Next-Generation HIV Antiretroviral Therapy and Vaccine Candidates

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "HIV Vaccines".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 13080

Special Issue Editors

Institute of Human Virology, University of Maryland, Baltimore, MD 21201, USA
Interests: virology; HIV Vaccine; clinical immunology
1. Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford OX1 2JD, UK
2. International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-8555, Japan
Interests: HIV vaccines; vaccine vectors, clinical trials; pre-clinical models; T cells

Special Issue Information

Dear Colleagues,

Despite many years of research, a successful vaccine or cure for HIV-1 remains among the highest priority areas of unmet need in infectious disease. The vaccine development path for the HIV-1 pathogen has been extremely challengin for different reasons, one of them being the pathogen’s high antigenic variability and immune evasion. Its high mutation rate allows it to evade immune responses by modifying its target immunogens during the course of infection. The development of safe, effective, and scalable therapeutic strategies to control viral replication in HIV-infected individuals in the absence of daily antiretroviral drugs is pivotal, and new vaccine strategies rely on our ability to identify the challenges posed by this pathogen. Understanding the pathogenesis and correlates of protection for this disease, and our ability to accurately direct immune responses and to vaccinate specific populations are such examples of these roadblocks. However, there are also some important translational science issues that need to be addressed. Therefore, I would like to encourage the submission of papers to this Special Issue that focus on novel approaches to vaccine development, including vaccine immunology, passive therapies, and genetic vaccination. Additionally, results from ongoing human vaccine clinical trials will also be integrated into this Special Issue. Moreover, being focused on a cure for HIV will address the problem of viral latency and how it is controlled and will emphasize cure-related human clinical trials.

With the view of their global health importance, adding new recent information on these subjects may elicit and identify areas of future investigation and collectively generate the knowledge required to design better vaccines, treatment methods, and networks that will facilitate transformative approaches to prevention and cure for this disease.

Dr. H.M. Manukumar
Prof. Tomas Hanke
Guest Editors

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Keywords

  • antiretroviral therapy
  • HIV vaccine
  • bioengineering
  • neutralizing antibodies
  • protein vaccines
  • combination regimens

Published Papers (5 papers)

