The diagnostic and therapeutic dilemma of the co-existence of BK virus nephropathy with acute rejection - an experience from a single Centre and review of the literature.

INTRODUCTION: BKV nephropathy (BKVN) is one of the major causes of graft loss with the advent of potent immunosuppressive drugs. The literature on the co-existence of acute rejection (AR) and BKVN is scarce. MATERIALS AND METHODS: This is a single-center retrospective analysis, where the allograft biopsies of patients transplanted between 2011 and 2021 were reviewed. The biopsies, which showed evidence of coexistent AR and BKVN, were included. In addition, demographic profiles, clinical presentation, treatment details, response to therapy, and follow-up were analyzed. RESULTS: Out of 1175 live transplants done between January 2011 and March 2021, 49 had BKVN representing 4.17%. Only seven patients (0.59%) had coexistent BKVN with AR. The mean serum creatinine at presentation was 2.3 mg/dl. The mean duration to diagnosis from transplant was seven months (range 3-22 months). All had significant viremia at presentation (17450-4,750,000 copies/ml). All biopsies showed type 1 inclusion bodies with SV40 positivity except one. Coexistent acute T cell-mediated rejection (TCMR) was found in five and acute ABMR in two patients. Three patients received pulse IV methylprednisolone, five received 2 g/kg IVIG, two received plasma exchange as upfront therapies. Maintenance immunosuppression reduction was made in all. Viremia clearance was noted at a mean duration of 3.5 months. However, three patients lost their grafts on follow-up. Four had stable graft function with a mean serum creatinine of 1.54 mg/dl. CONCLUSION: Intensifying immunosuppression to treat AR followed by a reduction in maintenance immunosuppression and IVIG and antiviral therapies seems better strategy and showed good long-term graft survival in patients with coexistent BKVN and AR.

Tumor Viruses and Their Associated Cancers: Remain on the Track with the Latest Advances.

Infection with certain types of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) viruses, known as tumor viruses or oncogenic viruses, can lead to cancer [...].

Scientific and clinical developments in Merkel cell carcinoma: A polyomavirus-driven, often-lethal skin cancer.

Merkel cell carcinoma (MCC) is a primary neuroendocrine skin cancer that recurs in ~40% of cases. Merkel cell polyomavirus (MCPyV) and ultraviolet (UV)-induced mutations are two major causative factors of MCC. Virus-positive MCCs express polyomavirus oncoproteins that are highly immunogenic yet are required for ongoing tumor growth. Virus-negative MCCs have a high burden of UV-DNA mutations that encode tumor-specific UV-neoantigens. Thus, both UV- and virus-induced MCCs are highly immunogenic, enabling diverse T-cell targeted therapies. Optimal MCC management is challenging given its rarity, aggressive nature, rapidly evolving care guidelines, and fundamental differences in management compared to other skin cancers. MCC is often managed aggressively with extensive surgery, radiotherapy or systemic therapy, frequently leading to toxicities that might have been avoidable while still achieving optimal disease control. Thus, multi-disciplinary care is crucial for providing patients with the best possible outcomes. The outlook for many patients with advanced MCC has progressed remarkably over the past decade due to PD-1 pathway blocking agents that provide durable benefit for a substantial subset of MCC patients. The management of early-stage MCC has also improved due to better approaches to integrate surgery and radiotherapy. Prognostic accuracy and ongoing surveillance have advanced due to stage-specific recurrence data and sophisticated "liquid biopsies" that allow early detection of disease recurrence. Here we summarize both recent striking progress and pressing challenges such as PD-(L)1-refractory MCC, and management of MCC patients with immune dysfunction. We also highlight diverse resources to allow providers to take advantage of recent progress in this fast-moving field.

Quality Is King: Fundamental Insights into Tumor Antigenicity from Virus-Associated Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare skin malignancy that is a paradigm cancer for solid tumor immunotherapy. MCCs associated with Merkel cell polyomavirus (virus-positive MCC [VP-MCC]) or chronic UV exposure (virus-negative MCC [VN-MCC]) are anti-PD(L)1 responsive, despite VP-MCC's low mutational burden. This suggests that antigen quality, not merely mutation quantity, dictates immunotherapy responsiveness, and cell-based therapies targeting optimal antigens may be effective. Despite VP-MCC's antigenic homogeneity, diverse T-cell infiltration patterns are observed, implying microenvironment plasticity and multifactorial contributions to immune recognition. Moreover, VP-MCC exemplifies how antitumor adaptive immunity can provide tumor burden biomarkers for early detection and disease monitoring.

