Lentiviruses infect both dividing and nondividing cells. In in pHP. The ability of this vector system to transduce dividthis study we characterized a lentiviral vector system coning and nondividing cell in vitro and in vivo was also demsisting of a packaging vector (pHP) and a transducing veconstrated. Compared with a Moloney murine leukemia tor (pTV) derived from a recombinant human immunodefivirus (MLV) vector, the HP/TV vectors transduced human ciency virus type 1 (HIV-1). In pHP, the long terminal muscle-, kidney-, liver-derived cell lines and CD34 + primary repeats (LTRs), the 5Ј untranslated leader and portions of hematopoietic progenitor cells more efficiently. Although the env and nef genes were deleted. The leader sequence the levels of the pTV transgene expression were high soon of pHP was substituted with a modified Rous sarcoma virus after transduction, the expression tended to decrease with (RSV) 59 bp leader containing a mutated RSV gag AUG time due either to the loss of proviral DNA or to the inactiand a functional 5Ј splice site. The pHP construct was vation of promoter activity, which was found to be cell typefound to direct Gag-Pol synthesis as efficiently as wild-type dependent. Analyses of extrachromosomal DNA showed HIV-1. The pTV construct contains sequences required for that the unintegrated proviral DNA of lentiviral vectors sur-RNA packaging, reverse transcription and integration, but vived much longer than that of the retroviral vectors. We lacks viral genes. Co-transfection of pHP, pTV and a vesdemonstrate that the HP/TV vector is capable of high icular stomatitis virus G (VSV-G) envelope plasmid proefficiency transduction and that long-term expression of duced vectors at titers of 10 5 -10 6 transducing units per lentiviral vectors is dependent on target cell type, the milliliter in 48 h. Replication-competent virus (RCV) was internal promoter and the transgene itself in the transducnot detected when deletions were made in the env gene ing vector.
The growth inhibitory effects of Vpr and Vpx are species- and cell type-dependent. HIV-1, HIV-2 and SIV Vpr are primarily cytostatic in mammalian cells and HIV-1 Vpr has been reported to induce apoptosis in human cells. Our previous studies have shown that HIV-1, HIV-2 and SIV Vpr and Vpx have differential cytostatic and cytotoxic effects in the yeast cells [Zhang et al.: Virology, 230:103-112; 1997]. Here, we further examined the apoptosis function of HIV-1 Vpr in different species of mammalian cells and investigated if other primate lentiviral Vpr and Vpx exert similar functions. Our results show that none of the primate lentiviral Vpr or Vpx we tested induces apoptosis in nonhuman species of mammalian cells. However, HIV-1 Vpr, but not HIV-2 or SIV Vpr and/or Vpx, induced apoptosis in different types of human cell lines. Further, the apoptotic effect of HIV-1 Vpr can be distinguished from that of the human interferon-gamma, a known proapoptotic protein, that HIV-1 Vpr shows little to no paracrine and/or bystander effect. When coexpressed with Bcl-2 or Bcl-X(L), the apoptotic effect of HIV-1 Vpr became markedly attenuated. These results indicate that the apoptotic effect of HIV-1 Vpr is species-dependent and is intracellularly modulated by the Bcl-2 family of proteins. Our study also suggests that the proapoptotic function of HIV-1 Vpr is developmentally associated with human but not nonhuman primate species.
The growth inhibitory effects of Vpr and Vpx are species- and cell type-dependent. HIV-1, HIV-2 and SIV Vpr are primarily cytostatic in mammalian cells and HIV-1 Vpr has been reported to induce apoptosis in human cells. Our previous studies have shown that HIV-1, HIV-2 and SIV Vpr and Vpx have differential cytostatic and cytotoxic effects in the yeast cells [Zhang et al.: Virology, 230:103–112; 1997]. Here, we further examined the apoptosis function of HIV-1 Vpr in different species of mammalian cells and investigated if other primate lentiviral Vpr and Vpx exert similar functions. Our results show that none of the primate lentiviral Vpr or Vpx we tested induces apoptosis in nonhuman species of mammalian cells. However, HIV-1 Vpr, but not HIV-2 or SIV Vpr and/or Vpx, induced apoptosis in different types of human cell lines. Further, the apoptotic effect of HIV-1 Vpr can be distinguished from that of the human interferon-γ, a known proapoptotic protein, that HIV-1 Vpr shows little to no paracrine and/or bystander effect. When coexpressed with Bcl-2 or Bcl-XL, the apoptotic effect of HIV-1 Vpr became markedly attenuated. These results indicate that the apoptotic effect of HIV-1 Vpr is species-dependent and is intracellularly modulated by the Bcl-2 family of proteins. Our study also suggests that the proapoptotic function of HIV-1 Vpr is developmentally associated with human but not nonhuman primate species.
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