Novel, in-natural-infection subdominant HIV-1 CD8+ T-cell epitopes revealed in human recipients of conserved-region T-cell vaccines

Borthwick, Nicola; Lin, Zhan; Akahoshi, Tomohiro; Llano, Anuska; Silva-Arrieta, Sandra; Ahmed, Tina; Dorrell, Lucy; Berthou, Christian; Murakoshi, Hayato; Takiguchi, Masafumi; Hanke, Tomáš

doi:10.1371/journal.pone.0176418

Cited by 28 publications

(39 citation statements)

References 40 publications

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“…Several conserved-element vaccine immunogens have been designed which connect the most conserved parts of the viral proteome, either directly in-frame or with linker sequences to form artificial conserved element immunogens. Vaccination with these immunogens aims to focus T cell responses against highly conserved epitopes that are generally subdominant in natural infection ( Barouch and Korber, 2010 ; Rolland et al, 2007 ; Mothe et al, 2015a ; Borthwick et al, 2017 ; Gorse et al, 2008 ). We interrogated four different conserved vaccine immunogen designs, HIVconsv ( Létourneau et al, 2007 ), HIVconsvX ( Ondondo et al, 2016 ), HIVACAT T cell Immunogen (HTI) ( Mothe et al, 2015a ), and the p24 conserved element (p24 CE) ( Kulkarni et al, 2013 ), using our dataset to examine (1) whether the immunogen contained epitopes targeted by circulating T cell responses in PLWH on ART and (2) whether the epitopes in the immunogen contained escape variant(s) found in OGVs recovered from of our participants.…”

Section: Resultsmentioning

confidence: 99%

The HIV-1 latent reservoir is largely sensitive to circulating T cells

Warren

Zhou²,

et al. 2020

eLife

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HIV-1 specific CD8+ T cells are an important component of HIV-1 curative strategies. Viral variants in the HIV-1 reservoir may limit the capacity of T cells to detect and clear virus-infected cells. We investigated the patterns of T cell escape variants in the replication-competent reservoir of 25 persons living with HIV-1 (PLWH) durably suppressed on ART. We identified all reactive T cell epitopes in the HIV-1 proteome for each participant and sequenced HIV-1 outgrowth viruses from resting CD4+ T cells. All non-synonymous mutations in reactive T cell epitopes were tested for their effect on the size of the T cell response, with a ≥50% loss defined as an escape mutation. The majority (68%) of T cell epitopes harbored no detectable escape mutations. These findings suggest that circulating T cells in PLWH on ART could contribute to control of rebound and could be targeted for boosting in curative strategies.

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Section: Resultsmentioning

confidence: 99%

The HIV-1 latent reservoir is largely sensitive to circulating T cells

Warren

Zhou²,

et al. 2020

eLife

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“…Conserved HIV T-cell epitopes for an effective HIV vaccine should induce broad (multiple subtype specificities) and potent (high magnitude) immunity against HIV. Conserved epitopes are often subdominant epitopes since excessive immunity against them or mutations will affect the fitness of the virus [ 92 , 93 ]. In addition, the immune responses to the dominant non-protective epitopes could potentially mask the immune responses to the protective conserved epitopes in a vaccinated host.…”

