T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy

3052 Background: Prognosis of ovarian cancer remains poor after initial responsiveness to surgery and chemotherapy followed by high recurrence and mortality rates and new experimental approaches are warranted. Our goal was to evaluate a novel DC-based vaccine, which exploits a unique dual loading strategy to amplify specific anti-tumor short- and long-term immune responses to delay or even prevent recurrent and metastatic disease. Methods: Monocytes were collected via apheresis, matured into DCs and pulsed with two universal tumor associated antigens (uTAA) in our GMP facility. DCs were loaded with TERT and Survivin via two different pathways (mRNA and peptide) to elicit CD8+ and CD4+T cells directly. Endpoints of the study were tolerability and safety, immunological and clinical responses. T cell responses against the IMP and loaded antigens were evaluated by cytokine bead array (CBA) and intracellular staining assays. Results: 15 non HLA-restricted patients with advanced ovarian cancer were enrolled 8 weeks after standard treatment (surgery and chemotherapy). Each patient was vaccinated intradermally on a weekly or fortnightly basis with a maximum of 8 doses of 13*106 double loaded DCs. The majority of treatment related side effects were grade 1 fever and erythema. Overall the therapy was well tolerated. Immune response data is available for 14/15 patients, 1 was withdrawn after the first administration. The IMP leads to strong immune responses with high frequency (>90%), which is proven for both uTAAs in CD8+ as well as CD4+ T cells. A clear positive trend in progression free survival is demonstrated compared to matched historical control. Conclusions: Therapy with our unique double loaded DC vaccine was feasible, safe and well-tolerated by patients. The vaccine was highly immune stimulatory and elicited both, long-term and short-term anti-tumor immune responses, establishing a promising platform for immune therapy for ovarian cancer and all solid tumors in general. The first two authors contributed equally. Clinical trial information: NCT01456065.

Download Full-text

Reduction of Retrovirus-Induced Immunosuppression by In Vivo Modulation of T Cells during Acute Infection

Journal of Virology ◽

10.1128/jvi.78.21.11641-11647.2004 ◽

2004 ◽

Vol 78 (21) ◽

pp. 11641-11647 ◽

Cited By ~ 41

Author(s):

Hong He ◽

Ronald J. Messer ◽

Shimon Sakaguchi ◽

Guojun Yang ◽

Shelly J. Robertson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Acute Infection ◽

Tumor Necrosis Factor Receptor ◽

Cell Responses ◽

Th1 Immune Responses ◽

Necrosis Factor

ABSTRACT Chronic infection with Friend retrovirus is associated with suppressed antitumor immune responses. In the present study we investigated whether modulation of T-cell responses during acute infection would restore antitumor immunity in persistently infected mice. T-cell modulation was done by treatments with DTA-1 anti- glucocorticoid-induced tumor necrosis factor receptor monoclonal antibodies. The DTA-1 monoclonal antibody is nondepleting and delivers costimulatory signals that both enhance the activation of effector T cells and inhibit suppression by regulatory T cells. DTA-1 therapy produced faster Th1 immune responses, significant reductions in both acute virus loads and pathology and, most importantly, long-term improvement of CD8+ T-cell-mediated antitumor responses.

Download Full-text

Th1/17 Polarization of CD4 T Cells Supports HIV-1 Persistence during Antiretroviral Therapy

Journal of Virology ◽

10.1128/jvi.01595-15 ◽

2015 ◽

Vol 89 (22) ◽

pp. 11284-11293 ◽

Cited By ~ 51

Author(s):

Hong Sun ◽

Dhohyung Kim ◽

Xiaodong Li ◽

Maja Kiselinova ◽

Zhengyu Ouyang ◽

...

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Cd4 T Cells ◽

Ex Vivo ◽

Memory Cell ◽

Viral Reservoir ◽

Target Cells ◽

Infected Cells ◽

Hiv 1

ABSTRACTThe ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection inex vivoassays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy.IMPORTANCECurrent antiretroviral therapy is very effective in suppressing active HIV-1 replication but does not fully eliminate virally infected cells. The ability of HIV-1 to persist long term despite suppressive antiretroviral combination therapy represents a perplexing aspect of HIV-1 disease pathogenesis, since most HIV-1 target cells are activated, short-lived CD4 T cells. This study suggests that CD4 T helper cells with Th1/17 polarization have a preferential role as a long-term reservoir for HIV-1 infection during antiretroviral therapy, possibly because these cells may imitate some of the functional properties traditionally attributed to stem cells, such as the ability to persist for extremely long periods of time and to repopulate their own pool size through homeostatic self-renewal. These observations support the hypothesis that HIV-1 persistence is driven by small subsets of long-lasting stem cell-like CD4 T cells that may represent particularly promising targets for clinical strategies aiming at HIV-1 eradication and cure.

