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. However, 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 multiple nucleosides alone or in combination with protease inhibitors.


METHODS
Axillary lymph-node biopsies from 12 patients with undetectable viraemia (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 presence of HIV by in situ hybridization and coculture. Four patients were receiving multiple nucleoside analogues alone or in one case with a suboptimally dosed protease inhibitor (group I). Protease inhibitor was added to the regimen of seven patients at least 6 months prior to lymph-node biopsy (group II). Standard flow cytometry and virological data were obtained from peripheral 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 analogues alone. Very low numbers of productively infected lymph node cells were detected in the protease inhibitor-treated group II. No trapping of virions on the follicular dendritic cell (FDC) network was detectable in protease inhibitor-treated patients. In contrast, large deposits of FDC-bound virions were observed in three out of five patients from group I. Virus cultures from lymph node cells were positive in these three group I patients compared with only one out of seven patients from group II. Sequencing reverse transcriptase and protease genes from these isolates revealed typical mutations conferring resistance to the previously administered nucleoside analogue. A more preserved lymph node architecture and less signs of immunopathological change were also observed in protease inhibitor-treated patients.


CONCLUSIONS
Undetectable plasma viraemia using the ultrasensitive PCR assay for prolonged periods of time does not always reflect complete HIV-1 suppression 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.
Ruiz
L
L
Retrovirology Laboratory, Fundació irsiCaixa, Badalona, Spain.
van Lunzen
J
J
Arno
A
A
Stellbrink
H J
HJ
Schneider
C
C
Rull
M
M
Castellà
E
E
Ojanguren
I
I
Richman
D D
DD
Clotet
B
B
Tenner-Racz
K
K
Racz
P
P
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D018920:Coculture Techniques; D003713:Dendritic Cells; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008221:Lymphoid Tissue / Q000821:virology; D009705:Nucleosides / Q000627:therapeutic use*; D012367:RNA, Viral; D019562:Viral Load; D014779:Virus Replication
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009705:Nucleosides; D012367:RNA, Viral