Our study has some limitations A potential shortcoming

Our study has some limitations. A potential shortcoming of our epitope mapping approach was lack of inclusion of variant peptides. Although our results are quite consistent with the comparable recognition of a larger panel of conserved and frequently occurring variant epitopes recently reported between LTNP/EC and progressors (Sunshine et al., 2014), our methods could have potentially biased our results toward detecting responses targeting conserved sequences. In addition, we did not establish cause-and-effect relationships between increased virus-specific CD8+ T-cell proliferative and cytotoxic capacities and immunologic control. However, there are several lines of evidence that suggest that cytotoxic capacity is not just an effect of reduced levels of viral replication. CD8+ T-cell proliferative and cytotoxic capacities are not restored when HIV RNA levels are suppressed by potent antiretroviral therapy (Migueles et al., 2009). In the rhesus macaque model, infection of animals carrying protective AG 013736 manufacturer with a cloned, highly pathogenic SIV commonly results in nonprogressive infection and control of SIV replication that is largely removed by CD8+ T-cell depletion (Friedrich et al., 2007). While these lines of evidence support that highly functional virus-specific CD8+ T cells are not simply an effect of reduced viremia, proof of causality would require control of virus replication following passive transfer of cells with intact proliferative and cytotoxic capacities into humans or animal models. Finally, the finding that a protective or weakly protective HLA allele is not a requirement to develop high-level restriction of viral replication has some implications for efforts to harness the cellular immune response in vaccines or immunotherapies. Induction of a response capable of mediating immunologic control in diverse populations would therefore not be confined to those expressing HLA molecules capable of presenting critical peptide epitopes. Considering that 25 distinct “weakly” protective or non-protective HLA proteins restricted almost 40 immunodominant CD8+ T-cell responses of the B*57/27neg LTNP/EC in the present study, the overall probability of carrying at least one of these alleles in the general population is quite high. Targeting the specificities dictated by HLA is therefore a much lower barrier for the cellular immune response to overcome in the setting of vaccines and immunotherapies than previously thought.
Author Contributions
Acknowledgments We thank the study participants for their generous donations of time and study specimens. This work was supported in part by the Intramural Research Programs of NIAID. Contributions made by S.J. were performed under contract number HHSN261200800001E.
Introduction Rubella disease is now prevented by vaccines, but remains poorly controlled in developing countries including Southeast Asia. Rubella is an acute infectious disease that normally follows a mild clinical course. However, infections during pregnancy, especially before week 12 of gestation, can cause severe birth defects known as congenital rubella syndrome (CRS) (Banatvala and Brown, 2004; Duszak, 2009). Clinical signs of CRS include cataract, glaucoma, heart disease, loss of hearing, brain dysfunction, and pigmentary retinopathy. These illnesses are clinically important, yet the pathogenesis of rubella virus (RV) infection in fetuses/newborns remains obscure due to the lack of a suitable animal model for this purpose. There have been very few reports in the literature of histopathological studies on CRS in humans and most appeared in the period from late 1960 to early 1970 (Töndury and Smith, 1966; Brookhouser and Bordley, 1973; Menser and Reye, 1974). In Vietnam, rubella epidemics occurred during the period from 2011 to 2012. Through this outbreak, our investigation based on molecular epidemiology showed that RV RNA was detectable in the placenta from all of 10 aborted fetuses and 10 newborns from pregnant women with rubella (Pham et al., 2013). Importantly, all newborns and aborted fetuses were found by gross examination to have congenital cataracts. To obtain more detailed information, we conducted further histopathological and immunohistochemical examinations in the aborted fetuses and herein discuss the pathogenicity of RV infection in human fetuses.