The primary and/or major sites of DENV replication in humans are not known yet. Therefore, it was unclear what cells or cell lines might be appropriate substrates for experiments relevant to the human condition. A survey of the literature suggested DENV could be identified most commonly in the liver, as it was associated with liver dysfunction and pathology but it was not clear whether this was due to the extensive phogocytic activity of the liver or that cells in the liver are more susceptible to infection than those in other tissues. However, in this study, all human cell lines including a number of liver cell lines, were extremely refractory to infection by the low passage DENV-1. The use of HuH7 cells in this study reflected that these cells appeared to be the best available rather than that they were a productive cell substrate. Other investigators have struggled to find human cell lines that are uniformly susceptible to infection by DENV from patient serum or by low passage DENV isolates. These investigations focussed on DENV infections in C6/36 mosquito cells. Mosquito cell is not a perfect representation to measure fitness; however, it is representation of mosquito vectors. Additional information may have been revealed if similar studies were undertaken in human cells, and more informative changes may have been revealed if similar studies were undertaken in human cells. However, it was not possible to identify a human cell line that was sufficiently susceptible to infection with all low passage strains of DENV. Furthermore, the most susceptible human cell line, HuH7, required a FBS supplement for growth and the FBS reduced the sensitivity of the ELISA method employed to quantitate DENV in culture supernatants. This study has provided clear evidence that the SCH772984 942183-80-4 lineage turnover in DENV transmission is not due to any selective pressures because of the variation in fitness within populations. While we observed a trend that fitness of extinct lineage DENV populations was more polarised than circulating lineage, impact of polarisation of fitness in population in DENV lineage extinction need to be further explored. As Myanmar is a hyperendemic country, the presence of multiple DENV serotypes may result in complex patterns of cross-immunity, which might determine which clades survive and which become extinct. The explanation for clade replacement may lie with the phenotype of the host with the more susceptible hosts being infected more readily after appearance of a new clade such that, after several years, the virus struggles to survive. A new clade, with a different phenotype, may be able to exploit hosts which the resident clade is struggling to infect. The term nocebo was created in analogy to the term placebo, and refers to the development of negative effects that are attributed to medication, albeit the drug itself does not explain the provocation of these symptoms.