Prospective analysis of BKV hemorrhagic cystitis in children and adolescents undergoing hematopoietic cell transplantation.

BK virus is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic cell transplantation (HCT). Viruses can be found in urine and serum samples of immunocompromised patients. Malignant diseases, age, cell source, day of granulocyte reconstitution, conditioning regimen, or use of total body irradiation may play an important role in BKV epidemiology, development of hemorrhagic cystitis course, and outcome. The aim of this study was to evaluate the incidence, clinical course, and risk factors for BKV-HC in children undergoing HCT. A total number of 133 patients who were prospectively tested for BKV colonization/infection were enrolled into this multicenter analysis. Episodes of BKV-HC occurred in 36/133 (27%) enrolled subjects. In a univariate analysis for BKV-HC incidence, the following factors were significant: age >5 years, peripheral blood transplantation, matched unrelated donor (MUD) transplantation, busulfan-cyclophosphamide-melphalan conditioning regimen, and acute myeloblastic leukemia (AML) diagnosis. Presence of acute graft-versus-host disease (aGVHD) in liver and gut GVHD was a significant risk factor of BKV-HC. No BKV-attributed deaths were reported. In multivariate analysis, the incidence of HC was significantly higher in patients with AML, age >5 years, MUD transplants, and children with GVHD. HC is a frequent complication after HCT among children causes prolonged hospitalization but rarely contributes to death. We identified risk factors of BKV-HC development in children, with focus on aGVHD: we concluded that excessive immune reaction connected with GVHD and immunosuppression drugs might play a pivotal role in the development of BKV-HC.

Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.

A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.

Case Report: Fatal Complications of BK Virus-Hemorrhagic Cystitis and Severe Cytokine Release Syndrome Following BK Virus-Specific T-Cells.

BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.

Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6-7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A.

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6-7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L'Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6-7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6-7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6-7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6-7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6-7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.

Antigenic competition in the generation of multi-virus-specific cell lines for immunotherapy of human cytomegalovirus, polyomavirus BK, Epstein-Barr virus and adenovirus infection in haematopoietic stem cell transplant recipients.

Adoptive transfer of multivirus-specific T cell lines (MVST) is an advanced tool for immunotherapy of virus infections after hematopoietic stem cell transplantation (HSCT). Their preparation includes activation of donor virus-specific T cells by the mixture of oligopeptides derived from immunodominant antigens of several most harmful viruses, i.e. human cytomegalovirus (HCMV), polyomavirus BK (BKV), Epstein-Barr virus (EBV) and adenovirus (ADV). The aim of our study was to find out whether antigenic competition may have an impact on the expansion of virus-specific T cells. MVST from several heathy blood donors were generated using a pulse of overlapping oligopeptides (PepMixes™, derived from the IE1 and pp65 CMV antigens, VP1 and LTAG BKV antigens, BZLF1 and EBNA1 proteins of EBV and hexon protein from ADV) and short time culture in the presence of IL-7 and IL-4. The amount of virus-specific T cells in MVST was measured by ELISPOT and flow cytometry after re-stimulation with individual antigens. To evaluate antigenic competition, MVST were expanded either with a complete set of antigens or with the mixture lacking some of them. MVST expanded with the antigen mixture including CMV antigens contained a lower proportion of the T cells of other antigen specificities. A similar inhibitory effect was not apparent for EBV-derived peptides. The competitive effect of CMV antigens was most pronounced in MVST from CMV-seropositive donors and was mediated by both IE1 and pp65-derived peptides. Antigenic competition did not influence the phenotype of either CMV- or BKV-specific T cells. Both T cell populations had an effector memory phenotype (CD45RO+, CD27-, CCR7-). However, CMV-specific T cells preferentially consist of CD8+ while in BKV-specific T cells, the CD4+ phenotype predominated. Modification of the MVST manufacture protocol to prevent antigenic competition may increase the efficacy of MVST in therapy of BKV infections in HSCT recipients.

T-cell adoptive immunotherapy for BK nephropathy in renal transplantation.