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Research

14 pages, 2731 KiB  
Article
Adenovirus DNA Polymerase Loses Fidelity on a Stretch of Eleven Homocytidines during Pre-GMP Vaccine Preparation
Vaccines 2022, 10(6), 960; https://doi.org/10.3390/vaccines10060960 - 16 Jun 2022
Cited by 1 | Viewed by 1625
Abstract
In this study, we invented and construct novel candidate HIV-1 vaccines. Through genetic and protein engineering, we unknowingly constructed an HIV-1-derived transgene with a homopolymeric run of 11 cytidines, which was inserted into an adenovirus vaccine vector. Here, we describe the virus rescue, [...] Read more.
In this study, we invented and construct novel candidate HIV-1 vaccines. Through genetic and protein engineering, we unknowingly constructed an HIV-1-derived transgene with a homopolymeric run of 11 cytidines, which was inserted into an adenovirus vaccine vector. Here, we describe the virus rescue, three rounds of clonal purification and preparation of good manufacturing practise (GMP) starting material assessed for genetic stability in five additional virus passages. Throughout these steps, quality control assays indicated the presence of the transgene in the virus genome, expression of the correct transgene product and immunogenicity in mice. However, DNA sequencing of the transgene revealed additional cytidines inserted into the original 11-cytidine region, and the GMP manufacture had to be aborted. Subsequent analyses indicated that as little as 1/25th of the virus dose used for confirmation of protein expression (106 cells at a multiplicity of infection of 10) and murine immunogenicity (108 infectious units per animal) met the quality acceptance criteria. Similar frameshifts in the expressed proteins were reproduced in a one-reaction in vitro transcription/translation employing phage T7 polymerase and E. coli ribosomes. Thus, the most likely mechanism for addition of extra cytidines into the ChAdOx1.tHIVconsv6 genome is that the adenovirus DNA polymerase lost its fidelity on a stretch of 11 cytidines, which informs future adenovirus vaccine designs. Full article
(This article belongs to the Special Issue Next-Generation HIV Antiretroviral Therapy and Vaccine Candidates)
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17 pages, 5946 KiB  
Article
NK Cells Acquire CCR5 and CXCR4 by Trogocytosis in People Living with HIV-1
Vaccines 2022, 10(5), 688; https://doi.org/10.3390/vaccines10050688 - 28 Apr 2022
Cited by 3 | Viewed by 2220
Abstract
NK cells play a major role in the antiviral immune response, including against HIV-1. HIV-1 patients have impaired NK cell activity with a decrease in CD56dim NK cells and an increase in the CD56CD16+ subset, and recently it has [...] Read more.
NK cells play a major role in the antiviral immune response, including against HIV-1. HIV-1 patients have impaired NK cell activity with a decrease in CD56dim NK cells and an increase in the CD56CD16+ subset, and recently it has been proposed that a population of CD56+NKG2C+KIR+CD57+ cells represents antiviral memory NK cells. Antiretroviral therapy (ART) partly restores the functional activity of this lymphocyte lineage. NK cells when interacting with their targets can gain antigens from them by the process of trogocytosis. Here we show that NK cells can obtain CCR5 and CXCR4, but barely CD4, from T cell lines by trogocytosis in vitro. By UMAP (Uniform Manifold Approximation and Projection), we show that aviremic HIV-1 patients have unique NK cell clusters that include cells expressing CCR5, NKG2C and KIRs, but lack CD57 expression. Viremic patients have a larger proportion of CXCR4+ and CCR5+ NK cells than healthy donors (HD) and this is largely increased in CD107+ cells, suggesting a link between degranulation and trogocytosis. In agreement, UMAP identified a specific NK cell cluster in viremic HIV-1 patients, which contains most of the CD107a+, CCR5+ and CXCR4+ cells. However, this cluster lacks NKG2C expression. Therefore, NK cells can gain CCR5 and CXCR4 by trogocytosis, which depends on degranulation. Full article
(This article belongs to the Special Issue Next-Generation HIV Antiretroviral Therapy and Vaccine Candidates)
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23 pages, 31561 KiB  
Article
Stepwise Conformational Stabilization of a HIV-1 Clade C Consensus Envelope Trimer Immunogen Impacts the Profile of Vaccine-Induced Antibody Responses
Vaccines 2021, 9(7), 750; https://doi.org/10.3390/vaccines9070750 - 06 Jul 2021
Cited by 10 | Viewed by 3761
Abstract
Stabilization of the HIV-1 Envelope glycoprotein trimer (Env) in its native pre-fusion closed conformation is regarded as one of several requirements for the induction of neutralizing antibody (nAb) responses, which, in turn, will most likely be a prerequisite for the development of an [...] Read more.
