Abstract
A
nef
gene is present in all primate lentiviruses, including human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus of macaque monkeys (SIVmac). However, the
nef
genes of HIV-1 and SIVmac exhibit minimal sequence identity, and not all properties are shared by the two. Nef sequences of SIVmac239 were replaced by four independent
nef
alleles of HIV-1 in a context that was optimal for expression. The sources of the HIV-1
nef
sequences included NL 4-3, a variant NL 4-3 gene derived from a recombinant-infected rhesus monkey, a patient
nef
allele, and a
nef
consensus sequence. Of 16 rhesus monkeys infected with these SHIVnef chimeras, 9 maintained high viral loads for prolonged periods, as observed with the parental SIVmac239, and 6 have died with AIDS 52 to 110 weeks postinfection. Persistent high loads were observed at similar frequencies with the four different SIV recombinants that expressed these independent HIV-1
nef
alleles. Infection with other recombinant SHIVnef constructions resulted in sequence changes in infected monkeys that either created an open
nef
reading frame or optimized the HIV-1
nef
translational context. The HIV-1
nef
gene was uniformly retained in all SHIVnef-infected monkeys. These results demonstrate that HIV-1
nef
can substitute for SIVmac
nef
in vivo to produce a pathogenic infection. However, the model suffers from an inability to consistently obtain persisting high viral loads in 100% of the infected animals, as is observed with the parental SIVmac239.
