In vivo immunogenicity of Tax(11–19) epitope in HLA-A2/DTR transgenic mice: Implication for dendritic cell-based anti-HTLV-1 vaccine

Sagar, Divya; Masih, Shet; Schell, Todd D.; Jacobson, Steven; Comber, Joseph D.; Philip, Ramila; Wigdahl, Brian; Jain, Pooja

doi:10.1016/j.vaccine.2014.03.087

Cited by 17 publications

(12 citation statements)

References 65 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HTLV-1 Tax is a pleiotropic transactivating protein known to be critical in immune activation detected in HAM/TSP [ 71 ]. It is also highly immunogenic, which results in a strong Tax-specific immune response [ 72 – 74 ]. HTLV-I Tax-specific CTLs have been shown to be elevated in peripheral blood and even higher in CSF of HAM/TSP patients, in part driven by high levels of HTLV-I proviral loads demonstrated in these compartments [ 18 , 62 , 75 ].…”

Section: Discussionmentioning

confidence: 99%

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

Anderson

Pleet

Enose-Akahata

et al. 2018

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

Background HTLV-1 infects over 20 million people worldwide and causes a progressive neuroinflammatory disorder in a subset of infected individuals called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The detection of HTLV-1 specific T cells in the cerebrospinal fluid (CSF) suggests this disease is immunopathologically mediated and that it may be driven by viral antigens. Exosomes are microvesicles originating from the endosomal compartment that are shed into the extracellular space by various cell types. It is now understood that several viruses take advantage of this mode of intercellular communication for packaging of viral components as well. We sought to understand if this is the case in HTLV-1 infection, and specifically if HTLV-1 proteins can be found in the CSF of HAM/TSP patients where we know free virus is absent, and furthermore, if exosomes containing HTLV-1 Tax have functional consequences. Results Exosomes that were positive for HTLV-1 Tax by Western blot were isolated from HAM/TSP patient PBMCs (25/36) in ex vivo cultures by trapping exosomes from culture supernatants. HTLV-1 seronegative PBMCs did not have exosomes with Tax (0/12), (Fisher exact test, p = 0.0001). We were able to observe HAM/TSP patient CSF (12/20) containing Tax + exosomes but not in HTLV-1 seronegative MS donors (0/5), despite the absence of viral detection in the CSF supernatant (Fisher exact test p = 0.0391). Furthermore, exosomes cultivated from HAM/TSP PBMCs were capable of sensitizing target cells for HTLV-1 specific CTL lysis. Conclusion Cumulatively, these results show that there are HTLV-1 proteins present in exosomes found in virus-free CSF. HAM/TSP PBMCs, particularly CD4 + CD25 + T cells, can excrete these exosomes containing HTLV-1 Tax and may be a source of the exosomes found in patient CSF. Importantly, these exosomes are capable of sensitizing an HTLV-1 specific immune response, suggesting that they may play a role in the immunopathology observed in HAM/TSP. Given the infiltration of HTLV-1 Tax-specific CTLs into the CNS of HAM/TSP patients, it is likely that exosomes may also contribute to the continuous activation and inflammation observed in HAM/TSP, and may suggest future targeted therapies in this disorder. Electronic supplementary material The online version of this article (10.1186/s40169-018-0204-7) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

Anderson

Pleet

Enose-Akahata

et al. 2018

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although an HTLV-1 preventative vaccine is feasible, no candidate vaccine has ever proceeded to clinical trial. Vaccine development efforts have used recombinant vaccinia virus vectors, protein immunization, DNA vaccine vectors, and peptide vaccines [ 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 ]. Collectively, these data suggest that an immune-based intervention based on vaccination alone is unlikely to be effective in the context of chronic HTLV-1 infection.…”

Section: Discussionmentioning

confidence: 99%

Hijacking Host Immunity by the Human T-Cell Leukemia Virus Type-1: Implications for Therapeutic and Preventive Vaccines

