R5 human immunodeficiency virus type 1 infection of fetal thymic organ culture induces cytokine and CCR5 expression.
Late-stage CCR5 tropic human immunodeficiency virus type 1 (HIV-1) isolates (R5 HIV-1) can deplete nearly all CD4+ thymocytes from human thymus/liver grafts, despite the fact that fewer than 5% of these cells express CCR5. To resolve this paradox, we studied the replication and cytopathic effects (CPE) of late-stage R5 HIV-1 biological clones from two progressors and two long-term nonprogressors (LTNP) in fetal thymic organ culture (FTOC) with and without added cytokines. We found that R5 HIV-1 clones from progressors but not LTNP were cytopathic in untreated FTOC. Moreover, R5 HIV-1 clones from progressors replicated to higher levels than LTNP-derived R5 HIV-1 clones in this system. In contrast, when FTOC was maintained in the presence of interleukin 2 (IL-2), IL-4, and IL-7, both progressor and LTNP clones exhibited similar replication and CPE, which were equal to or greater than the levels achieved by progressor-derived R5 HIV-1 clones in untreated FTOC. This finding was likely due to IL-2-induced CCR5 expression on CD4+ thymocytes in FTOC. R5 HIV-1 clones showed greater pathogenesis for CCR5+ cells but also showed evidence of CPE on CCR5- cells. Furthermore, infection of FTOC by R5 HIV-1 induced IL-10 and transforming growth factor beta (TGF-beta) expression. Both IL-10 and TGF-beta in turn induced CCR5 expression in FTOC. Induction of CCR5 expression via cytokine induction by R5 HIV-1 infection of CCR5+ thymocytes likely permitted further viral replication in newly CCR5+ thymocytes. CCR5 expression, therefore, is a key determinant of pathogenesis of R5 HIV-1 in FTOC.
Choudhary
Shailesh K
SK
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697-3900, USA.
Choudhary
Neelima R
NR
Kimbrell
Katherine C
KC
Colasanti
Jonathan
J
Ziogas
Argyrios
A
Kwa
David
D
Schuitemaker
Hanneke
H
Camerini
David
D
D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral; D005333:Fetus; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D009924:Organ Culture Techniques; D019713:Receptors, CCR5 / Q000378:metabolism*; D013950:Thymus Gland / Q000821:virology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014779:Virus Replication
D016207:Cytokines; D019713:Receptors, CCR5; D016212:Transforming Growth Factor beta; D016753:Interleukin-10