Differential effects of R5 and X4 human immunodeficiency virus type 1 infection on CD4+ cell proliferation and activation

Abstract

Human immunodeficiency virus type 1 (HIV-1) isolates can be distinguished by their chemokine coreceptor usage. Non-syncytium-inducing (NSI), macrophage-tropic viruses utilize CCR5 and are called R5 viruses; syncytium-inducing (SI) isolates use CXCR4 and are known as X4 viruses. R5 and X4 HIV isolates are both transmitted but, in most cases, R5 viruses predominate in the blood prior to the development of AIDS-related pathogenesis. The reason for the selective growth of the R5 strain is not known, but could reflect a replication advantage of R5 viruses over X4 viruses in CD4+cells. To explore this possibility, eight phenotypically distinct viruses were used to infect CD4+cells and cellular proliferation and activation were evaluated. In unstimulated CD4+cells, R5 virus isolates increased the level of cell activation compared with X4 virus isolates and uninfected control cells. In CD4+cells that were stimulated with interleukin 2, both R5 and X4 viruses were found to decrease the level of cell proliferation and reduce the majority of the activation markers studied when compared with uninfected control CD4+cells from the same donors. However, although equal amounts of CD4+cells were infected, R5 virus-infected CD4+cells showed a two- to fourfold increase in cellular proliferation over X4 viruses, as measured by [3H]thymidine incorporation (P=0·001) and nuclear expression of Ki67 (P=0·001). In addition, a larger proportion of CD4+T cells infected with R5 viruses had significantly higher levels of activation-marker expression (e.g. CD25, CD71 and HLA-DR) than CD4+T lymphocytes infected with X4 viruses (P<0·02). Taken together, these results indicate that CD4+cells infected with R5 virus isolates may have a selective advantage over X4 virus-infected CD4+T cells for survival and, hence, virus spread.