Virus-specific Immune Responses Research Articles

Accelerated heterologous prime-boost adenovirus vector-based SIV vaccine in neonatal rhesus monkeys

Background A pediatric HIV-1 vaccine is required to protect infants against HIV-1 transmission from breastfeeding. Such a vaccine would need to induce protective immunity at mucosal surfaces in neonates as soon as possible after birth. Recombinant adenovirus (rAd) vectors have been shown to elicit potent systemic and mucosal virus-specific immune responses in adult non-human primates and humans but have not previously been studied in detail in infants. Methods Newborn rhesus monkeys were injected intramuscular (i.m.) with 10^11 viral particles of rAd serotype 26 or 35 vectors expressing SIVmac239 Gag. Peripheral blood was collected to determine systemic Gag-specific cellular and humoral immune responses. At week 52, peripheral lymph nodes, bronchoalveolar lavage (BAL) and pinch biopsies of colorectal, duodenal and oral cavity mucosa were collected to evaluate mucosal Gag-specific T lymphocyte responses. Results A single injection of rAd26 encoding SIVmac239 Gag in rhesus monkeys on the day of birth elicited detectable SIV-specific cellular immune responses, but these responses were transient and waned quickly. In contrast, an accelerated heterologous prime-boost regimen involving administration of rAd35 at birth and rAd26 at 4 weeks of life elicited potent and durable Gag-specific cellular and humoral immune responses in neonatal rhesus monkeys, including mucosal responses that remained detectable at one year of age. Conclusion These results suggest the potential of an accelerated heterologous rAd prime-boost regimen as a candidate neonatal HIV-1 vaccine in newborns.

Hepatitis C Virus-Specific Cell-Mediated Immune Responses in Children Born to Mothers Infected with Hepatitis C Virus

ObjectiveTo investigate the association between hepatitis C virus (HCV)-specific cell-mediated immunity (CMI) responses and viral clearance in children born to mothers infected with HCV.Study designA cross-sectional study of children from a mother-infant cohort in Egypt were enrolled to detect CMI responses to recombinant core and nonstructural HCV antigens (nonstructural segments NS3, NS4a/b, and NS5 of the HCV genome) using an interferon-gamma enzyme-linked immunospot assay. Children born to mothers with chronic HCV were enrolled into 3 groups: transiently viremic (n = 5), aviremic (n = 36), and positive control (n = 6), which consisted of 1 child with chronic HCV from this cohort and another 5 children with chronic HCV from a companion study. Children without HCV born to mothers without HCV (n = 27) served as a negative control group. Wilcoxon rank sum test was used to compare the magnitude of CMI responses between groups.ResultsNone of the 6 control children who were positive for HCV responded to any HCV antigen, and 4 (80%) of 5 children with transient viremia responded to at least one HCV antigen, compared with 5 (14%) of 36 and 3 (11%) of 27 children in the aviremic and negative control groups, respectively. Children with transient viremia elicited stronger responses than did negative controls (P = .005), positive controls (P = .011), or children without HCV viremia (P = .012), particularly to nonstructural antigens.ConclusionsHCV-specific CMI responses were significantly higher in magnitude and frequency among transiently infected children compared with those persistently infected. This suggests CMI responses may be associated with past viral clearance and can identify children at high risk of infection, who can be targeted for health education, screening, and follow-up.

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

Regulatory T cells (Tregs) play a pivotal role in the maintenance of tolerance as well as in the control of immune activation, particularly during chronic infections. In the setting of HIV infection, the majority of studies have reported an increase in Treg frequency but a decrease in absolute number in all immune compartments of HIV-infected individuals. Several nonexclusive mechanisms have been postulated to explain this preferential Treg accumulation, including peripheral survival, increased proliferation, increased peripheral conversion, and tissue redistribution. The role played by Tregs during HIV infection is still poorly understood, as two opposing hypotheses have been proposed. A detrimental role of Tregs during HIV infection was suggested based on the evidence that Tregs suppress virus-specific immune responses. Conversely, Tregs could be beneficial by limiting immune activation, thus controlling the availability of HIV targets as well as preventing immune-based pathologies. Despite the technical difficulties, getting a better understanding of the mechanisms regulating Treg dynamics remains important, as it will help determine whether we can successfully manipulate Treg function or number to the advantage of the infected host. The aim of this review is thus to discuss the recent findings on Treg homeostasis and function in the setting of HIV infection.