INTRODUCTION: BK virus (BKPyV) nephropathy occurs in 1%-10% of kidney transplant recipients, with suboptimal therapeutic options. CASE: A 54-year-old woman received a transplant in March 2017. BKPyV was detected at 1.5 × 102  copies/mL within a month, necessitating halving of mycophenolate and addition of leflunomide. Allograft histology in December showed polyomavirus nephropathy treated with intravenous immunoglobulin and cessation of mycophenolate. In February 2018, cidofovir and ciprofloxacin were commenced. In April, tacrolimus was reduced while introducing everolimus. A second graft biopsy in August showed increasing polyoma virus infection and a subsequent biopsy in September for worsening renal function showed 30% of tubular reactivity for simian virus 40 (SV40). Allogeneic BKPyV-reactive T cells were generated from the patient's daughter and infused over 10 sessions starting late September. The fourth allograft biopsy in November 2018 demonstrated involvement of BKPyV in 50% of tubules. Allograft function continued to decline, requiring hemodialysis from December 2018. Allograft nephrectomy after 6 months showed <1% SV40 in preserved tubules and 80% interstitial fibrosis. DISCUSSION: We conclude that the T-cell adoptive immunotherapy reduced BKPyV load significantly despite extensive infection, but attendant fibrosis and tubular atrophy led to graft failure. Early intervention with T-cell therapy may prove efficacious in BKPyV nephropathy.

Human Papillomavirus, MicroRNA and their Role in Cervical Cancer Progression, Diagnosis and Treatment Response: A Comprehensive Review.

Human Papillomavirus (HPV) is sexually transmitted and linked with vaginal, vulvar and cervix cancers in females, penile cancer in male, while anal and oropharyngeal cancer in both genders. Cervical cancer is ranked as third most identified cancer among females globally and is the fourth leading reason of cancer related mortality. The main aim of current study is to highlight the key role of miRNA in cervical cancer development, progression and their therapeutic responses. Current study entailed more than 50 PubMed cited articles related to miRNA role in cervical cancer. Studies have elucidated the role of miRNAs regulation in gene expression at post-transcriptional and translational level by targeting significant genes and therefore involved in cervical cancer. miRNAs control several cellular pathways involved in development of pre-malignant to metastatic stage and proliferation to malignancy. Current review elucidated and elaborated the key role of miRNA their application, treatment and therapeutic responses in cervical cancer.

Update on the Management of BK Virus Infection.

The BK polyomavirus was isolated in 1971; it has been a significant risk factor for both graft dysfunction and failure in renal transplant recipients. So far, no specific treatment option has been available for effective treatment or prophylaxis for BK virus infections. Although the use of heavy immunosuppression has been the main risk factor for BK virus infection, other risk factors are equally important, including elderly recipients, prior rejection episodes, male sex, human leukocyte antigen mismatching, prolonged cold ischemia time, pretransplant BK virus serostatus, and ureteral stenting. Regular follow-up for BK virus infections according to each institution's policy has been, so far, effective in detecting patients with BK virus viremia and consequently preventing allograft loss. The mainstay of management continues to be reduction of immunosuppression. However, newer options are providing new insights, such as cellular immunotherapy. In this review, we will address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.

Effects of intravenous immunoglobulin therapy and Fc gamma receptor polymorphisms on BK virus nephropathy in kidney transplant recipients.

BACKGROUND: BK virus nephropathy (BKVN) is a major complication in kidney transplant patients. This study aimed to investigate the efficacy of intravenous immunoglobulin (IVIG) therapy against persistent BKVN and to evaluate the association between persistent BKVN and Fc gamma receptor (FcγR) single nucleotide polymorphisms (SNPs). METHODS: A total of 86 patients out of 279 kidney recipients with BKVN were investigated in a single-center retrospective study. The majority of 86 patients were Hispanic and Asian (69.8% and 17.4%). Patients were treated with adjunctive IVIG or standard therapy (controls). Subgroup analysis was performed between IVIG responders and non-responders. BK virus copy number and serum creatinine (SCr) were measured to evaluate the impact of IVIG. We analyzed the association between the response to IVIG and genotype at FcγR3A (rs396991) and FcγR2A (rs1801274) SNPs. RESULTS: Viral load in IVIG non-responders was significantly higher than in responders at the time of diagnosis (219 271.8 vs 29 816.3 copies/mL, P = .015) and after 6 months of IVIG use (12 789.5 vs 1369.5 copies/mL, P < .001). However, analyses SNP of FcγR2A (OR = 0.807, CI = 0.435-1.496 P = .495) and FcγR3A (OR = 0.997, CI = 0.505-1.970, P = .993) SNPs showed no significant differences between the 2 groups. CONCLUSION: IVIG appears to lower BK DNA viral load significantly in patients with persistent BKVN. However, no associations were identified between BKVN and FcγR2A or FcγR3A SNPs.

