Primary and recombinant HIV type 1 strains resistant to protease inhibitors are pathogenic in mature human lymphoid tissues

Preserved peripheral CD4(+) T cell counts despite virologic failure in pati ents undergoing protease inhibitor (PI)-containing antiviral regimens are a frequent occurrence in human immunodeficiency virus (HIV) disease. One hyp othesis to explain the relative sparing of CD4+ T cells is that HIV strains exhibiting PI resistance concomitantly are attenuated in terms of cytopath icity for mature T cells. To test this hypothesis, we used a three-dimensio nal human tonsil histoculture microenvironment to assess the pathogenic pot ential of a panel of primary and recombinant HIV-1 strains derived from pat ients experiencing PI failure. All the viruses tested replicated efficientl y in these cultures and, in some cases, better than comparable wild-type vi ral isolates. Furthermore, the PI-resistant strains depleted CD4(+) T cells potently and comparably with wild-type isolates in these ex vivo lymphoid tissues. These results demonstrate that PI-resistant viruses are not inhere ntly less pathogenic for mature T cells. Therefore, the sustained periphera l lymphocyte counts in patients with selective virologic failure may be due to specific defects in viral replication in other cell compartments or to an undefined host adaptation to viral infection during PI therapy.