Protease inhibitor-resistant HIV-1 from patients with preserved CD4 cell counts is cytopathic in activated CD4 T lymphocytes

Objective: To evaluate CD4 T-cell cytopathicity of protease inhibitor (PI)- resistant isolates from patients with preserved CD4 cell counts after long- term virologic failure. Methods: PI-resistant primary isolates from 14 patients with stable or incr easing CD4 T-cell counts despite long-term virologic failure during continu ous combination therapy were examined. Replication and cytopathicity were a ssessed in activated peripheral blood mononuclear cell cultures in the pres ence and absence of PI using titered stocks of primary HIV-1 isolates and d uring initial viral isolation. Also studied were PI-sensitive isolates from four of these patients after therapy discontinuation and reversion to PI-s ensitive virus and from seven antiretroviral drug-naive patients. Corecepto r use, syncytia-inducing (SI) phenotype and protease sequences were determi ned by standard methods. Results: All isolates obtained during continued therapy showed genetic mark ers of PI resistance and decreased phenotypic susceptibility. PI-resistant SI isolates were highly to moderately cytopathic whereas non-syncytia-induc ing isolates were moderately to weakly cytopathic. PI-susceptible and PI-re sistant isolates obtained after discontinuation of therapy were equally cyt opathic at similar replication levels. The cytopathicity of PI-resistant is olates was not altered by PI and was similar to that of isolates from untre ated subjects. Conclusions: Primary isolates from patients showing virologic rebound witho ut net CD4 T-cell loss during continued therapy are as cytopathic as PI-sen sitive isolates with equivalent input infectious titer. As with PI-sensitiv e isolates, cytopathicity of PI-resistant viruses was determined primarily by coreceptor preference. These results suggest that the sustained immunolo gic response observed after failure of PI-containing regimens is not due to the emergence of PI-resistant strains that are intrinsically less cytopath ic for activated peripheral CD4 lymphocytes. (C) 2001 Lippincott Williams & Wilkins.