Effects and long-term follow-up of using umbilical cord blood-derived mesenchymal stromal cells in pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis after unrelated cord blood transplantation.

This is a retrospective study to evaluate the efficacy and safety of umbilical cord blood-derived mesenchymal stromal cells (MSCs) for the treatment of pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis (BKV-HC) after unrelated cord blood transplantation (UCBT). Thirteen pediatric patients with severe BKV-HC from December 2013 to December 2015 were treated with MSCs. The number of MSCs transfused in each session was 1 × 106 /kg once a week until the symptoms improved. The median follow-up time was 1432 (89-2080) days. The median frequency of MSC infusion was 2 (1-3), with eight cured cases and five effective cases; the total efficacy rate was 100%. The copy number of urine BKV DNA was 4.43 (0.36-56.9) ×108 /mL before MSC infusion and 2.67 (0-56.3) ×108 /mL after MSC infusion; the difference was not significant (P = .219). There were no significant differences in the overall survival, disease-free survival, and the incidence of relapse and acute and chronic graft-versus-host disease between the MSC infusion group and non-MSC infusion group. There was also no significant difference in the cytomegalovirus, Epstein-Barr virus (EBV), and fungal and bacterial infection rates between the two groups. Although umbilical cord blood-derived MSCs do not reduce the number of BKV DNA copies in the urine, the cells have a high efficacy rate and minimal side effects in treating severe BKV-HC after UCBT among pediatric patients. MSCs do not affect the rates of relapse, long-term infection, or survival of patients with leukemia.

Diagnostics, treatment, and immune response in BK polyomavirus infection after pediatric kidney transplantation.

After pediatric kidney transplantation BK polyomavirus (BKPyV) infections are associated with an increased risk of graft loss by BKPyV-associated nephropathy (BkPyVAN). However, suitable prognostic markers for the individual outcome of BKPyV infections are missing and the management of therapeutic interventions remains a challenge to the success of pediatric kidney transplantation. This review gives an overview on current diagnostic and therapeutic strategies in the field of BKPyV infections after pediatric kidney transplantation. Methods determining the individual immune response to BKPyV are described and their usability is discussed. There is growing evidence that BKPyV-specific T cells (BKPyV-Tvis) may serve as prognostic markers in order to steer immunosuppressive therapy in pediatric kidney recipients with BKPyV viremia in future. Prospective randomized trials in viremic kidney recipients comparing Tvis-steered therapeutic intervention with standard reduction of immunosuppression are needed before implementation of BKPyV-Tvis monitoring in routine care of BKPyV infections.

Trichodysplasia spinulosa mimicking lichen nitidus in a renal transplant patient.

Trichodysplasia spinulosa (TS) is a rare cutaneous condition associated with the TSPyV and characterized by skin-colored, folliculocentric papules with keratin spicule formation. TS is seen almost exclusively in immunosuppressed individuals, often presenting in patients with a history of solid organ transplantation or chemotherapy for a lymphoreticular malignancy. We report a case of widespread TS in a 9-year-old girl with a history of renal transplantation complicated by BK viremia, which is also caused by a polyomavirus, BKPyV. The clinical presentation of TS in this case morphologically resembled the more common, harmless skin condition known as "lichen nitidus," and was more extensive than expected for TS, creating a diagnostic challenge. This case illustrates an important presentation of severe TS of which transplant teams, oncologists, primary care providers, and dermatologists should be aware.

Infectious disease risks in pediatric renal transplantation.