Stabilization of the HIV-1 Envelope glycoprotein trimer (Env) in its native pre-fusion closed conformation is regarded as one of several requirements for the induction of neutralizing antibody (nAb) responses, which, in turn, will most likely be a prerequisite for the development of an efficacious preventive vaccine. Here, we systematically analyzed how the stepwise stabilization of a clade C consensus (ConC) Env immunogen impacts biochemical and biophysical protein traits such as antigenicity, thermal stability, structural integrity, and particle size distribution. The increasing degree of conformational rigidification positively correlates with favorable protein characteristics, leading to optimized homogeneity of the protein preparations, increased thermal stability, and an overall favorable binding profile of structure-dependent broadly neutralizing antibodies (bnAbs) and non-neutralizing antibodies (non-nAbs). We confirmed that increasing the structural integrity and stability of the Env trimers positively correlates with the quality of induced antibody responses by the immunogens. These and other data contribute to the selection of ConCv5 KIKO as novel Env immunogens for use within the European Union’s H2020 Research Consortium EHVA (European HIV Alliance) for further preclinical analysis and phase 1 clinical development. Full article
(This article belongs to the Special Issue Next-Generation HIV Antiretroviral Therapy and Vaccine Candidates)
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24 pages, 2768 KiB  
Article
Augmenting the Immune Response against a Stabilized HIV-1 Clade C Envelope Trimer by Silica Nanoparticle Delivery
Vaccines 2021, 9(6), 642; https://doi.org/10.3390/vaccines9060642 - 11 Jun 2021
Cited by 8 | Viewed by 2637
Abstract
The delivery of HIV-1 envelope (Env) trimer-based immunogens on the surface of nanoparticles holds promise to promote immunogenicity with the aim of inducing a potent, durable and broad neutralizing antibody (bnAb) response. Towards that goal, we examined the covalent conjugation of Env to [...] Read more.
The delivery of HIV-1 envelope (Env) trimer-based immunogens on the surface of nanoparticles holds promise to promote immunogenicity with the aim of inducing a potent, durable and broad neutralizing antibody (bnAb) response. Towards that goal, we examined the covalent conjugation of Env to 100 nm and 200 nm silica nanoparticles (SiNPs) to optimize conjugation density and attachment stability. Env was redesigned to enable site-specific cysteine-mediated covalent conjugation while maintaining its structural integrity and antigenicity. Env was anchored to different sized SiNPs with a calculated spacing of 15 nm between adjacent trimers. Both particle sizes exhibited high in vitro stability over a seven-day period. After attachment, 100 nm particles showed better colloidal stability compared to 200 nm particles. Importantly, the antigenic profile of Env was not impaired by surface attachment, indicating that the quaternary structure was maintained. In vitro Env uptake by dendritic cells was significantly enhanced when Env was delivered on the surface of nanoparticles compared to soluble Env. Furthermore, multivalent Env displayed efficiently activated B cells even at Env concentrations in the low nanomolar range. In mice, antibody responses to nanoparticle-coupled Env were stronger compared to the free protein and had equivalent effects at lower doses and without adjuvant. Full article
(This article belongs to the Special Issue Next-Generation HIV Antiretroviral Therapy and Vaccine Candidates)
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15 pages, 1585 KiB  
Article
Virus Evolution and Neutralization Sensitivity in an HIV-1 Subtype B′ Infected Plasma Donor with Broadly Neutralizing Activity
Vaccines 2021, 9(4), 311; https://doi.org/10.3390/vaccines9040311 - 25 Mar 2021
Cited by 6 | Viewed by 1755
Abstract
We sought to analyze the evolutionary characteristics and neutralization sensitivity of viruses in a human immunodeficiency virus type 1 (HIV-1) subtype B′ infected plasma donor with broadly neutralizing activity, which may provide information for new broadly neutralizing antibodies (bNAbs) isolation and immunogen design. [...] Read more.
We sought to analyze the evolutionary characteristics and neutralization sensitivity of viruses in a human immunodeficiency virus type 1 (HIV-1) subtype B′ infected plasma donor with broadly neutralizing activity, which may provide information for new broadly neutralizing antibodies (bNAbs) isolation and immunogen design. A total of 83 full-length envelope genes were obtained by single-genome amplification (SGA) from the patient’s plasma at three consecutive time points (2005, 2006, and 2008) spanning four years. In addition, 28 Env-pseudotyped viruses were constructed and their neutralization sensitivity to autologous plasma and several representative bNAbs were measured. Phylogenetic analysis showed that these env sequences formed two evolutionary clusters (Cluster I and II). Cluster I viruses vanished in 2006 and then appeared as recombinants two years later. In Cluster II viruses, the V1 length and N-glycosylation sites increased over the four years of the study period. Most viruses were sensitive to concurrent and subsequent autologous plasma, and to bNAbs, including 10E8, PGT121, VRC01, and 12A21, but all viruses were resistant to PGT135. Overall, 90% of Cluster I viruses were resistant to 2G12, while 94% of Cluster II viruses were sensitive to 2G12. We confirmed that HIV-1 continued to evolve even in the presence of bNAbs, and two virus clusters in this donor adopted different escape mechanisms under the same humoral immune pressure. Full article
(This article belongs to the Special Issue Next-Generation HIV Antiretroviral Therapy and Vaccine Candidates)
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