Section: Conserved T-cell Epitopes Associated With Anti-hiv Activity(mentioning

confidence: 99%

Conserved HIV Epitopes for an Effective HIV Vaccine

Sahay¹,

Nguyen²,

Yamamoto³

2017

J Clin Cell Immunol

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Despite major advances in antiretroviral therapy against HIV-1, an effective HIV vaccine is urgently required to reduce the number of new cases of HIV infections in the world. Vaccines are the ultimate tool in the medical arsenal to control and prevent the spread of infectious diseases such as HIV/AIDS. Several failed phase-IIb to –III clinical vaccine trials against HIV-1 in the past generated a plethora of information that could be used for better designing of an effective HIV vaccine in the future. Most of the tested vaccine candidates produced strong humoral responses against the HIV proteins; however, failed to protect due to: 1) the low levels and the narrow breadth of the HIV-1 neutralizing antibodies and the HIV-specific antibody-dependent Fc-mediated effector activities, 2) the low levels and the poor quality of the anti-HIV T-cell responses, and 3) the excessive responses to immunodominant non-protective HIV epitopes, which in some cases blocked the protective immunity and/or enhanced HIV infection. The B-cell epitopes on HIV for producing broadly neutralizing antibodies (bNAbs) against HIV have been extensively characterized, and the next step is to develop bNAb epitope immunogen for HIV vaccine. The bNAb epitopes are often conformational epitopes and therefore more difficult to construct as vaccine immunogen and likely to include immunodominant non-protective HIV epitopes. In comparison, T-cell epitopes are short linear peptides which are easier to construct into vaccine immunogen free of immunodominant non-protective epitopes. However, its difficulty lies in identifying the T-cell epitopes conserved among HIV subtypes and induce long-lasting, potent polyfunctional T-cell and cytotoxic T lymphocyte (CTL) activities against HIV. In addition, these protective T-cell epitopes must be recognized by the HLA prevalent in the country(s) targeted for the vaccine trial. In conclusion, extending from the findings from previous vaccine trials, future vaccines should combine both T- and B-cell epitopes as vaccine immunogen to induce multitude of broad and potent immune effector activities required for sterilizing protection against global HIV subtypes.

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“…These can inhibit in vitro replication of viruses of 4 major global clades [ 8 , 9 , 11 , 21 ] and, in HIV-1-positive patients, provided a preliminary signal of controlling HIV-1 viremia after pausing antiretroviral treatment [ 12 ]. As we demonstrated previously, having induced robust CD8 + T-cells response in the volunteers of this trial provides a further opportunity to identify novel subdominant, but potentially protective HIV-1 epitopes [ 22 ]. Accumulation of knowledge about protective epitopes may in turn help predict early success or failure of future candidate T-cell vaccines against HIV-1.…”

Section: Discussionmentioning

confidence: 91%

Randomized phase I trial HIV-CORE 003: Depletion of serum amyloid P component and immunogenicity of DNA vaccination against HIV-1

et al. 2018

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BackgroundThe failure of DNA vaccination in humans, in contrast to its efficacy in some species, is unexplained. Observational and interventional experimental evidence suggests that DNA immunogenicity may be prevented by binding of human serum amyloid P component (SAP). SAP is the single normal DNA binding protein in human plasma. The drug (R)-1-[6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, miridesap), developed for treatment of systemic amyloidosis and Alzheimer’s disease, depletes circulating SAP by 95–99%. The proof-of-concept HIV-CORE 003 clinical trial tested whether SAP depletion by CPHPC would enhance the immune response in human volunteers to DNA vaccination delivering the HIVconsv immunogen derived from conserved sub-protein regions of HIV-1.MethodsHuman volunteers received 3 intramuscular immunizations with an experimental DNA vaccine (DDD) expressing HIV-1-derived immunogen HIVconsv, with or without prior depletion of SAP by CPHPC. All subjects were subsequently boosted by simian (chimpanzee) adenovirus (C)- and poxvirus MVA (M)-vectored vaccines delivering the same immunogen. After administration of each vaccine modality, the peak total magnitudes, kinetics, functionality and memory subsets of the T-cell responses to HIVconsv were thoroughly characterized.ResultsNo differences were observed between the CPHPC treated and control groups in any of the multiple quantitative and qualitative parameters of the T-cell responses to HIVconsv, except that after SAP depletion, there was a statistically significantly greater breadth of T-cell specificities, that is the number of recognized epitopes, following the DDDC vaccination.ConclusionsThe protocol used here for SAP depletion by CPHPC prior to DNA vaccination produced only a very modest suggestion of enhanced immunogenicity. Further studies will be required to determine whether SAP depletion might have a practical value in DNA vaccination for other plasmid backbones and/or immunogens.Trial registrationClinicaltrials.gov NCT02425241

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Novel, in-natural-infection subdominant HIV-1 CD8+ T-cell epitopes revealed in human recipients of conserved-region T-cell vaccines

Cited by 28 publications

References 40 publications

The HIV-1 latent reservoir is largely sensitive to circulating T cells

The HIV-1 latent reservoir is largely sensitive to circulating T cells

Conserved HIV Epitopes for an Effective HIV Vaccine

Randomized phase I trial HIV-CORE 003: Depletion of serum amyloid P component and immunogenicity of DNA vaccination against HIV-1

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