A community-based survey of varicella-zoster virus-specific immune responses in the elderly

BackgroundIn the USA, live attenuated varicella-zoster virus (VZV) vaccine is licensed for use in people 50 or older, to reduce the incidence and/or severity of herpes zoster. However, this vaccine is not yet available in Japan, and the immunity profile for VZV in older people has not been investigated in detail in Japan. ObjectivesThe aim of this study was to conduct a detailed survey about the immunity profile for VZV in older people in Japan. Study designA panel of immunologic tests (skin test, ELISPOT, gpELISA, IAHA and NT) were used to analyze the immunity to VZV in the subjects. And an interview about zoster history was carried out with each of the subjects. ResultsCellular immunity test (skin test and ELISPOT) results declined with increasing age; on the contrary, humoral immunity test (gpELISA, IAHA and NT) results increased with advancing age. In addition, strongly boosted humoral immunity was found in the subjects with zoster history, however relatively small increase was found in cellular immunity test results. ConclusionsCell-mediated immunity (CMI) to VZV decreased and humoral immunity increased with increasing age in this population.

RLR-mediated production of interferon-β by a human dendritic cell subset and its role in virus-specific immunity

Cytosolic RIG-I-like helicases (RLR) are PRRs involved in type I IFN production and antiviral immunity. This study focuses to the comparison of the expression, function, and signaling cascades associated to RLR in the previously identified CD14(-)DC-SIGN(+)PPARγ(low)CD1a(+) and CD14(low)DC-SIGN(+)PPARγ(high)CD1a(-) human moDC subsets. Our results revealed that the expression of RLR genes and proteins as well as the activity of the coupled signaling pathways are significantly higher in the CD1a(+) subset than in its phenotypically and functionally distinct counterpart. Specific activation of RLR in moDCs by poly(I:C) or influenza virus was shown to induce the secretion of IFN-β via IRF3, whereas induction of proinflammatory cytokine responses were predominantly controlled by TLR3. The requirement of RLR-mediated signaling in CD1a(+) moDCs for priming naïve CD8(+) T lymphocytes and inducing influenza virus-specific cellular immune responses was confirmed by RIG-I/MDA5 silencing, which abrogated these functions. Our results demonstrate the subset-specific activation of RLR and the underlying mechanisms behind its cytokine secretion profile and identify CD1a(+) moDCs as an inflammatory subset with specialized functional activities. We also provide evidence that this migratory DC subset can be detected in human tonsil and reactive LNs.

Response surface methodology to determine optimal measles-specific cytokine responses in human peripheral blood mononuclear cells

Limitations of assay variability, labor costs, and availability of cells can affect the conduct of large population-based studies. The ability to determine optimal conditions for laboratory assessment of immune outcomes, including measurement of cytokines, can reduce the number of peripheral blood mononuclear cells (PBMCs) needed, reduce the labor costs involved, and the variability in secreted cytokine response by pooling cytokines from the same cell culture supernatant. Previously, we used response surface methodology to predict optimal conditions for vaccinia virus-stimulated cytokine responses in recipients of smallpox vaccine. Here, we apply the same approach for a measles vaccine study.PBMCs were collected from vaccinated subjects, and seven cytokines (IFN-γ, IL-2, TNF-α, IL-10, IFN-α, IFN-λ1, and IL-6) involved in measles virus-specific cytokine immune responses were examined. PBMCs were stimulated with differing multiplicity of infection (MOI) and days in culture (incubation time). Response surface methodology was used to select the optimal MOI and incubation time for each secreted cytokine.Our results demonstrate that each cytokine's optimal conditions (MOI and incubation time) differ for each virus (measles vs. vaccinia) and each cytokine's optimal conditions for each virus can be predicted using response surface methodology. These conditions allow for cytokines with overlapping optimal conditions to be pooled from the same supernatant in culture to reduce the number of PBMCs used, the costs involved, and assay variability. Therefore, response surface methodology is an effective technique that can be used to optimize antigen-specific secreted cytokines prior to population-based studies.

