudrier and Michel Roger

Viruses 2018, 10(4), 215; https://doi.org/10.3390/v10040215 - 23 Apr 2018

Cited by 9 | Viewed by 5315

Abstract

Africa accounts for the majority of global human immunodeficiency virus (HIV) infections, most of which affect women through heterosexual intercourse. Currently, there is no cure for HIV and the development of vaccines and microbicides remains the best solution to eradicate the pandemic. We [...] Read more.

Africa accounts for the majority of global human immunodeficiency virus (HIV) infections, most of which affect women through heterosexual intercourse. Currently, there is no cure for HIV and the development of vaccines and microbicides remains the best solution to eradicate the pandemic. We and others have identified HIV highly-exposed seronegative (HESN) individuals among African female commercial sex workers (CSWs). Analyses of genital samples from HESNs have demonstrated potent innate and anti-inflammatory conditions, HIV-specific CD4⁺ and CD8⁺ T-cells as well as immunoglobulins (Igs), and increased regulatory cell populations, all of which support a delicate balance between strength and control against HIV intrusion. Moreover, we have recently shown that frequencies of innate marginal zone (MZ) B-cells are decreased in the blood of HESNs when compared to HIV-uninfected non-CSW women, suggesting their recruitment to peripheral sites. This coincides with the fact that levels of B lymphocyte stimulator (BLyS/BAFF), known to shape the MZ pool and whose overexpression leads to MZ deregulation in HIV-infected progressors, are significantly lower in the blood of HESNs when compared to both HIV-infected CSWs and HIV-uninfected non-CSW women. Interestingly, MZ B-cells can bind HIV gp120 and produce specific IgG and IgA, and have a propensity for B regulatory potential, which could help both the fight against HIV and maintenance of low inflammatory conditions in HESNs. HESN individuals provide an exceptional opportunity to identify important clues for the development of protective devices, and efforts should aim at soliciting immune responses observed in the context of their natural immunity to HIV. Full article

(This article belongs to the Special Issue HIV Vaccines)

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22 pages, 39127 KiB

Open AccessReview

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

by Oliver Ringel, Vincent Vieillard, Patrice Debré, Jutta Eichler, Hildegard Büning and Ursula Dietrich

Viruses 2018, 10(4), 197; https://doi.org/10.3390/v10040197 - 15 Apr 2018

Cited by 16 | Viewed by 7381

Abstract

Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced [...] Read more.

Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of “classical” vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine. Full article

(This article belongs to the Special Issue HIV Vaccines)

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26 pages, 8998 KiB

Open AccessReview

Advances in HIV-1 Vaccine Development

by Yong Gao, Paul F. McKay and Jamie F. S. Mann

Viruses 2018, 10(4), 167; https://doi.org/10.3390/v10040167 - 01 Apr 2018

Cited by 55 | Viewed by 8626

Abstract

An efficacious HIV-1 vaccine is regarded as the best way to halt the ongoing HIV-1 epidemic. However, despite significant efforts to develop a safe and effective vaccine, the modestly protective RV144 trial remains the only efficacy trial to provide some level of protection [...] Read more.

An efficacious HIV-1 vaccine is regarded as the best way to halt the ongoing HIV-1 epidemic. However, despite significant efforts to develop a safe and effective vaccine, the modestly protective RV144 trial remains the only efficacy trial to provide some level of protection against HIV-1 acquisition. This review will outline the history of HIV vaccine development, novel technologies being applied to HIV vaccinology and immunogen design, as well as the studies that are ongoing to advance our understanding of vaccine-induced immune correlates of protection. Full article

(This article belongs to the Special Issue HIV Vaccines)

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