REGIONS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 NEF REQUIRED FOR FUNCTION IN-VIVO

In vivo studies in monkeys and humans have indicated that immunodefici ency viruses with Nef deleted are nonpathogenic in immunocompetent hos ts, and this has motivated a search for live attenuated vaccine candid ates. However, the mechanisms of action of Nef remain elusive. To defi ne the regions of human immunodeficiency virus type 1 (HIV-1) Nef whic h mediate in vivo pathogenicity, a series of mutated isogenic viruses were inoculated into human thymic implants in SCID-hu mice. Mutation o f several regions, including the myristoylation site at the second gly cine and a region encompassing amino acids 41 through 49 of Nef, profo undly affected pathogenicity. Surprisingly, mutations of prolines in e ither of the two distant PXXP SH3 binding domains did not affect patho genicity, indicating that these regions are not required for Nef activ ity in developing T-lineage cells. These data suggest that some functi ons of Nef described in vitro may not be relevant for in vivo pathogen icity.