This study shows that memory CTL responses against HIV-1 RT, integrase and protease are detectable in most patients at different stages of disease. The capacity of CTL to recognize simultaneously clusters of epitopes may become important for the immune control to reinforce antiretroviral drug efficiency.
We previously identified an immunodominant CD4+ T cell determinant in the carboxy-terminal region of HIV-1 reverse transcriptase (RT528-543). The present study aimed at enumerating all the potential sites of HIV-1 RT recognized by Th cells in the BALB/c (H-2d) mouse model. To achieve this we used a panel of 62 overlapping 15-mer synthetic peptides covering the whole RT sequence to assay the following parameters: (i) immunogenicity in naive BALB/c mice injected either with peptides pools or individual peptides; (ii) antigenicity, as detected by their ability to restimulate in vitro T cells from BALB/c mice primed with native RT; (iii) MHC class II (Ad)-binding capacity as measured by the inhibition of the antigen-specific, Ad-restricted presentation of unfolded apamin (4-Acm) by fixed antigen-presenting cells to Ad/4-Acm-specific, interleukin-2-producing T hybridoma cells; and (iv) the presence of typical or degenerate consensus Ad-binding motifs. The results in this study permitted identification of three novel immunodominant RT mouse CD4+ T cell sites (RT276-290, RT375-389 and RT411-425) located in regions of limited polymorphism among RT from several HIV isolates. Some of these RT segments were found to be in the vicinity of B cell or H-2Kk- or HLA-A2-restricted cytotoxic T lymphocyte epitopes. Finally, the approach used in this study was found to be very efficient for enumerating most T cell recognition sites in a complex protein, a result that would have not been achieved by a single parameter-based analysis.
Mapping and possible diagnostic meaning of a highly conserved, linear NS4 epitope (NS4/3), located outside the C100-3 antigen within the carboxyl terminal proportion of the NS4 region, with major immunoreactivity with specimens of patients with HCV infection from various geographic origins is described. Transient, acute-phase IgM anti-HCV NS4/3 was detected coincidentally or earlier than active IgG anti-HCV NS4/3 response with four well-characterized seroconversion panels. GenBank alignment studies identified patch homologies between the NS4/3 sequence and a number of non-HCV proteins, which may explain part of the cross-reactivity of the NS4/3 epitope. Some of the "false positive reactivities" of the NS4/3 epitope with asymptomatic blood donors, not being confirmed with FDA-approved anti-HCV assays without the NS4/3 epitope, may be explained by recognition of very early seroconversion antibodies.
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