Mucosal immunization with recombinant influenza hemagglutinin protein and poly gamma-glutamate/chitosan nanoparticles induces protection against highly pathogenic influenza A virus

Intranasal administration of recombinant influenza hemagglutinin (rHA) antigen or inactivated virus with nanoparticles (NPs) composed of poly-γ-glutamic acid (γ-PGA) and chitosan which are safe, natural materials, and able to target the mucosal membrane as a mucosal adjuvant, could induce a high degree of protective mucosal immunity in the respiratory tract. Intranasal immunization with mixture of rHA antigen or inactivated virus and γ-PGA/chitosan nanoparticles (PC NPs) induced not only a high anti-HA immunoglobulin A (IgA) response in lung and IgG response in serum, including anti-HA neutralizing antibodies, but also an influenza virus-specific cell-mediated immune response. Also, PC NPs could function as a potential mucosal adjuvant when it was compared with the well-known mucosal adjuvant, cholera toxin (CT). Intranasal administration of rHA antigen or inactivated virus with PC NPs protected mice against challenge with a lethal dose of the highly pathogenic influenza A H5N1 virus. These results suggested that application of PC NPs with a subunit antigen of influenza produced by prokaryotic expression system provides several solutions to the current problems of the influenza vaccines using inactivated influenza virus. Moreover, our finding about a sufficient function of PC NPs to elevate vaccine efficacy led us to consider that it can be useful in clinical applications as a potent mucosal adjuvant with safety.

Development of fetal and placental innate immune responses during establishment of persistent infection with bovine viral diarrhea virus

Transplacental viral infections are dependent upon complex interactions between feto-placental and maternal immune responses and the stage of fetal development at which the infection occurs. Bovine viral diarrhea virus (BVDV) has the ability to cross the placenta and infect the fetus. Infection early in gestation with non-cytopathic (ncp) BVDV leads to persistent infection. Establishment of fetal persistent infection results in life-long viremia, virus-specific immunotolerance, and may have detrimental developmental consequences. We have previously shown that heifers infected experimentally with ncp BVDV type 2 on d. 75 of gestation had transient robust up-regulation of the type I interferon (IFN) stimulated genes (ISGs) 3–15 days after viral inoculation. Blood from persistently infected (PI) fetuses, collected 115 days post maternal infection, demonstrated moderate chronic up-regulation of ISGs. This infection model was used to delineate timing of the development of innate immune responses in the fetus and placenta during establishment of persistent infection. It was hypothesized that: (i) chronic stimulation of innate immune responses occurs following infection of the fetus and (ii) placental production of the type I IFN contributes to up-regulation of ISGs in PI fetuses. PI fetuses, generated by intranasal inoculation of pregnant heifers with ncp BVDV, and control fetuses from uninfected heifers, were collected via Cesarean sections on d. 82, 89, 97, 192, and 245 of gestation. Fetal viremia was confirmed starting on d. 89. Significant up-regulation of mRNA encoding cytosolic dsRNA sensors –RIG-I and MDA5 – was detected on d. 82–192. Detection of viral dsRNA by cytosolic sensors leads to the stimulation of ISGs, which was reflected in significant up-regulation of ISG15 mRNA in fetal blood on d. 89, 97, and 192. No difference in IFN-α and IFN-β mRNA concentration was found in fetal blood or caruncular tissue, while a significant increase in both IFN-α and IFN-β mRNA was seen in cotyledons from PI fetuses on d. 192. It is concluded that fetuses respond to early gestational ncp BVDV infection by induction of the type I IFN pathway, resulting in chronic up-regulation of ISGs. Cotyledonary tissue contributes to up-regulation of ISGs by increased production of IFNs. The innate immune response might partially curtail viral replication in PI fetuses, but is not able to eliminate the virus in the absence of a virus-specific adaptive immune response.

Accelerated Heterologous Adenovirus Prime-Boost SIV Vaccine in Neonatal Rhesus Monkeys

A pediatric human immunodeficiency virus type 1 (HIV-1) vaccine would be desirable to protect infants against HIV-1 transmission from breast-feeding. Such a vaccine would need to induce protective immunity at mucosal surfaces in neonates as soon as possible after birth. Recombinant adenovirus (rAd) vectors have been shown to elicit potent systemic and mucosal virus-specific immune responses in adult nonhuman primates and humans, but these vectors have not previously been comprehensively studied in infants. In this study, we demonstrate that a single injection of rAd26 encoding simian immunodeficiency virus mac239 (SIVmac239) Gag on the day of birth elicited detectable Gag-specific cellular immune responses in rhesus monkeys, but these responses were transient and waned quickly. In contrast, an accelerated heterologous prime-boost regimen involving administration of rAd35 at birth and rAd26 at 4 weeks of life elicited potent and durable Gag-specific cellular and humoral immune responses in neonatal rhesus monkeys, including mucosal responses that remained detectable at 1 year of age. These results suggest the potential of an accelerated heterologous rAd prime-boost regimen as a candidate HIV-1 vaccine for newborns.

Immune responses in pigs induced by recombinant DNA vaccine co-expressing swine IL-18 and membrane protein of porcine reproductive and respiratory syndrome virus.

