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-cell 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 wild-type or PI-resistant protease domains, as well as uncloned isolates from patients, in activated peripheral blood mononuclear cells, human thymic organ cultures and human thymus implants in SCID-hu Thy/Liv mice. In most cases, wild-type and PI-resistant HIV-1 isolates replicated to similar degrees in peripheral blood mononuclear cells. However, the replication of PI-resistant 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-resistant HIV-1 to replicate efficiently in thymus contributes to the preservation of CD4+ T-cell counts in patients showing virologic rebound on PI therapy.
Stoddart
C A
CA
Gladstone Institute of Virology and Immunology, University of California at San Francisco, San Francisco, California, USA.
Liegler
T J
TJ
Mammano
F
F
Linquist-Stepps
V D
VD
Hayden
M S
MS
Deeks
S G
SG
Grant
R M
RM
Clavel
F
F
McCune
J M
JM
D000328:Adult; D000818:Animals; D018791:CD4 Lymphocyte Count; D004352:Drug Resistance, Microbial; D016332:Fetal Tissue Transplantation; D005434:Flow Cytometry; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009924:Organ Culture Techniques; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000502:physiology* / Q000821:virology; D013950:Thymus Gland / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation / Q000821:virology*; D019562:Viral Load; D014779:Virus Replication
D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D016333:HIV Protease