The human immunodeficiency virus type 1 nef gene can to a large extent replace simian immunodeficiency virus nef in vivo

The nef gene of the pathogenic simian immunodeficiency virus (SIV) 239 clon e was replaced with primary human immunodeficiency virus type 1 (HIV-1) nef alleles to investigate whether HIV-1 Nef can substitute for SIV Nef in viv o. Initially, two rhesus macaques were infected with the chimeric viruses ( Nef-SHIVs). Most of the nef alleles obtained from both animals predicted in tact open reading frames. Furthermore, forms containing upstream nucleotide substitutions that enhanced expression of the inserted gene became predomi nant. One animal maintained high viral loads and slowly progressed to immun odeficiency. nef long terminal repeat sequences amplified from this animal were used to generate a second generation of Nef-SHIVs. Two macaques, which were subsequently infected with a mixture of cloned chimeric viruses, show ed high viral loads and progressed to fatal immunodeficiency. Five macaques received a single molecular clone, named SHIV-40K6. The SHIV-40K6 nef alle le was active in CD4 and class I major histocompatibility complex downregul ation and enhanced viral infectivity and replication. Notably, all of the m acaques inoculated with SHIV-40K6 showed high levels of viral replication e arly in infection. During later stages, however, the course of infection wa s variable. Three animals maintained high viral loads and developed immunod eficiency. Of the remaining two macaques, which showed decreasing viral loa ds after the acute phase of infection, only one efficiently controlled vira l replication and remained asymptomatic during 1.5 years of follow-up. The other animal showed an increasing viral load and developed signs of progres sive infection during later stages. Our data demonstrate that HIV-1 nef can , to a large extent, functionally replace SIVmac nef in vivo.