REQUIREMENT OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 NEF FOR IN-VIVO REPLICATION AND PATHOGENICITY

The role of human immunodeficiency virus type 1 (HIV-1) accessory genes in pathogenesis has remained unclear because of the lack of a suitable in vivo model. The most controversial of these genes is nef. We investigated the requirement for Nef for in vivo replication and pathogenicity of two isolates of HIV-1 (HIV-1(JR-CSF) and HIV-1(NL+3)) in human fetal thymus and liver implants in severe combined immunodeficient mice. HIV-1(JR-CSF) and HIV-1(NL4-3) differ in their in vitro phenotypes in that HIV-1(JR-CSF) does not induce syncytia and is relatively noncytopathic, while HIV-1(NL4-3) is highly cytopathic and readily inducers syncytia. The nef mutants of both isolates grew with kinetics similar to those of parental virus strains in stimulated peripheral blood Iymphocytes but demonstrated attenuated growth properties in vivo. HIV-1(NL4-3) induced severe depletion of human thymocytes within 6 necks of infection, whereas its nef mutant did not. Thus, HIV-1 Nef is required for efficient in vivo viral replication and pathogenicity.