interferon-gamma, perhaps 60 percent become infected, with virus yields going up proportionately.
In this case, memory T-cells and CD8 T-cells are present in high numbers because of the recent infection with a crossreactive strain. These T-cells are stimulating their MHC molecules, and as a result they wind up acting at least in part as antigen-presenting cells. They also bear cross-one, cross-two FC receptors on their surface; secondary infection is more efficient because crossreactive antibodies bind to the viral protein and help it enter via the FC receptors. The result is more infected monocytes, which function as virus factories.
Activated T-cells produce cytokines and other products that can affect capillary action, and killed monocyte may also release vasoactive compounds. The target cell for dengue infection appears to be the RE monocyte, and virus antigen is not seen in endothelial cells. Researchers currently believe that endothelial cells are leaking because of cytokine alteration of their function. Hence, research is focusing on the serum, T-cells, and other peripheral monocytes in order to understand the basic mechanism of immunopathogenesis.
Human T-cell Responses to Dengue. The three-dimensional structure of an HLA class II MHC molecule shows a so-called A-2 crypt that holds an endogenous peptide—the antigen. In the case of the dengue virus, CD4 T-cells initially recognize the infection in the form of dengue peptides being presented in HLA class II molecules on the surface of antigen-presenting cells.
Following primary infection with dengue type 1, stimulated peripheral blood monocytes will respond most strongly to the dengue-1 antigen, but there is also a lesser response to the three other serotypes. Analysis shows that about 1 cell in 1,000 will be positive for dengue-1, and about 1 cell in 10,000 will be positive for dengue-2, 3, and 4. To determine the smallest amino acid sequence that CD4 T-cells would recognize, researchers identified and reproduced these crossreactive T-cells using limiting dilution cloning. They then conducted a series of experiments in which the cells were infected with vaccinia virus that expresses the dengue protein. As the protein was truncated, peptide analysis identified the amino acid sequence to which the CD4 T-cell clone responded—in this case, viral nonstructural protein 3 (NS-3).
The results confirm the polymorphism of T-cell response to dengue virus NS-3. As with hepatitis C, dengue NS-3 apparently contains multiple T-cell epitopes with very different specificities. In the case of a subject who had been immunized with dengue-3, all T-cell clones recognized the epitope for dengue-3, but with four degrees of crossreactivity: (1) just dengue-3; (2) dengue-2, 3, and 4, but not 1; (3) dengue-1, 2, and 3, but not 4; and (4) dengue-1 through -4 plus West Nile and yellow fever virus, both of which are also flaviviruses. In another subject immunized with dengue-4, analysis found T-cell clones that reacted to (5) just dengue-4; (6) dengue-2 and 4; and (7) dengue-1, 2, 3, and 4. Within each serotype, there were three or four distinct epitopes on the viral NS-3.
This polymorphism—multiple T-cell epitopes to the viral protein—probably is not unique to dengue. But in dengue it contributes to the T-cell activation level because of the epidemiology of the close circulating viruses.