Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue

Objective: Lymphoid tissue provides a reservoir where HIV can persist. Howe ver, therapies incorporating a protease inhibitor can target this reservoir . This study was designed to investigate the relative long-term effects on lymph-node viral load and cellular architecture of regimens containing mult iple nucleosides alone or in combination with protease inhibitors. Methods: Axillary lymph-node biopsies from 12 patients with undetectable vi raemia (viral load < 20 copies/ml; mean CD4 cells 525 x 10(6)/l for a mean period of 25 months (range, 10-52 months) were investigated for the presenc e of HIV by in situ hybridization and coculture. Four patients were receivi ng multiple nucleoside analogues alone or in one case with a suboptimally d osed protease inhibitor (group I). Protease inhibitor was added to the regi men of seven patients at least 6 months prior to lymph-node biopsy (group I I). Standard flow cytometry and virological data were obtained from periphe ral blood every 3 months. Results: By in situ hybridization, more productively infected CD4+ T cells were found in the lymph nodes of group I patients treated with nucleoside a nalogues alone. Very low numbers of productively infected lymph node cells were detected in the protease inhibitor-treated group II. No trapping of vi rions on the follicular dendritic cell (FDC) network was detectable in prot ease inhibitor-treated patients. In contrast, large deposits of FDC-bound v irions were observed in three out of five patients from group I. Virus cult ures from lymph node cells were positive in these three group I patients co mpared with only one out of seven patients from group II. Sequencing revers e transcriptase and protease genes from these isolates revealed typical mut ations conferring resistance to the previously administered nucleoside anal ogue. A more preserved lymph node architecture and less signs of immunopath ological change were also observed in protease inhibitor-treated patients. Conclusions: Undetectable plasma viraemia using the ultrasensitive PCR assa y for prolonged periods of time does not always reflect complete HIV-1 supp ression within the lymphoid compartment. Our results suggest that protease inhibitor-containing regimens target HIV reservoirs in lymphoid tissue more effectively and preserve or restore lymph node architecture. (C) 1999 Lipp incott Williams & Wilkins.