A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies

Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down. Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8 + T-cell responses, notably taking into account their different lifespans. Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia. We argue that, although escape from or progressive loss of quality of CD8 + T-cell responses can accelerate disease progression, the underlying cause of the breakdown of virus control is the loss of antibody induction due to depletion of CD4 + T cells. Furthermore, strong antibody responses can prevent CD8 + T-cell escape from occurring for an extended period, even in the presence of highly efficacious CD8 + T-cell responses.

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An Enhanced Synthetic Multiclade DNA Prime Induces Improved Cross-Clade-Reactive Functional Antibodies when Combined with an Adjuvanted Protein Boost in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.00652-15 ◽

2015 ◽

Vol 89 (18) ◽

pp. 9154-9166 ◽

Cited By ~ 14

Author(s):

Megan C. Wise ◽

Natalie A. Hutnick ◽

Justin Pollara ◽

Devin J. F. Myles ◽

Constance Williams ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Consensus Sequence ◽

Vaccine Trial ◽

T Cell Responses ◽

Antiretroviral Drugs ◽

Cell Responses ◽

Protein Boost ◽

Hiv 1

ABSTRACTThe search for an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine remains a pressing need. The moderate success of the RV144 Thai clinical vaccine trial suggested that vaccine-induced HIV-1-specific antibodies can reduce the risk of HIV-1 infection. We have made several improvements to the DNA platform and have previously shown that improved DNA vaccines alone are capable of inducing both binding and neutralizing antibodies in small-animal models. In this study, we explored how an improved DNA prime and recombinant protein boost would impact HIV-specific vaccine immunogenicity in rhesus macaques (RhM). After DNA immunization with either a single HIV Env consensus sequence or multiple constructs expressing HIV subtype-specific Env consensus sequences, we detected both CD4+and CD8+T-cell responses to all vaccine immunogens. These T-cell responses were further increased after protein boosting to levels exceeding those of DNA-only or protein-only immunization. In addition, we observed antibodies that exhibited robust cross-clade binding and neutralizing and antibody-dependent cellular cytotoxicity (ADCC) activity after immunization with the DNA prime-protein boost regimen, with the multiple-Env formulation inducing a more robust and broader response than the single-Env formulation. The magnitude and functionality of these responses emphasize the strong priming effect improved DNA immunogens can induce, which are further expanded upon protein boost. These results support further study of an improved synthetic DNA prime together with a protein boost for enhancing anti-HIV immune responses.IMPORTANCEEven with effective antiretroviral drugs, HIV remains an enormous global health burden. Vaccine development has been problematic in part due to the high degree of diversity and poor immunogenicity of the HIV Env protein. Studies suggest that a relevant HIV vaccine will likely need to induce broad cellular and humoral responses from a simple vaccine regimen due to the resource-limited setting in which the HIV pandemic is most rampant. DNA vaccination lends itself well to increasing the amount of diversity included in a vaccine due to the ease of manufacturing multiple plasmids and formulating them as a single immunization. By increasing the number of Envs within a formulation, we were able to show an increased breadth of responses as well as improved functionality induced in a nonhuman primate model. This increased breadth could be built upon, leading to better coverage against circulating strains with broader vaccine-induced protection.

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The Case for S2: The Potential Benefits of the S2 Subunit of the SARS-CoV-2 Spike Protein as an Immunogen in Fighting the COVID-19 Pandemic

Frontiers in Immunology ◽

10.3389/fimmu.2021.637651 ◽

2021 ◽

Vol 12 ◽

Author(s):

Priyanka Shah ◽

Gabriela A. Canziani ◽

Erik P. Carter ◽

Irwin Chaiken

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Rapid Development ◽

T Cell Responses ◽

Receptor Binding Domain ◽

Vaccine Research ◽

Neutralization Potential ◽

Cell Responses ◽

Potential Benefits ◽

Hiv 1

As COVID-19 cases continue to rise, it is imperative to learn more about antibodies and T-cells produced against the causative virus, SARS-CoV-2, in order to guide the rapid development of therapies and vaccines. While much of the current antibody and vaccine research focuses on the receptor-binding domain of S1, a less-recognized opportunity is to harness the potential benefits of the more conserved S2 subunit. Similarities between the spike proteins of both SARS-CoV-2 and HIV-1 warrant exploring S2. Possible benefits of employing S2 in therapies and vaccines include the structural conservation of S2, extant cross-reactive neutralizing antibodies in populations (due to prior exposure to common cold coronaviruses), the steric neutralization potential of antibodies against S2, and the stronger memory B-cell and T-cell responses. More research is necessary on the effect of glycans on the accessibility and stability of S2, SARS-CoV-2 mutants that may affect infectivity, the neutralization potential of antibodies produced by memory B-cells, cross-reactive T-cell responses, antibody-dependent enhancement, and antigen competition. This perspective aims to highlight the evidence for the potential advantages of using S2 as a target of therapy or vaccine design.

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HIV-1-Based Virus-like Particles that Morphologically Resemble Mature, Infectious HIV-1 Virions

Viruses ◽

10.3390/v11060507 ◽

2019 ◽

Vol 11 (6) ◽

pp. 507 ◽

Cited By ~ 4

Author(s):

Christopher A. Gonelli ◽

Georges Khoury ◽

Rob J. Center ◽

Damian F.J. Purcell

Keyword(s):

T Cell ◽

Dna Vaccine ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Expression Vectors ◽

Virus Like Particles ◽

Cell Responses ◽

Hiv 1

A prophylactic vaccine eliciting both broad neutralizing antibodies (bNAbs) to the HIV-1 envelope glycoprotein (Env) and strong T cell responses would be optimal for preventing HIV-1 transmissions. Replication incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present authentic-structured, virion-associated Env to elicit bNAbs, and also stimulate T cell responses. Here, we optimize our DNA vaccine plasmids as VLP expression vectors for efficient Env incorporation and budding. The original vector that was used in human trials inefficiently produced VLPs, but maximized safety by inactivating RNA genome packaging, enzyme functions that are required for integration into the host genome, and deleting accessory proteins Vif, Vpr, and Nef. These original DNA vaccine vectors generated VLPs with incomplete protease-mediated cleavage of Gag and were irregularly sized. Mutations to restore function within the defective genes revealed that several of the reverse transcriptase (RT) deletions mediated this immature phenotype. Here, we made efficient budding, protease-processed, and mature-form VLPs that resembled infectious virions by introducing alternative mutations that completely removed the RT domain, but preserved most other safety mutations. These VLPs, either expressed from DNA vectors in vivo or purified after expression in vitro, are potentially useful immunogens that can be used to elicit antibody responses that target Env on fully infectious HIV-1 virions.

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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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HIV mRNA Vaccines—Progress and Future Paths

Vaccines ◽

10.3390/vaccines9020134 ◽

2021 ◽

Vol 9 (2) ◽

pp. 134

Author(s):

Zekun Mu ◽

Barton F. Haynes ◽

Derek W. Cain

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccination Strategy ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Cytotoxic T Cell ◽

Therapeutic Vaccines ◽

Cell Responses ◽

Broadly Neutralizing Antibody ◽

Cytotoxic T Cell Responses

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

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