Multiple blocks to human immunodeficiency virus type 1 replication in rodent cells

The recent identification of human gene products that are required for earl y steps in the human immunodeficiency virus type 1 (HIV-1) life cycle has r aised the possibility that rodents might be engineered to support HIV-1 inf ection. Therefore, we have examined the ability of modified mouse, rat, and hamster cell lines to support productive HIV-1 replication. Rodent cells, engineered to support Tat function by stable expression of a permissive cyc lin T1 protein, proved to be able to support reverse transcription, integra tion, and early gene expression at levels comparable to those observed in h uman cell lines. Surprisingly, however, levels of CD4- and coreceptor-depen dent virus entry were reduced to a variable but significant extent in both mouse and rat fibroblast cell lines. Additional posttranscriptional defects were observed, including a reduced level of unspliced HIV-1 genomic RNA an d reduced structural gene expression. Furthermore, the HIV-1 Gag precursor is generally inefficiently processed and is poorly secreted from mouse and rat cells in a largely noninfectious form. These posttranscriptional defect s, together, resulted in a dramatically reduced yield of infectious virus ( up to 10,000-fold) over a single cycle of HIV-1 replication, as compared to human cells. Interestingly, these defects were less pronounced in one hams ter cell line, CHO, which not only was able to produce infectious HIV-1 par ticles at a level close to that observed in human cells, but also could sup port transient, low-level HIV-1 replication. Importantly, the blocks to inf ectious virus production in mouse and rat cells are recessive, since they c an be substantially suppressed by fusion with uninfected human cells, These studies imply the existence of one or more human gene products, either lac king or nonfunctional in most rodent cells that are critical for infectious HIV-1 virion morphogenesis.