HIV protease cleavage sites vaccine augments quality of T cell responses during ART

AbstractAfter over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers a novel approach to developing an effective HIV vaccine.One Sentence SummaryThe anti-PCS T cell responses and the immune environment induced by the novel PCS vaccine are key correlates of vaccine efficacy

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A vectorized sequence-coupling model for predicting HIV protease cleavage sites in proteins

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)85285-7 ◽

1993 ◽

Vol 268 (23) ◽

pp. 16938-16948

Author(s):

K.C. Chou

Keyword(s):

Coupling Model ◽

Hiv Protease ◽

Cleavage Sites ◽

Protease Cleavage ◽

Protease Cleavage Sites

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Recruitment of highly functional SARS-CoV-2-specific CD8+ T cell receptors mediating cytotoxicity of virus-infected target cells in non-severe COVID-19

10.1101/2021.07.20.21260845 ◽

2021 ◽

Author(s):

Karolin I. Wagner ◽

Laura M. Mateyka ◽

Sebastian Jarosch ◽

Vincent Grass ◽

Simone Weber ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

Hla Class I ◽

Cd8 T Cell ◽

Target Cells ◽

Cell Responses ◽

Cell Immunity ◽

Engineered T Cells

T cell immunity is crucial for the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and has been widely characterized on a quantitative level. In contrast, the quality of such T cell responses has been poorly investigated, in particular in the case of CD8+ T cells. Here, we explored the quality of SARS-CoV-2-specific CD8+ T cell responses in individuals who recovered from mild symptomatic infections, through which protective immunity should develop, by functional characterization of their T cell receptor (TCR) repertoire. CD8+ T cell responses specific for SARS-CoV-2-derived epitopes were low in frequency but could be detected robustly early as well as late - up to twelve months - after infection. A pool of immunodominant epitopes, which accurately identified previous SARSCoV- 2 infections, was used to isolate TCRs specific for epitopes restricted by common HLA class I molecules. TCR-engineered T cells showed heterogeneous functional avidity and cytotoxicity towards virus-infected target cells. High TCR functionality correlated with gene signatures of T cell function and activation that, remarkably, could be retrieved for each epitope:HLA combination and patient analyzed. Overall, our data demonstrate that highly functional HLA class I TCRs are recruited and maintained upon mild SARS-CoV-2 infection. Such validated epitopes and TCRs could become valuable tools for the development of diagnostic tests determining the quality of SARS-CoV-2-specific CD8+ T cell immunity, and thereby investigating correlates of protection, as well as to restore functional immunity through therapeutic transfer of TCR-engineered T cells.

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Detection of tumor antigens and tumor-antigen specific T cells in NSCLC patients: Correlation of the quality of T cell responses with NSCLC subtype

Immunology Letters ◽

10.1016/j.imlet.2020.01.001 ◽

2020 ◽

Vol 219 ◽

pp. 46-53

Author(s):

Ondrej Palata ◽

Nada Podzimkova Hradilova ◽

Dagmar Mysiková ◽

Beata Kutna ◽

Hana Mrazkova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Antigen ◽

Tumor Antigens ◽

T Cell Responses ◽

Cell Responses ◽

Nsclc Patients

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Sirolimus Enhances the Magnitude and Quality of Viral-Specific CD8+ T-Cell Responses to Vaccinia Virus Vaccination in Rhesus Macaques

American Journal of Transplantation ◽

10.1111/j.1600-6143.2010.03407.x ◽

2011 ◽

Vol 11 (3) ◽

pp. 613-618 ◽

Cited By ~ 76

Author(s):

A. P. Turner ◽

V. O. Shaffer ◽

K. Araki ◽

C. Martens ◽

P. L. Turner ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

Rhesus Macaques ◽

T Cell Responses ◽

Cd8 T Cell ◽

Virus Vaccination ◽

Cell Responses

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Impaired Quality of the Hepatitis B Virus (HBV)-Specific T-Cell Response in Human Immunodeficiency Virus Type 1-HBV Coinfection

Journal of Virology ◽

10.1128/jvi.00183-09 ◽

2009 ◽

Vol 83 (15) ◽

pp. 7649-7658 ◽

Cited By ~ 25

Author(s):

