Research

880 KiB

Open AccessArticle

HIV-1 Env-Specific Memory and Germinal Center B Cells in C57BL/6 Mice

by Martina Soldemo, Gabriel K. Pedersen and Gunilla B. Karlsson Hedestam

Viruses 2014, 6(9), 3400-3414; https://doi.org/10.3390/v6093400 - 05 Sep 2014

Cited by 6 | Viewed by 8132

Continued efforts to define the immunogenic properties of the HIV-1 envelope glycoproteins (Env) are needed to elicit effective antibody (Ab) responses by vaccination. HIV-1 is a highly neutralization-resistant virus due to conformational and glycan shielding of conserved Ab determinants on the virus spike. [...] Read more.

Continued efforts to define the immunogenic properties of the HIV-1 envelope glycoproteins (Env) are needed to elicit effective antibody (Ab) responses by vaccination. HIV-1 is a highly neutralization-resistant virus due to conformational and glycan shielding of conserved Ab determinants on the virus spike. Elicitation of broadly neutralizing Abs that bind poorly accessible epitope regions on Env is therefore extremely challenging and will likely require selective targeting of specific sub-determinants. To evaluate such approaches there is a pressing need for in vivo studies in both large and small animals, including mice. Currently, most mouse immunization studies are performed in the BALB/c strain; however, the C57BL/6 strain offers improved possibilities for mechanistic studies due to the availability of numerous knock-out strains on this genetic background. Here, we compared Env immunogenicity in BALB/c and C57BL/6 mice and found that the magnitude of the antigen-specific response was somewhat lower in C57BL/6 than in BALB/c mice by ELISA but not significantly different by B cell ELISpot measurements. We then established protocols for the isolation of single Env-specific memory B cells and germinal center (GC) B cells from immunized C57BL/6 mice to facilitate future studies of the elicited response at the monoclonal Ab level. We propose that these protocols can be used to gain an improved understanding of the early recruitment of Env-specific B cells to the GC as well as the archiving of such responses in the memory B cell pool following immunization. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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Open AccessArticle

Divergence of Primary Cognate B- and T-Cell Proliferative Responses to Subcutaneous and Intravenous Immunization with Virus-Like Particles

by Vladimir Temchura, Svetlana Kalinin, Ghulam Nabi, Bettina Tippler, Thomas Niezold and Klaus Überla

Viruses 2014, 6(8), 3334-3347; https://doi.org/10.3390/v6083334 - 22 Aug 2014

Cited by 12 | Viewed by 6530

Abstract

A major advantage of virus-like particle (VLP) vaccines against HIV is their structural identity to wild-type viruses, ensuring that antigen-specific B-cells encounter the envelope protein in its natural conformation. For the induction of affinity-matured antibodies, the B-cells must also obtain help from T-cells [...] Read more.

A major advantage of virus-like particle (VLP) vaccines against HIV is their structural identity to wild-type viruses, ensuring that antigen-specific B-cells encounter the envelope protein in its natural conformation. For the induction of affinity-matured antibodies, the B-cells must also obtain help from T-cells that are restricted by linear epitopes. Using B- and T-cell transgenic mouse models, we compared the efficacy of modified HIV-VLPs delivered by subcutaneous and intravenous immunization to stimulate primary B- and T-cell proliferative responses in different lymphoid organs. VLPs containing an influenza virus hemagglutinin epitope within the HIV-Gag protein induced comparable primary cognate T-cell proliferative responses in the draining lymph node and the spleen, irrespective of the delivery route. In contrast, after subcutaneous immunization with HIV-Gag VLPs containing hen egg lysozyme (HEL) on their surface, the proliferative response of transgenic HEL-specific B-cells was restricted to the draining lymph nodes, while intravenous VLP immunization primarily induced a B-cell proliferative response in the spleen. In vitro co-culture experiments further revealed that the presentation of VLP-associated surface antigens by dendritic cells to cognate B-cells is inefficient. This is consistent with a direct triggering of the B-cell proliferative response by the VLPs and suggests that HIV VLPs may indeed be suitable to directly promote the expansion of B-cells specific for conformational epitopes that are unique to functionally-active Env spikes on the virion. Further investigations are warranted to explore potential differences in the quality and protective potency of HIV-specific antibody responses induced by the two routes. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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Open AccessCommunication

Pseudo-Mannosylated DC-SIGN Ligands as Potential Adjuvants for HIV Vaccines

by Angela Berzi, Norbert Varga, Sara Sattin, Patrizio Antonazzo, Mara Biasin, Irene Cetin, Daria Trabattoni, Anna Bernardi and Mario Clerici

Viruses 2014, 6(2), 391-403; https://doi.org/10.3390/v6020391 - 27 Jan 2014

Cited by 21 | Viewed by 7539

Abstract

The development of new and effective adjuvants may play a fundamental role in improving HIV vaccine efficacy. New classes of vaccine adjuvants activate innate immunity receptors, notably toll like receptors (TLRs). Adjuvants targeting the C-Type lectin receptor DC-SIGN may be alternative or complementary [...] Read more.