Pise-Masison¹,

Franchini²

2022

Viruses

View full text Add to dashboard Cite

Human T-cell Leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory diseases. High viral DNA burden (VL) in peripheral blood mononuclear cells is a documented risk factor for ATLL and HAM/TSP, and patients with HAM/TSP have a higher VL in cerebrospinal fluid than in peripheral blood. VL alone is not sufficient to differentiate symptomatic patients from healthy carriers, suggesting the importance of other factors, including host immune response. HTLV-1 infection is life-long; CD4+-infected cells are not eradicated by the immune response because HTLV-1 inhibits the function of dendritic cells, monocytes, Natural Killer cells, and adaptive cytotoxic CD8+ responses. Although the majority of infected CD4+ T-cells adopt a resting phenotype, antigen stimulation may result in bursts of viral expression. The antigen-dependent “on-off” viral expression creates “conditional latency” that when combined with ineffective host responses precludes virus eradication. Epidemiological and clinical data suggest that the continuous attempt of the host immunity to eliminate infected cells results in chronic immune activation that can be further exacerbated by co-morbidities, resulting in the development of severe disease. We review cell and animal model studies that uncovered mechanisms used by HTLV-1 to usurp and/or counteract host immunity.

show abstract

“…The epitopes identified using Nano-LC/MS/MS methods did not always correspond to previously identified immunodominant epitopes. For example, the well-studied HLA-A2-specific Tax(11–19) epitope which has previously been shown to exhibit immunodominance (16) was found only in the low confidence/low level MS/MS data (Xcorr < 1.5). One potential explanation for this observation is difference in epitope specificity in acute versus chronic stages of infections (22).…”

Section: Discussionmentioning

confidence: 99%

“…However, most treatments, when delivered to patients afflicted with ATLL or HAM/TSP, do not yield satisfactory success (14). The median survival time of ATLL, despite vigorous treatment attempts with chemotherapy, interferon therapy, and antiviral drugs, continues to be measured in months (16). Thus, developing a therapeutic vaccine against HTLV-1 presents a unique set of challenges, given its tremendous genetic stability and its ability to hide from the immune system through modification of its genetic material, such as in ATLL patients (14).…”

Section: Introductionmentioning

confidence: 99%

In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection

Mulherkar

Karabudak

Ginwala

et al. 2018

Vaccine

Self Cite

View full text Add to dashboard Cite

Human T-cell leukemia virus type 1 (HTLV-1) has infected approximately 20 million people worldwide. While 90% are asymptomatic, 5% develop severe diseases including adult T-cell leukemia/lymphoka (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). No vaccine against HTLV-1 exists, and screening programs are not universal. However, patients with chronic HTLV-1 infection have high frequencies of HTLV-1-activated CD8+ T cells, and the two main HLA alleles (A2, A24) are present in 88% of infected individuals. We thus utilized an immunoproteomics approach to characterize MHC-I restricted epitopes presented by HLA-A2+, A24+ MT-2 and SLB-1 cell lines. Unlike traditional motif prediction algorithms, this approach identifies epitopes associated with cytotoxic T-cell responses in their naturally processed forms, minimizing differences in antigen processing and protein expression levels. Out of nine identified peptides, we confirmed six novel MHC-I restricted epitopes that were capable of binding HLA-A2 and HLA-A24 alleles and used in vitro and in vivo methods to generate CD8+ T cells specific for each of these peptides. MagPix MILLIPLEX data showed that in vitro generated epitope-specific CD8+ T cells secreted IFN-γ, granzyme B, MIP-1α, TNF-α, perforin and IL-10 when cultured in the presence of MT-2 cell line. Degranulation assay confirmed cytotoxic response through surface expression of CD107 on CD8+ T cells when cultured with MT-2 cells. A CD8+ T-cell killing assay indicated significant antiviral activity of CD8+ T cells specific against all identified peptides. In vivo generated CD8+ T cells similarly demonstrated immunogenicity on ELISpot, CD107 degranulation assay, and MagPix MILLIPLEX analysis. These epitopes are thus candidates for a therapeutic peptide-based vaccine against HTLV-1, and our results provide preclinical data for the advancement of such a vaccine.

show abstract

In vivo immunogenicity of Tax(11–19) epitope in HLA-A2/DTR transgenic mice: Implication for dendritic cell-based anti-HTLV-1 vaccine

Cited by 17 publications

References 65 publications

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

Hijacking Host Immunity by the Human T-Cell Leukemia Virus Type-1: Implications for Therapeutic and Preventive Vaccines

In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection

Contact Info

Product

Resources

About