In this study, two DNA vaccines, which express the membrane (M) protein of porcine respiratory and reproductive syndrome virus (PRRSV) (pEGFP-M) and co-express both M and swine IL-18 (pEGFP-IL18-M), were constructed and their abilities to induce humoral and cellular responses in piglets were comparatively evaluated. Experimental results showed that both recombinant DNA vaccines could not elicit neutralizing antibodies in the immunized piglets. However, both DNA vaccines elicited Th1-biased cellular immune responses. Notably, pigs immunized with the plasmid pEGFP-IL18-M developed significantly higher levels of IFN-γ and IL-2 production response and stronger specific T-lymphocyte proliferation response than the pigs inoculated with the plasmids pEGFP-M and pEGFP-IL18 (P < 0.05). These results illustrated that co-expression of M and IL-18 proteins could significantly improve the potency of DNA vaccination on the activation of vaccine-induced virus-specific cell-mediated immune responses in pigs, which may be used as a strategy to develop a new generation of vaccines against highly pathogenic PRRSV.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.

Regulatory T Cell Frequencies Do Not Correlate with Breadth or Magnitude of HIV-1-Specific T Cell Responses

Regulatory T Cell Frequencies Do Not Correlate with Breadth or Magnitude of HIV-1-Specific T Cell Responses

Hepatitis C virus-specific cellular immune responses in individuals with no evidence of infection

The detection of hepatitis C virus (HCV)-specific T cell responses in HCV-uninfected, presumably unexposed, subjects could be due to an underestimation of the frequency of spontaneously resolving infections, as most acute HCV infections are clinically silent. To address this hypothesis, HCV-specific cellular immune responses were characterized, in individuals negative for an HCV PCR assay and humoral response, with (n = 32) or without (n = 33) risk of exposure to HCV. Uninfected volunteers (n = 20) with a chronically HCV-infected partner were included as positive controls for potential exposure to HCV and HCV infection, respectively. HCV-specific T cell responses in freshly isolated peripheral blood mononuclear cells were studied ex vivo by ELISPOT and CFSE-based proliferation assays using panels of HCV Core and NS3-derived peptides. A pool of unrelated peptides was used as a negative control, and a peptide mix of human cytomegalovirus, Epstein-Bar virus and Influenza virus as a positive control. Overall, 20% of presumably HCV-uninfected subject tested had detectable T-cell responses to the virus, a rate much higher than previous estimates of HCV prevalence in developed countries. This result would be consistent with unapparent primary HCV infections that either cleared spontaneously or remained undetected by conventional serological assays.

Foxp3+ Regulatory T Cells Control Persistence of Viral CNS Infection

We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4+ CD25+ Foxp3+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8+ T cells predominantly recognising the H-2Db-presented viral hemagglutinin epitope MV-H22–30 (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.

Transfer of HBV Genomes Using Low Doses of Adenovirus Vectors Leads to Persistent Infection in Immune Competent Mice

Studies of mechanisms responsible for the persistence of hepatitis B virus (HBV) infection have been hindered by a lack of appropriate animal models. HBV genomes can be delivered to livers of mice using hydrodynamic injection or high doses of an adenoviral vector; these lead to clearance of HBV. We found that infection of immunocompetent mice with low doses of an adenoviral vector resulted in persistent HBV infection; the mice neither underwent seroconversion to production of antibodies against HBV nor developed a strong HBV-specific effector T-cell response. As in patients with chronic HBV infection, DNA vaccination failed to generate T cells that cleared infection. This model of persistent HBV infection could be used to study the pathogenesis of chronic HBV infection and develop new therapeutic strategies.

Plasticity and Virus Specificity of the Airway Epithelial Cell Immune Response during Respiratory Virus Infection

Airway epithelial cells (AECs) provide the first line of defense in the respiratory tract and are the main target of respiratory viruses. Here, using oligonucleotide and protein arrays, we analyze the infection of primary polarized human AEC cultures with influenza virus and respiratory syncytial virus (RSV), and we show that the immune response of AECs is quantitatively and qualitatively virus specific. Differentially expressed genes (DEGs) specifically induced by influenza virus and not by RSV included those encoding interferon B1 (IFN-B1), type III interferons (interleukin 28A [IL-28A], IL-28B, and IL-29), interleukins (IL-6, IL-1A, IL-1B, IL-23A, IL-17C, and IL-32), and chemokines (CCL2, CCL8, and CXCL5). Lack of type I interferon or STAT1 signaling decreased the expression and secretion of cytokines and chemokines by the airway epithelium. We also observed strong basolateral polarization of the secretion of cytokines and chemokines by human and murine AECs during infection. Importantly, the antiviral response of human AECs to influenza virus or to RSV correlated with the infection signature obtained from peripheral blood mononuclear cells (PBMCs) isolated from patients with acute influenza or RSV bronchiolitis, respectively. IFI27 (also known as ISG12) was identified as a biomarker of respiratory virus infection in both AECs and PBMCs. In addition, the extent of the transcriptional perturbation in PBMCs correlated with the clinical disease severity. Our results demonstrate that the human airway epithelium mounts virus-specific immune responses that are likely to determine the subsequent systemic immune responses and suggest that the absence of epithelial immune mediators after RSV infection may contribute to explaining the inadequacy of systemic immunity to the virus.