The development of new and effective adjuvants may play a fundamental role in improving HIV vaccine efficacy. New classes of vaccine adjuvants activate innate immunity receptors, notably toll like receptors (TLRs). Adjuvants targeting the C-Type lectin receptor DC-SIGN may be alternative or complementary to adjuvants based on TRL activation. Herein we evaluate the ability of the glycomimetic DC-SIGN ligand Polyman 19 (PM 19) to modulate innate immune responses. Results showed that PM 19 alone, or in combination with TLR agonists, induces the expression of cytokines, β chemokines and co-stimulatory molecules that may, in turn, modulate adaptive immunity and exert anti-viral effects. These results indicate that the suitability of this compound as a vaccine adjuvant should be further evaluated. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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Review

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Open AccessReview

Architectural Insight into Inovirus-Associated Vectors (IAVs) and Development of IAV-Based Vaccines Inducing Humoral and Cellular Responses: Implications in HIV-1 Vaccines

by Kyriakos A. Hassapis, Dora C. Stylianou and Leondios G. Kostrikis

Viruses 2014, 6(12), 5047-5076; https://doi.org/10.3390/v6125047 - 17 Dec 2014

Cited by 5 | Viewed by 6493

Abstract

Inovirus-associated vectors (IAVs) are engineered, non-lytic, filamentous bacteriophages that are assembled primarily from thousands of copies of the major coat protein gp8 and just five copies of each of the four minor coat proteins gp3, gp6, gp7 and gp9. Inovirus display studies have [...] Read more.

Inovirus-associated vectors (IAVs) are engineered, non-lytic, filamentous bacteriophages that are assembled primarily from thousands of copies of the major coat protein gp8 and just five copies of each of the four minor coat proteins gp3, gp6, gp7 and gp9. Inovirus display studies have shown that the architecture of inoviruses makes all coat proteins of the inoviral particle accessible to the outside. This particular feature of IAVs allows foreign antigenic peptides to be displayed on the outer surface of the virion fused to its coat proteins and for more than two decades has been exploited in many applications including antibody or peptide display libraries, drug design, and vaccine development against infectious and non-infectious diseases. As vaccine carriers, IAVs have been shown to elicit both a cellular and humoral response against various pathogens through the display of antibody epitopes on their coat proteins. Despite their high immunogenicity, the goal of developing an effective vaccine against HIV-1 has not yet materialized. One possible limitation of previous efforts was the use of broadly neutralizing antibodies, which exhibited autoreactivity properties. In the past five years, however, new, more potent broadly neutralizing antibodies that do not exhibit autoreactivity properties have been isolated from HIV-1 infected individuals, suggesting that vaccination strategies aimed at producing such broadly neutralizing antibodies may confer protection against infection. The utilization of these new, broadly neutralizing antibodies in combination with the architectural traits of IAVs have driven the current developments in the design of an inovirus-based vaccine against HIV-1. This article reviews the applications of IAVs in vaccine development, with particular emphasis on the design of inoviral-based vaccines against HIV-1. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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566 KiB

Open AccessReview

Challenges in the Design of a T Cell Vaccine in the Context of HIV-1 Diversity

by Marcel Tongo and Wendy A. Burgers

Viruses 2014, 6(10), 3968-3990; https://doi.org/10.3390/v6103968 - 23 Oct 2014

Cited by 15 | Viewed by 6682

Abstract

The extraordinary variability of HIV-1 poses a major obstacle to vaccine development. The effectiveness of a vaccine is likely to vary dramatically in different populations infected with different HIV-1 subtypes, unless innovative vaccine immunogens are developed to protect against the range of HIV-1 [...] Read more.

The extraordinary variability of HIV-1 poses a major obstacle to vaccine development. The effectiveness of a vaccine is likely to vary dramatically in different populations infected with different HIV-1 subtypes, unless innovative vaccine immunogens are developed to protect against the range of HIV-1 diversity. Immunogen design for stimulating neutralizing antibody responses focuses on “breadth” – the targeting of a handful of highly conserved neutralizing determinants on the HIV-1 Envelope protein that can recognize the majority of viruses across all HIV-1 subtypes. An effective vaccine will likely require the generation of both broadly cross-neutralizing antibodies and non-neutralizing antibodies, as well as broadly cross-reactive T cells. Several approaches have been taken to design such broadly-reactive and cross-protective T cell immunogens. Artificial sequences have been designed that reduce the genetic distance between a vaccine strain and contemporary circulating viruses; “mosaic” immunogens extend this concept to contain multiple potential T cell epitope (PTE) variants; and further efforts attempt to focus T cell immunity on highly conserved regions of the HIV-1 genome. Thus far, a number of pre-clinical and early clinical studies have been performed assessing these new immunogens. In this review, the potential use of these new immunogens is explored. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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Open AccessReview

