[PMC free article] [PubMed] [CrossRef] [Google Scholar] 26. us to distinguish infections by these viruses based on T cell reactions and to characterize those reactions. We found that gamma interferon (IFN-) and tumor necrosis element alpha (TNF-) T cell reactions to NS3 differentiated DENV and ZIKV infections with 94% level of sensitivity and 92% specificity. In general, we also showed that pDENV and sDENV instances and pZIKV and ZIKVwpDENV instances elicit related T cell response patterns and that HIV-infected individuals display T cell reactions that are lower than those demonstrated by HIV-negative individuals. These results possess important implications for DENV and ZIKV diagnostic and vaccine development and provide crucial insights into the T cell response in individuals with multiple flaviviral infections. mosquitoes transmit globally relevant flaviviruses, including dengue computer virus (DENV) and Zika computer virus (ZIKV). DENV is present as four antigenic serotypes, DENV1 to DENV4 (1). These viruses have a wide geographic distribution, with approximately 390 million infections annually and more than a quarter of the worlds populace at risk (2). Prior to 2015, ZIKV was regarded as obscure and was known to circulate in Africa and Southeast Asia as two independent viral lineages, African and Asian (3). While most are asymptomatic, the medical demonstration of ZIKV illness resembles that of dengue, including fever, rash, conjunctivitis, arthralgia, and myalgia (4). In early 2015, thousands of 10-Oxo Docetaxel Asian ZIKV instances appeared in northeast Brazil, with accompanying reports of severe neuropathology, including congenital microcephaly and Guillain-Barr syndrome (5, 6). In February 2016, the World Health Organization declared ZIKV a general public health emergency of international concern (7). By June 2016, autochthonous transmission of ZIKV had been reported in 40 countries and in territories throughout South and ATF1 Central America and the Caribbean (8). The emergence of ZIKV in regions of DENV endemicity is definitely of particular concern and relevant for diagnostic and vaccine development. The cocirculation of these genetically related viruses can result in coinfection or sequential exposure, which has been shown to potentiate cross-reactive immunity at both the antibody (Ab) and T cell levels (9,C12). The envelope (E) protein is the major target of the antibody response in humans during flaviviral illness (1). Antibody-based assays were found to detect considerable cross-reactivity to ZIKV E protein with additional flaviviruses, requiring confirmation by plaque reduction neutralization checks (PRNTs) (11, 13,C16). These checks, however, are challenged in their ability to confirm infection in individuals with multiple flaviviral infections, especially during the acute and early convalescent phases. Several studies have also demonstrated that most DENV-immune serums or DENV E monoclonal antibodies cross-react with ZIKV but consist of limited cross-neutralization activity and may instead enhance ZIKV illness, known as antibody-dependent enhancement (ADE) (17,C22). In contrast, recent studies reported that antibodies to ZIKV nonstructural 10-Oxo Docetaxel protein 1 (NS1) were able to discriminate infections by these viruses (23, 24). We previously showed that mixtures of DENV and ZIKV NS1-centered enzyme-linked immunosorbent assays (ELISAs) were capable of distinguishing confirmed instances with respect to past and present flaviviral infections, including main DENV (pDENV) and main ZIKV (pZIKV), ZIKV with main DENV (ZIKVwpDENV), and secondary DENV (sDENV) infections (12). These ELISAs are applicable for routine serological checks for 10-Oxo Docetaxel DENV and ZIKV and are also useful in retrospective studies to identify individuals with main and multiple flaviviral infections. Preexisting T cell reactions to DENV have also been shown to happen with 10-Oxo Docetaxel reactions to peptides encoded throughout the ZIKV proteome. DENV-naive mice challenged with ZIKV developed ZIKV-specific CD8+ T cells, whereas DENV-immune mice challenged with ZIKV elicited cross-reactive CD8+ T cells that reduced levels of infectious ZIKV (25). A study in humans infected with Asian ZIKV shown that DENV serostatus influences the T cell response to ZIKV (10). DENV-immune individuals showed CD4+ and CD8+ T cell reactions to ZIKV that occurred more rapidly and that were of higher magnitude than those demonstrated by DENV-naive ZIKV-infected individuals. In addition, different patterns of immunodominant T cell reactions were.