Impaired replication of protease inhibitor-resistant HIV-1 in human thymus

Many HIV-1-infected patients treated with protease inhibitors (PI) develop PI-resistant HIV-1 variants and rebounds in viremia, but their CD4(+) T-cel l counts often do not fall. We hypothesized that in these patients, T-cell counts remain elevated because PI-resistant virus spares intrathymic T-cell production. To test this, we studied recombinant HIV-1 clones containing w ild-type or PI-resistant protease domains, as well as uncloned isolates fro m patients, in activated peripheral blood mononuclear cells, human thymic o rgan cultures and human thymus implants in SCID-hu Thy/Liv mice. In most ca ses, wild-type and PI-resistant HIV-1 isolates replicated to similar degree s in peripheral blood mononuclear cells. However, the replication of PI-res istant but not wild-type HIV-1 isolates was highly impaired in thymocytes. In addition, patients who had PI-resistant HIV-1 had abundant thymus tissue as assessed by computed tomography. We propose that the inability of PI-re sistant HIV-1 to replicate efficiently in thymus contributes to the preserv ation of CD4(+) T-cell counts in patients showing virologic rebound on PI t herapy.