Characterization of a CD4-independent clinical HIV-1 that can efficiently infect human hepatocytes through chemokine (C-X-C motif) receptor 4

Abstract

HIV-1 isolates are prominently CD4-dependent and, to date, only a few laboratory-adapted CD4-independent strains have been reported. Therefore, whether CD4-independent viruses may exist in HIV-1-infected patients has remained unclear. Here, we report the successful isolation of a CD4-independent clinical HIV-1 strain, designated SDA-1, from the viral quasispecies of a therapy-naive HIV-1 and Pneumocystis jirovecii pneumonia patient in the late-stage of AIDS with extremely low CD4 cell count (CD4 = 1/microl). We characterized this virus and further explored whether it could infect or induce pathological effects in human hepatocytes. To determine coreceptor usage and CD4-independent infection, the HIV-1 envelope (Env)-pseudotypes and Env-chimeric viruses were used. SDA-1 was able to infect CD4 cell lines through either chemokine (C-X-C motif) receptor 4 or CCR5. It still maintained the ability to infect CD4 cells through multiple coreceptors of chemokine (C-X-C motif) receptor 4, chemokine (C-C motif) receptor 5, chemokine (C-C motif) receptor 3 and chemokine (C-C motif) receptor 8. Productive infection by SDA-1 was noted in both CD4-negative hepatoma cells and primary cultured human hepatocytes. Moreover, we demonstrated that SDA-1 could efficiently infect human hepatocytes on both static and mitotic phases through chemokine (C-X-C motif) receptor 4, without inducing apoptotic cell death. The present study provides evidence that emergence of CD4-independent HIV-1 virus in vivo may occur in HIV-1-infected patients. In addition, these results shed light on the mechanisms involved in liver damage in HIV-1-infected individuals, which could have important implications concerning the range of mutability and the pathogenesis of AIDS.