Oral Abstract Presentations|
Session Day and Time: Thursday 10 am - 12:30 pm
Presentation Time: 12:00
Room: Ballroom A
Background: The induction of effective humoral immune responses involves bi-directional interactions between B cells and CD4+ T-cells, the most important of which is the upregulation on activated B cells of CD80/CD86 that then stimulate CD4+ T-cells through ligation of CD28. Here we report the effect of HIV viremia on the capacity of B cells to stimulate CD4+ T-cells through CD80/CD86-CD28 interactions.
Methods: B-cells isolated from peripheral blood mononuclear cells (PBMC) were stimulated with goat anti-human IgM and CD40 ligand (CD40L). At day 2, cells were recovered, stained for activation markers, irradiated, and incubated with allogeneic CD4+ T-cells isolated from PBMCs of healthy HIV- individuals. CD4+ T-cells were assayed at day 5 for activation, as measured by expression of CD25 and CD40L, and for proliferation by thymidine incorporation.
Results: In healthy HIV- donors, CD4 T-cell responsiveness to activated B-cells was dependent on levels of CD80/CD86 expression on B-cells, as indicated by lack of activation and proliferation in the presence of blocking mAbs against CD80/CD86. In the majority of HIV-infected viremic patients (pts) studied, B-cells were ineffective at stimulating CD4+ T-cells although partial responses could be reconstituted by the addition of exogenous CD28 ligands. The lack of B-cell stimulatory function in HIV viremic pts was associated with a reduced induction of CD80/CD86 on the activated B-cells as well as with a reduction in activation and proliferation of responding CD4+ T-cells. The latter phenomenon was similar to that observed in healthy HIV- donors with blocking anti-CD80/CD86 mAbs. In longitudinal analyses, where the impact of HIV plasma viremia on CD4+ T responsiveness to B-cells was investigated, reduction of plasma viremia by effective antiretroviral therapy resulted in the normalization of the ability of B-cells to upregulate CD80/CD86 upon BCR/CD40-triggering, thus restoring their capacity to stimulate CD4+ T-cells.
Conclusions: B-cells of HIV-infected viremic pts show impaired induction of co-stimulatory molecules CD80/CD86 that leads to inadequate stimulation of CD28 on responder CD4+ T-cells. These findings provide new insight into the scope of B-ell defects associated with viremia in HIV disease and how these defects may impact cognate interactions with CD4+ T-cells.