Gm. Aldrovandi et al., REGIONS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 NEF REQUIRED FOR FUNCTION IN-VIVO, Journal of virology, 72(9), 1998, pp. 7032-7039
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.