Clinical and immunological aspects of human parvovirus B19 infection

Abstract: Human parvovirus B19 (B19) causes erythema infectiosum, a limited disease of childhood also known as the fifth disease or slapped cheek syndrome, referring to the characteristic facial rash. It normally infects through the respiratory route, even though transmission via blood products and transplanted organs occur. B 19 infection is common with a seroprevalence in the elderly of about 80%. In adults, the presentation is diffuse with arthropathy as a main feature. B 19 causes a lytic infection of predominantly erythroid precursors, resulting in a decrease in reticulocyte count and hemoglobin level. In patients with underlying hematological disease, transient aplastic crisis may ensue that is sometimes fatal. In immunocompromised individuals, B19 can cause persistent infection and chronic anemia. Mainly humoral responses are reported, although recent data has indicated an importance also of the cellular immune system, but little is known about the CD8+ T cell response in B19 infection and other resolving infections in man. Persistent infection despite the presence of neutralizing antibodies has been observed in individuals with long-lasting B19-related symptoms resembling those of the chronic fatigue syndrome. An association between B19 and this disease as well as some other clinical entities, such as rheumatoid arthritis, has been proposed but is not established. About one third of maternal infections are transmitted to the fetus, which may cause fetal hydrops and intrauterine fetal death (lUFD). Adverse outcome is reported to be confined to the second trimester, but indications of late cases warrant further study. We therefore examined all cases of IUFD in gestational week 22 or later that occurred in our geographical area between the years 1993 and 1999. By PCR, we found B19 DNA in 14% of the cases, suggesting B19 to be a common cause of IUFD also in late gestation. The lack of the classical clinical features of fetal hydrops and evident maternal infection, and a sometimes long time-span between maternal infection and IUFD, make early diagnosis and therapeutic intervention difficult in these cases. However, the inclusion of B19 PCR in the investigation of all cases of IUFD will contribute to increase the number where an etiology is established. In addition, this finding should be considered in a situation when vaccination of certain riskgroups is possible. We have previously reported an inhibitory effect on the erythropoiesis in vitro of empty capsids containing both structural proteins. Here we showed a similar effect on the hematopoiesis of only the major capsid protein that was retained also after fragmentation. Bone marrow cells from a patient with polycythemia vera were suppressed, and an effect of this protein in vivo was indicated in a pilot study in non-human primates. Together, these findings nourish the idea of a B19-derived medicament for hematopoietic suppression in various applications, such as for treatment of polycythemia vera. We assessed the CD8+ T cell responses, by means of interferon gamma detection in an enzyme-linked immunospot assay, to the entire B19 immunome in five IgM-positive symptomatic individuals. We detected sustained responses of high amplitudes for up to two years after primary infection. The responses were presumably antigen-driven and directed to a few epitopes that were unchanged over time. Our findings indicate a virus-host interaction not believed to be a feature of resolving infections. In contrast to the capsid-directed humoral response, we defined ten novel CD8+ T cell epitopes that all but one were directed to the non-structural protein. The epitopes open for further immunological study, and make a T cell directed vaccination approach possible. In symptomatic persistently infected individuals with an intact humoral response, we detected low CD8+ T cell responses that were skewed towards the capsid. This is the first finding of an aberration in the immunological response in these individuals, which may be the result of continuous antigenic stimulation or might represent a mechanism for the development of viral persistence.