J. Judy Chang ◽

Sunee Sirivichayakul ◽

Anchalee Avihingsanon ◽

Alex J. V. Thompson ◽

Peter Revill ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

T Cell Response ◽

Cell Responses ◽

B Virus ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Hepatits B virus (HBV)-specific T cells play a key role both in the control of HBV replication and in the pathogenesis of liver disease. Human immunodeficiency virus type 1 (HIV-1) coinfection and the presence or absence of HBV e (precore) antigen (HBeAg) significantly alter the natural history of chronic HBV infection. We examined the HBV-specific T-cell responses in treatment-naïve HBeAg-positive and HBeAg-negative HIV-1-HBV-coinfected (n = 24) and HBV-monoinfected (n = 39) Asian patients. Peripheral blood was stimulated with an overlapping peptide library for the whole HBV genome, and tumor necrosis factor alpha and gamma interferon cytokine expression in CD8+ T cells was measured by intracellular cytokine staining and flow cytometry. There was no difference in the overall magnitude of the HBV-specific T-cell responses, but the quality of the response was significantly impaired in HIV-1-HBV-coinfected patients compared with monoinfected patients. In coinfected patients, HBV-specific T cells rarely produced more than one cytokine and responded to fewer HBV proteins than in monoinfected patients. Overall, the frequency and quality of the HBV-specific T-cell responses increased with a higher CD4+ T-cell count (P = 0.018 and 0.032, respectively). There was no relationship between circulating HBV-specific T cells and liver damage as measured by activity and fibrosis scores, and the HBV-specific T-cell responses were not significantly different in patients with either HBeAg-positive or HBeAg-negative disease. The quality of the HBV-specific T-cell response is impaired in the setting of HIV-1-HBV coinfection and is related to the CD4+ T-cell count.

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Artificial neural network method for predicting HIV protease cleavage sites in protein

Journal of Protein Chemistry ◽

10.1007/bf02780962 ◽

1998 ◽

Vol 17 (7) ◽

pp. 607-615 ◽

Cited By ~ 11

Author(s):

Yu -Dong Cai ◽

Hanry Yu ◽

Kuo -Chen Chou

Keyword(s):

Neural Network ◽

Artificial Neural Network ◽

Hiv Protease ◽

Cleavage Sites ◽

Neural Network Method ◽

Protease Cleavage ◽

Network Method ◽

Protease Cleavage Sites ◽

Artificial Neural Network Method ◽

Artificial Neural

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Artificial neural network model for predicting HIV protease cleavage sites in protein

Advances in Engineering Software ◽

10.1016/s0965-9978(98)00046-5 ◽

1998 ◽

Vol 29 (2) ◽

pp. 119-128 ◽

Cited By ~ 55

Author(s):

Yu-Dong Cai ◽

Kuo-Chen Chou

Keyword(s):

Neural Network ◽

Artificial Neural Network ◽

Network Model ◽

Neural Network Model ◽

Artificial Neural Network Model ◽

Hiv Protease ◽

Cleavage Sites ◽

Protease Cleavage ◽

Protease Cleavage Sites ◽

Artificial Neural

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Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

Journal of Virology ◽

10.1128/jvi.01469-17 ◽

2017 ◽

Vol 91 (24) ◽

Cited By ~ 82

Author(s):

Alba Grifoni ◽

John Pham ◽

John Sidney ◽

Patrick H. O'Rourke ◽

Sinu Paul ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Zika Virus ◽

T Cell Responses ◽

Cross Reactivity ◽

T Cell Response ◽

T Cell Immunity ◽

Cell Responses ◽

Cell Immunity

ABSTRACT While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV structural proteins (E, prM, and C) are major targets of both the CD4 and CD8 T cell responses, whereas DENV T cell epitopes are found primarily in nonstructural proteins. IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how preexisting DENV T cell immunity modulates Zika T cell responses is of great relevance, as the two viruses often cocirculate and Zika virus has been spreading in geographical regions where DENV is endemic or hyperendemic. Our data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude, and quality of the T cell response. Additionally, we show that ZIKV-specific responses target different proteins than DENV-specific responses, pointing toward important implications for vaccine design against this global threat.

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