ABSTRACT
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.
Subject(s)
HIV Infections/virology , HIV Protease Inhibitors/pharmacology , HIV Protease/metabolism , HIV-1/drug effects , HIV-1/physiology , T-Lymphocytes/physiology , Thymus Gland/virology , Virus Replication , 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 Protease/genetics , HIV-1/enzymology , HIV-1/genetics , Humans , Mice , Mice, SCID , Middle Aged , Organ Culture Techniques , Recombination, Genetic , T-Lymphocytes/virology , Thymus Gland/pathology , Thymus Gland/physiopathology , Thymus Gland/transplantation , Viral LoadABSTRACT
Oral administration of 2'-deoxy-3'-oxa-4'-thiocytidine (BCH-10652), a nucleoside analog structurally similar to lamivudine (3TC), caused dose-dependent inhibition of viral replication in SCID-hu Thy/Liv mice infected with human immunodeficiency virus type 1 NL4-3 and with an NL4-3 clone containing the M184V mutation in reverse transcriptase that confers resistance to 3TC. These experiments demonstrate the utility of this mouse model for evaluating drug resistance and for performing direct comparisons between antiviral compounds in vivo.
Subject(s)
Anti-HIV Agents/pharmacology , Deoxycytidine/analogs & derivatives , HIV-1/drug effects , Lamivudine/pharmacology , Thionucleosides/pharmacology , Animals , Deoxycytidine/pharmacology , Disease Models, Animal , Drug Resistance, Microbial , HIV Infections/drug therapy , HIV Infections/virology , HIV Reverse Transcriptase/genetics , HIV-1/physiology , Humans , Leukocytes, Mononuclear/virology , Mice , Mice, SCID , Reverse Transcriptase Inhibitors/pharmacology , Virus Replication/drug effectsABSTRACT
Some individuals infected with only R5 strains of human immunodeficiency virus type 1 progress to AIDS as quickly as individuals harboring X4 strains. We determined that three R5 viruses were much less pathogenic than an X4 virus in SCID-hu Thy/Liv mice, suggesting that R5 virus-mediated rapid disease progression is associated with host, not viral, factors.
