A recent comparison of two rhesus cytomegalovirus (RhCMV) genomes revealed that the region at the right end of the U(L) genome component (U(L)b') undergoes genetic alterations similar to those observed in serially passaged human cytomegalovirus (HCMV). To determine the coding content of authentic wild-type RhCMV in this region, the U(L)b' sequence was amplified from virus obtained from naturally infected rhesus macaques without passage in vitro. A total of 24 open reading frames (ORFs) potentially encoding >99 amino acid residues were identified, 10 of which are related to HCMV ORFs and 15 to previously listed RhCMV ORFs. In addition, the analysis revealed a cluster of three novel alpha chemokine-like ORFs, bringing the number of predicted alpha chemokine genes in this region to six. Three of these six genes exhibit a high level of sequence diversity, as has been observed for the HCMV alpha chemokine gene UL146.
BackgroundThe worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence. Here, we propose that rhesus macaques could serve as a relevant model to define the impact of chronic viral infections on host immunity in the aging host. We evaluated whether chronic rhesus CMV (RhCMV) infection, similar to HCMV infection in humans, would modulate normal immunological changes in the aging individual by taking advantage of the unique resource of rhesus macaques that were bred and raised to be Specific Pathogen Free (SPF-2) for distinct viruses.ResultsOur results demonstrate that normal age-related immunological changes in frequencies, activation, maturation, and function of peripheral blood cell lymphocytes in humans occur in a similar manner over the lifespan of rhesus macaques. The comparative analysis of age-matched SPF-2 and non-SPF macaques that were housed under identical conditions revealed distinct differences in certain immune parameters suggesting that chronic pathogen exposure modulated host immune responses. All non-SPF macaques were infected with RhCMV, suggesting that chronic RhCMV infection was a major contributor to altered immune function in non-SPF macaques, although a causative relationship was not established and outside the scope of these studies. Further, we showed that immunological differences between SPF-2 and non-SPF macaques were already apparent in adolescent macaques, potentially predisposing RhCMV-infected animals to age-related pathologies.ConclusionsOur data validate rhesus macaques as a relevant animal model to study how chronic viral infections modulate host immunity and impact immunosenescence. Comparative studies in SPF-2 and non-SPF macaques could identify important mechanisms associated with inflammaging and thereby lead to new therapies promoting healthy aging in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-015-0030-3) contains supplementary material, which is available to authorized users.
Human cytomegalovirus (HCMV) infection is usually asymptomatic in immunocompetent people. However, it may cause severe and, sometimes, fatal disease in immunologically immature or immunocompromised individuals, such as transplant recipients, human immunodeficiency virus (HIV)-infected patients, and developing fetuses (4, 63). The clinical significance of HCMV has increased due to the increased number of organ allograft transplant recipients and HIV-infected individuals. Furthermore, HCMV is the leading infectious cause for birth defects in newborns. Development of a safe and effective HCMV vaccine is thus required for those people at risk for HCMV infection and disease and has been placed in the top priority by the Institute of Medicine for the clinical and economic benefit that a vaccine would produce (64).Studies of HCMV immunity are important for the development of vaccines. Although the nature of protective immune responses to HCMV infection is incompletely defined, clinical observations in immunocompromised humans and congenital infection have pointed to the importance of neutralizing antibody and cytotoxic T-lymphocyte (CTL) responses in controlling HCMV disease. Neutralizing antibodies appear to be critical for limiting the incidence and severity of HCMV congenital infection following primary and nonprimary maternal infection (10, 25) and the severity of HCMV disease in transplant patients and HIV-infected patients (1, 2, 10). Likewise, the recovery of HCMV-specific CD8 ϩ CTL response in organ recipients correlates to the protection from HCMV disease after transplantation (36,(54)(55)(56). In addition, passive transfer of ex vivo-expanded CD8 ϩ HCMV-specific CTL clones from seropositive donors reconstitutes cellular immunity in seronegative bone marrow recipients and prevents the onset of viremia and HCMV-related disease (68). Investigations into HCMV antigens that induce protective immunity have shown that glycoprotein B (gB) is the immunodominant target for neutralizing antibodies (13, 43) and lower matrix phosphoprotein 65 (pp65) is the principal target for HCMVspecific CTL responses after natural infection (11,28,45,70). Studies of gB-and pp65-based DNA vaccines in the murine and guinea pig CMV models have demonstrated the ability of gB and pp65 to stimulate CTL and neutralizing antibody responses that confer protection against CMV infection and disease (46-48, 59, 60, 71). However, since results obtained in mice do not always predict the responses in humans (42, 69), experimental studies in nonhuman primates can provide insight into the efficacy of vaccine strategies prior to commencement of clinical trials in humans.
A vaccine consisting of rhesus cytomegalovirus (RhCMV) pp65-2, gB and IE1 expressed via modiWed vaccinia Ankara (MVA) was evaluated in rhesus macaques with or without prior priming with expression plasmids for the same antigens. Following two MVA treatments, comparable levels of anti-gB, pp65-2 and neutralizing antibody responses, and pp65-2-and IE1-speciWc cellular immune responses were detected in both vaccinated groups. Similar reductions in plasma peak viral loads were observed in these groups compared to untreated controls. This study demonstrates the immunogenicity and protective eYcacy of rMVA-based RhCMV subunit vaccines in a primate host and warrants further investigation to improve the eYcacy of subunit vaccines against CMV.
BackgroundHuman cytomegalovirus (HCMV) expresses a viral ortholog (CMVIL-10) of human cellular interleukin-10 (cIL-10). Despite only ∼26% amino acid sequence identity, CMVIL-10 exhibits comparable immunosuppressive activity with cIL-10, attenuates HCMV antiviral immune responses, and contributes to lifelong persistence within infected hosts. The low sequence identity between CMVIL-10 and cIL-10 suggests vaccination with CMVIL-10 may generate antibodies that specifically neutralize CMVIL-10 biological activity, but not the cellular cytokine, cIL-10. However, immunization with functional CMVIL-10 might be detrimental to the host because of its immunosuppressive properties.Methods and FindingsStructural biology was used to engineer biologically inactive mutants of CMVIL-10 that would, upon vaccination, elicit a potent immune response to the wild-type viral cytokine. To test the designed proteins, the mutations were incorporated into the rhesus cytomegalovirus (RhCMV) ortholog of CMVIL-10 (RhCMVIL-10) and used to vaccinate RhCMV-infected rhesus macaques. Immunization with the inactive RhCMVIL-10 mutants stimulated antibodies against wild-type RhCMVIL-10 that neutralized its biological activity, but did not cross-react with rhesus cellular IL-10.ConclusionThis study demonstrates an immunization strategy to neutralize RhCMVIL-10 biological activity using non-functional RhCMVIL-10 antigens. The results provide the methodology for targeting CMVIL-10 in vaccine, and therapeutic strategies, to nullify HCMV's ability to (1) skew innate and adaptive immunity, (2) disseminate from the site of primary mucosal infection, and (3) establish a lifelong persistent infection.
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