Mechanisms of Viral Persistence
RhCMV, like HCMV, can establish either latent or persistent, low-level expression following acute viremia. Using the RhCMV model, Dr. Barry’s laboratory is examining the type(s) of infected cells and patterns of viral expression/replication at different stages of infection, and the kinetics and specificity of host immune responses during infection. Considerable effort is being devoted to analysis of RhCMV infection in immunocompetent hosts to form the foundation for pathogenesis and vaccine studies. Special emphasis is being placed on virally encoded proteins that can modulate host immune responses.
Mechanisms of Cytomegalic Fetal Disease
Fetuses infected with RhCMV exhibit outcomes very similar to human infants congenitally infected with HCMV. Recent studies indicate that infection of the fetus at earlier times of gestation is more likely to result in severe disease than infection at later times. This is due to decreasing susceptibility of the fetal CNS to damaging infection and increasing levels of protective antiviral antibodies transferred from the mother to the fetus as gestation proceeds. Current and future work is aimed at the mechanisms of pathogenesis associated with intrauterine RhCMV infection, transplacental transport of maternal antibodies to the fetus, identification of immune correlates of protection, and strategies that limit or prevent fetal disease following intrauterine RhCMV infection.
Anti-Herpesvirus Vaccine Strategies
Because there are no current effective vaccines for HCMV, work in the Barry laboratory is directed at vaccination strategies for the prevention of persistent RhCMV infection in immunocompetent hosts. Different methods of vaccination, including DNA immunization, subunit vaccines, attenuated viral vaccines, and combined strategies are being compared, as well as different immunogens. Additional studies are underway to measure the efficacy of vaccination in terms of attenuation of disease. Ongoing studies are directed at determining whether there exists a threshold of antiviral immunity required to protect the host from infection and disease.
Human cytomegalovirus (HCMV) typically establishes lifelong persistent, but asymptomatic, infections in healthy individuals. However, it causes substantial morbidity and mortality in immunocompromised patients (2). Opportunistic infections with HCMV are common in patients with the acquired immune deficiency syndrome (AIDS) or in immunosuppressed solid organ/bone marrow transplant recipients. HCMV is also a leading cause of birth defects following congenital infection of fetuses. The drugs currently approved for treatment of HCMV are limited by toxicity and/or low bioavailability, and there is no licensed vaccine for HCMV. There is a clear need for new and safer treatment options for HCMV disease. Development and testing of new drugs and therapeutic strategies would be greatly enhanced by availability of an animal model system that appropriately models the virology and pathogenesis of HCMV. Our goal is to establish a non-human primate model that will 1) enable rapid in vivo evaluation of promising anti-HCMV drugs, and 2) allow development of therapeutic strategies for HCMV under clinically relevant conditions. Ultimately, we predict that this model can be used to test therapies for CMV infections during AIDS, transplantation, or fetal development in a primate host that can be experimentally manipulated.
Eberhardt MK, Barry PA. Pathogen Manipulation of cIL-10 Signaling Pathways: Opportunities for Vaccine Development? Curr Top Microbiol Immunol. 2014;380:93-128. doi: 10.1007/978-3-662-43492-5_5. PubMed PMID: 25004815.
Deere JD, Barry PA. Using the nonhuman primate model of HCMV to guide vaccine development. Viruses. 2014 Mar 27;6(4):1483-501. doi: 10.3390/v6041483. PubMed PMID: 24681748; PubMed Central PMCID: PMC4014706.
Eberhardt MK, Deshpande A, Chang WL, Barthold SW, Walter MR, Barry PA. Vaccination against a virus-encoded cytokine significantly restricts viral challenge. J Virol. 2013 Nov;87(21):11323-31. doi: 10.1128/JVI.01925-13. Epub 2013 Aug 14. PubMed PMID: 23946461; PubMed Central PMCID: PMC3807330.
Lemay DG, Hovey RC, Hartono SR, Hinde K, Smilowitz JT, Ventimiglia F,Schmidt KA, Lee JW-S, Islas-Trejo A, Silva PI, Korf I, Medrano JF, Barry PA, and German JB. Sequencing the transcriptome of milk production: milk trumps mammary tissue. BMC Genomics, 14:872, 2013.
Carroll JD, Matzinger SR, Barry PA, McChesney MB, Fairman J, Miller CJ. The effectiveness of influenza vaccination of elderly rhesus macaques is dramatically improved by addition of a cationic lipid/DNA adjuvant. J Infect Dis, 209:24-31, 2014.
Jones-Engel L, Feeroz M, Soliven K, Small C, Engel G, Pacheco MA, Yee J, Wang X, M. Hasan M, Oh G, Levine K, Alam SMR, Craig K, Jackson D, Lee E-G, Barry P, Lerche N, Escalante A, Matsen IV F, and Linial M. Population Dynamics of Rhesus Macaques and Associated Foamy Virus in Bangladesh. Emerging Microbes Infection, in press, 2014.
Assaf BT, Mansfield KG, Westmoreland SV, Strelow L, Barry PA, and Kaur A. Limited Dissemination and Shedding of the UL128-Complex-Intact, UL/b’-Defective Rhesus Cytomegalovirus Strain 180.92. J Virol, in press, 2014.
Gilardi K, Oxford KL, Barry PA, Gardner-Roberts D, Spelman L, Barry PA, Cranfield MR, and Lowenstine LJ. Further Evidence for Human – Primate Viral Transmission: Human Herpes Simplex Virus -1 in a Wild-Caught Gorilla. Emerg Infect Dis, in press, 2014.
Wussow F, Chiuppesi F, Martinez J, Flechsig C, Campo J, Newell M, Tran E, La Rosa C, Longmate J, Barry PA*, and Diamond DJ*. Human Cytomegalovirus Vaccine Based on the Envelope UL128 Complex. Submitted to PLoS Pathogens, 2014. (*: Co-senior authors).
Eberhardt MK and Barry PA. Pathogen Manipulation of cIL-10 Signaling Pathways: Opportunities for Vaccine Development? Curr Topics Microbiol Immunol, in press, 2014.