Download Full-text

Multifunctional T Cell Response to DosR and Rpf Antigens Is Associated with Protection in Long-Term Mycobacterium tuberculosis-Infected Individuals in Colombia

Clinical and Vaccine Immunology ◽

10.1128/cvi.00217-16 ◽

2016 ◽

Vol 23 (10) ◽

pp. 813-824 ◽

Cited By ~ 19

Author(s):

Leonar Arroyo ◽

Mauricio Rojas ◽

Kees L. M. C. Franken ◽

Tom H. M. Ottenhoff ◽

Luis F. Barrera

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Immune Responses ◽

Mononuclear Cells ◽

T Cell Response ◽

Short Term ◽

Content Type ◽

Long Term Culture

ABSTRACTMultifunctional T cells have been shown to be protective in chronic viral infections. In mycobacterial infections, however, evidence for a protective role of multifunctional T cells remains inconclusive. Short-term cultures of peripheral blood mononuclear cells stimulated with theMycobacterium tuberculosisRD1 antigens 6-kDa early secretory antigenic target (ESAT6) and 10-kDa culture filtrate antigen (CFP10), which are induced in the early infection phase, have been mainly used to assess T cell multifunctionality, although long-term culture assays have been proposed to be more sensitive than short-term assays for assessment of memory T cells, which are essential for long-term immunity. Here we used a long-term culture assay system to study the T cell immune responses to theM. tuberculosislatency-associated DosR antigens and reactivation-associated Rpf antigens, compared to ESAT6 and CFP10, in patients with pulmonary tuberculosis (PTB) and household contacts of PTB patients with long-term latent tuberculosis infection (ltLTBI), in a community in whichM. tuberculosisis endemic. Our results showed that the DosR antigens Rv1737c (narK2) and Rv2029c (pfkB) and the Rv2389c (rpfD) antigen ofM. tuberculosisinduced higher frequencies of CD4+or CD8+mono- or bifunctional (but not multifunctional) T cells producing interferon gamma (IFN-γ) and/or tumor necrosis alpha (TNF-α) in ltLTBI, compared to PTB. Moreover, the frequencies of CD4+and/or CD8+T cells with a CD45RO+CD27+phenotype were higher in ltLTBI than in PTB. Thus, the immune responses to selected DosR and Rpf antigens may be associated with long-term latency, correlating with protection fromM. tuberculosisreactivation in ltLTBI. Further study of the functional and memory phenotypes may contribute to further discrimination between the different states ofM. tuberculosisinfections.

Download Full-text

Relationship between the Size of the Human Immunodeficiency Virus Type 1 (HIV‐1) Reservoir in Peripheral Blood CD4+T Cells and CD4+:CD8+T Cell Ratios in Aviremic HIV‐1–Infected Individuals Receiving Long‐Term Highly Active Antiretroviral Therapy

The Journal of Infectious Diseases ◽

10.1086/340521 ◽

2002 ◽

Vol 185 (11) ◽

pp. 1672-1676 ◽

Cited By ~ 72

Author(s):

Tae‐Wook Chun ◽

J. Shawn Justement ◽

Punita Pandya ◽

Claire W. Hallahan ◽

Mary McLaughlin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Antiretroviral Therapy ◽

Highly Active Antiretroviral Therapy ◽

Cd8 T Cell ◽

Highly Active ◽

Immunodeficiency Virus ◽

Hiv 1

Download Full-text

Predicting the risk of re-infection from SARS-CoV-2 using the known pattern of adaptive immune response to previous human coronavirus outbreaks

10.31219/osf.io/7ctze ◽

2020 ◽

Author(s):

Ademola Samuel Ojo ◽

Paul Toluwatope Okediji ◽

Ayotemide P. Akin-Onitolo ◽

Olusegun S. Ojo ◽

Oluyinka Oladele Opaleye

Keyword(s):

Immune Response ◽

T Cells ◽

Severe Acute Respiratory Syndrome ◽

Immune Responses ◽

Adaptive Immune Response ◽

The Body ◽

Short Term ◽

Adaptive Immune ◽

Short And Long Term

This paper attempts to answer the question: are recovered COVID-19 patients protected from re-infection? This review draws evidence from comparisons between immune responses to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV), which are phylogenetically closely related to Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). Relevant studies were identified and reviewed based on searches conducted using PubMed. Full-text original studies on short- and long-term immune responses to human coronaviruses were included. The immune dysfunction and clinical manifestations in SARS-CoV-2, SARS-CoV, and MERS-CoV were found to be similar. Infections with SARS-CoV and MERS-CoV trigger the production of antibodies and memory B- and T-cells. Serum IgM is detectable within 7 days, peak at 21-30 days and become undetectable by 180 days. IgG is detectable at 7 days, peak at 90 days, and decline to undetected levels by 2 years post-infection. Memory B- and T-cells persist in the body for up to 2 and 6 years respectively after initial infection. The short-term risk of SARS-CoV-2 re-infection is predictably low based on similarities in the short term adaptive immune response to kindred coronaviruses. However, more research will be required to determine the long-term adaptive immunity to SARS-CoV-2 and factors that may influence the existence of short- and long-term immunity against the virus.

Download Full-text

MCMV-based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00814-5 ◽

2022 ◽

Author(s):

Yeonsu Kim ◽

Xiaoyan Zheng ◽

Kathrin Eschke ◽

M. Zeeshan Chaudhry ◽

Federico Bertoglio ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Influenza A ◽

High Morbidity ◽

Single Shot ◽

Respiratory Pathogens ◽

Antigenic Peptides ◽

Immune Protection ◽

Vaccine Vectors

AbstractGlobal pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.

Download Full-text