Mechanisms of HIV Protein Degradation into Epitopes: Implications for Vaccine Design

by Marijana Rucevic, Julie Boucau, Jens Dinter, Georgio Kourjian and Sylvie Le Gall

Viruses 2014, 6(8), 3271-3292; https://doi.org/10.3390/v6083271 - 21 Aug 2014

Cited by 6 | Viewed by 5741

Abstract

The degradation of HIV-derived proteins into epitopes displayed by MHC-I or MHC-II are the first events leading to the priming of HIV-specific immune responses and to the recognition of infected cells. Despite a wealth of information about peptidases involved in protein degradation, our [...] Read more.

The degradation of HIV-derived proteins into epitopes displayed by MHC-I or MHC-II are the first events leading to the priming of HIV-specific immune responses and to the recognition of infected cells. Despite a wealth of information about peptidases involved in protein degradation, our knowledge of epitope presentation during HIV infection remains limited. Here we review current data on HIV protein degradation linking epitope production and immunodominance, viral evolution and impaired epitope presentation. We propose that an in-depth understanding of HIV antigen processing and presentation in relevant primary cells could be exploited to identify signatures leading to efficient or inefficient epitope presentation in HIV proteomes, and to improve the design of immunogens eliciting immune responses efficiently recognizing all infected cells. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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Open AccessReview

Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models

by Iskra Tuero and Marjorie Robert-Guroff

Viruses 2014, 6(8), 3129-3158; https://doi.org/10.3390/v6083129 - 15 Aug 2014

Cited by 13 | Viewed by 6034

Abstract

An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV [...] Read more.

An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinical studies in non-human primate models have facilitated progress in mucosal vaccine development by evaluating candidate vaccine approaches, developing methodologies for collecting and assessing mucosal samples, and providing clues to immune correlates of protective immunity for further investigation. In this review we have focused on non-human primate studies which have provided important information for future design of vaccine strategies, targeting of mucosal inductive sites, and assessment of mucosal immunity. Knowledge gained in these studies will inform mucosal vaccine design and evaluation in human clinical trials. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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Open AccessReview

Recombinant Salmonella enterica Serovar Typhimurium as a Vaccine Vector for HIV-1 Gag

by Nyasha Chin'ombe

Viruses 2013, 5(9), 2062-2078; https://doi.org/10.3390/v5092062 - 28 Aug 2013

Cited by 13 | Viewed by 6360

Abstract

The HIV/AIDS epidemic remains a global health problem, especially in Sub-Saharan Africa. An effective HIV-1 vaccine is therefore badly required to mitigate this ever-expanding problem. Since HIV-1 infects its host through the mucosal surface, a vaccine for the virus needs to trigger mucosal [...] Read more.

The HIV/AIDS epidemic remains a global health problem, especially in Sub-Saharan Africa. An effective HIV-1 vaccine is therefore badly required to mitigate this ever-expanding problem. Since HIV-1 infects its host through the mucosal surface, a vaccine for the virus needs to trigger mucosal as well as systemic immune responses. Oral, attenuated recombinant Salmonella vaccines offer this potential of delivering HIV-1 antigens to both the mucosal and systemic compartments of the immune system. So far, a number of pre-clinical studies have been performed, in which HIV-1 Gag, a highly conserved viral antigen possessing both T- and B-cell epitopes, was successfully delivered by recombinant Salmonella vaccines and, in most cases, induced HIV-specific immune responses. In this review, the potential use of Salmonella enterica serovar Typhimurium as a live vaccine vector for HIV-1 Gag is explored. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

Other

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164 KiB

Open AccessOpinion

Is a Pacific Coexistence Between Virus and Host the Unexploited Path That May Lead to an HIV Functional Cure?

by Jonathan Fior

Viruses 2013, 5(2), 753-757; https://doi.org/10.3390/v5020753 - 21 Feb 2013

Cited by 2 | Viewed by 7042

Abstract

The SupT1 cell line supports optimal HIV-1 replication, and prolonged in vitro replication in SupT1 cells renders the virus significantly less virulent. This raises the question of whether the infusion of SupT1 cells could be used as a cell-based therapy to induce a [...] Read more.

The SupT1 cell line supports optimal HIV-1 replication, and prolonged in vitro replication in SupT1 cells renders the virus significantly less virulent. This raises the question of whether the infusion of SupT1 cells could be used as a cell-based therapy to induce a pacific coexistence between the HIV virus and its human host. In a recent study, I investigated this potential therapeutic strategy in vitro. The results suggested that this approach should be further explored in HIV-susceptible animal models. Such studies may lead to the development of a functional cure for HIV infection. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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