Impaired replication of protease inhibitor-resistant HIV-1 in human thymus

Nat Med. 2001 Jun;7(6):712-8. doi: 10.1038/89090.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • CD4 Lymphocyte Count
  • Drug Resistance, Microbial
  • Fetal Tissue Transplantation
  • Flow Cytometry
  • HIV Core Protein p24 / metabolism
  • HIV Infections / immunology
  • HIV Infections / pathology
  • HIV Infections / virology*
  • HIV Protease / genetics
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Humans
  • Mice
  • Mice, SCID
  • Middle Aged
  • Organ Culture Techniques
  • Recombination, Genetic
  • T-Lymphocytes / physiology*
  • T-Lymphocytes / virology
  • Thymus Gland / pathology
  • Thymus Gland / physiopathology
  • Thymus Gland / transplantation
  • Thymus Gland / virology*
  • Viral Load
  • Virus Replication*


  • HIV Core Protein p24
  • HIV Protease Inhibitors
  • HIV Protease