Evaluation of virus-specific cellular immune response in transplant patients.

Virus-specific immune responses have a major impact on the outcome of the infection. Viral agents that are characterized by latency, such as herpesviruses and polyomaviruses, require a continuous immune control to reduce the extent of viral reactivation, as viral clearance cannot be accomplished, independently from the anti-viral treatment. In transplant patients, morbidity and mortality related to viral infections are significantly increased. In fact, the key steps of activation of T-cells are major target for anti-rejection immunosuppressive therapy and anti-viral immune response may be altered when infected cells and cellular effectors of immune response coexist in a transplanted organ. The role of cellular immune response in controlling viral replication and the main methods employed for its evaluation will be discussed. In particular, the main features, including both advantages and limitations, of available assays, including intracellular cytokine staining, major histocompatibility complex - multimer-based assays, Elispot assay, and QuantiFERON test, will be described. The potential applications of these assays in the transplant context will be discussed, particularly in relation to cytomegalovirus and polyomavirus BK infection. The relevance of introducing viro-immunological monitoring, beside virological monitoring, in order to identify the risk profile for viral infections in the transplant patients will allows for define a patient-tailored clinical management, particular in terms of modulation of immunosuppressive therapy and anti-viral administration.

Clinical Pathophysiology of Human T-Lymphotropic Virus-Type 1-Associated Myelopathy/Tropical Spastic Paraparesis

Human T-lymphotropic virus type 1 (HTLV-1), a human retrovirus, is the causative agent of a progressive neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic inflammatory disease of the central nervous system and is characterized by unremitting myelopathic symptoms such as spastic paraparesis, lower limb sensory disturbance, and bladder/bowel dysfunction. Approximately 0.25–3.8% of HTLV-1-infected individuals develop HAM/TSP, which is more common in women than in men. Since the discovery of HAM/TSP, significant advances have been made with respect to elucidating the virological, molecular, and immunopathological mechanisms underlying this disease. These findings suggest that spinal cord invasion by HTLV-1-infected T cells triggers a strong virus-specific immune response and increases proinflammatory cytokine and chemokine production, leading to chronic lymphocytic inflammation and tissue damage in spinal cord lesions. However, little progress has been made in the development of an optimal treatment for HAM/TSP, more specifically in the identification of biomarkers for predicting disease progression and of molecular targets for novel therapeutic strategies targeting the underlying pathological mechanisms. This review summarizes current clinical and pathophysiological knowledge on HAM/TSP and discusses future focus areas for research on this disease.

Fatal Pancreatitis in Simian Immunodeficiency Virus SIV mac251 -Infected Macaques Treated with 2′,3′-Dideoxyinosine and Stavudine following Cytotoxic-T-Lymphocyte-Associated Antigen 4 and Indoleamine 2,3-Dioxygenase Blockade

Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4⁺-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIV(mac251) and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.

Immunobiology of Merkel Cell Carcinoma: Implications for Immunotherapy of a Polyomavirus-Associated Cancer

Merkel cell carcinoma (MCC) is an aggressive skin malignancy with a high mortality rate and an increasing incidence. The recent discovery of Merkel cell polyomavirus has revolutionized our understanding of MCC pathogenesis. Viral oncoproteins appear to play a critical role in tumor progression and are expressed in the majority of MCC tumors. Virus-specific humoral and cellular immune responses are detectable in MCC patients and are linked to the natural history of the disease. Despite persistent expression of immunogenic viral proteins, however, MCC tumors are able to evade the immune system. Understanding of the mechanisms of immune evasion employed by MCC tumors is rapidly increasing and offers opportunities for development of rational immune therapies to improve patient outcomes. Here we review recent discoveries in MCC with a special focus on the pathogenic role of Merkel cell polyomavirus and the immunobiology of this virus-associated disease.