Renal transplantation is a vital treatment option in children with ESRD with more than 10,000 pediatric kidney transplants and survival rates of greater than 80% at 10 years post-transplant in the USA alone. Despite these advances, infection remains a significant cause of morbidity in pediatric recipients. Screening potential organ donors and recipients is imperative to identify and mitigate infectious risks in the transplant patient. Despite the unique risks of each patient, the timing of many infections post-transplant is predictable. In early post-transplant infections (within 30 days), bacterial and fungal pathogens predominate with donor-derived events and nosocomial infections. In the intermediate period (31-180 days after transplant), latent infections from donor organs, such as EBV and CMV, develop. Late infections occurring > 180 days after the transplant can be due to latent pathogens or community-acquired organisms. Approaching an infectious evaluation in a pediatric kidney recipient requires finesse to diagnose and treat this vulnerable population in a timely manner. The following article highlights the most relevant and common infections including clinical manifestations, risk factors, diagnostic techniques, and treatment options.

Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention: Hepatitis viruses, human T-cell leukemia viruses, herpesviruses, and Epstein-Barr virus.

In 1964, the first human oncovirus, Epstein-Barr virus, was identified in Burkitt lymphoma cells. Since then, 6 other human oncoviruses have been identified: human papillomavirus, Merkel cell polyomavirus, hepatitis B and C viruses, human T-cell lymphotropic virus-1, and human herpesvirus-8. These viruses are causally linked to 12% of all cancers, many of which have mucocutaneous manifestations. In addition, oncoviruses are associated with multiple benign mucocutaneous diseases. Research regarding the pathogenic mechanisms of oncoviruses and virus-specific treatment and prevention is rapidly evolving. Preventative vaccines for human papillomavirus and hepatitis B virus are already available. This review discusses the mucocutaneous manifestations, pathogenesis, diagnosis, treatment, and prevention of oncovirus-related diseases. The first article in this continuing medical education series focuses on diseases associated with human papillomavirus and Merkel cell polyomavirus, while the second article in the series focuses on diseases associated with hepatitis B and C viruses, human T-cell lymphotropic virus-1, human herpesvirus-8, and Epstein-Barr virus.

Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention: Papillomaviruses and Merkel cell polyomavirus.

In 1964, the first human oncovirus, Epstein-Barr virus, was identified in Burkitt lymphoma cells. Since then, 6 other human oncoviruses have been identified: human papillomavirus, Merkel cell polyomavirus, hepatitis B and C viruses, human T-cell lymphotropic virus-1, and human herpesvirus-8. These viruses are causally linked to 12% of all cancers, many of which have mucocutaneous manifestations. In addition, oncoviruses are associated with multiple benign mucocutaneous diseases. Research regarding the pathogenic mechanisms of oncoviruses and virus-specific treatment and prevention is rapidly evolving. Preventative vaccines for human papillomavirus and hepatitis B virus are already available. This review discusses the mucocutaneous manifestations, pathogenesis, diagnosis, treatment, and prevention of oncovirus-related diseases. The first article in this continuing medical education series focuses on diseases associated with human papillomavirus and Merkel cell polyomavirus, while the second article in the series focuses on diseases associated with hepatitis B and C viruses, human T-cell lymphotropic virus-1, human herpesvirus-8, and Epstein-Barr virus.

The implication of CRISPR/Cas9 genome editing technology in combating human oncoviruses.

It is evidenced that 20% of all tumors in humans are caused by oncoviruses, including human papilloma viruses, Epstein-Barr virus, Kaposi sarcoma virus, human polyomaviruses, human T-lymphotrophic virus-1, and hepatitis B and C viruses. Human immunodeficiency virus is also involved in carcinogenesis, although not directly, but by facilitating the infection of many oncoviruses through compromising the immune system. Being intracellular parasites with the property of establishing latency and integrating into the host genome, these viruses are a therapeutic challenge for biomedical researchers. Therefore, strategies able to target nucleotide sequences within episomal or integrated viral genomes are of prime importance in antiviral or anticancerous armamentarium. Recently, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a powerful genome editing tool. Standing out as a precise and efficient oncoviruses method, it has been extensively applied in recent experimental ventures in the field of molecular medicine, particularly in combating infections including tumor inducing viruses. This review is aimed at collating the experimental and clinical advances in CRISPR/Cas9 technology in terms of its applications against oncoviruses. Primarily, it will focus on the application of CRISPR/Cas9 in combating tumor viruses, types of mechanisms targeted, and the significant outcomes till date. The technical pitfalls of the CRISPR/Cas9 and the comparative approaches in evaluating this technique with respect to other available alternatives are also described briefly. Furthermore, the review also discussed the clinical aspects and the ethical, legal, and social issues associated with the use of CRISPR/Cas9.