INFECTION OF HUMAN MARROW STROMA BY HUMAN IMMUNODEFICIENCY VIRUS-1 (HIV-1) IS BOTH REQUIRED AND SUFFICIENT FOR HIV-1-INDUCED HEMATOPOIETIC SUPPRESSION IN-VITRO - DEMONSTRATION BY GENE MODIFICATION OF PRIMARY HUMAN STROMA

Patients with human immunodeficiency virus-1 (HIV-1) infection often p resent with bone marrow (BM) failure that may affect all hematopoietic lineages. It is presently unclear whether this failure reflects a dir ect viral impairment of the CD34(+) hematopoietic progenitor cells or whether the virus affects the BM microenvironment. To study the effect s of HIV-1 on the BM microenvironment, we examined the stromal cell mo nolayers in long-term BM culture (LTBMC), which are the in vitro equiv alent of the hematopoietic microenvironment. We assessed the hematopoi etic support function (HSF) of human stromal layers by determining the cellular proliferation and colony-forming ability of hematopoietic pr ogenitors from BM cells grown on the stromal layers, We show that the HSF is reduced by in vitro infection of the human stromal cell layer b y a monocytotropic isolate of HIV-1 (JR-FL). There is no loss of HSF w hen the stromal cell layer is resistant to HIV-1 replication, either u sing murine stromal cell layers that are innately resistant to HIV-1 i nfection or using human stromal cells genetically modified to express a gene that inhibits HIV-1 replication (an RRE decoy), Decreased HSF w as seen using either human or murine hematopoietic cells, if the strom al cells were human cells that were susceptible to HIV-1 infection, Th ese in vitro studies implicate HIV-1 replication in the stroma as the essential component causing decreased hematopoietic cell production in HIV-1 infection. (C) 1997 by The American Society of Hematology.