Presence of intact vpu and nef genes in nonpathogenic SHIV is essential for acquisition of pathogenicity of this virus by serial passage in macaques

Use of the macaque model of human immunodeficiency virus (HIV) pathogenesis has shown that the accessory genes nef and vpu are important in the pathogenicity of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). We examined the ability of two nonpathogenic SHIVs, SHIV_PPC and ΔvpuΔnefSHIV_PPC, to gain pathogenicity by rapid serial passage in macaques. In this study, each virus was passaged by blood intravenously four times at 4-week intervals in macaques. Animals were monitored for 40 weeks for levels of CD4 T cells and quantitative measures of virus infection. ΔvpuΔnefSHIV_PPC maintained a limited phase of productive replication in the four animals, with no loss of CD4⁺ T cells, whereas SHIV_PPC became more pathogenic in later passages, judging by plasma viral load and viral mRNA in lymph nodes, infectious peripheral blood mononuclear cells and CD4⁺ T cell loss. The nef, LTR, and env of the SHIV_PPC viruses underwent numerous mutations, compared to ΔvpuΔnefSHIV_PPC. This study confirms the seminal role that nef, LTR, and vpu could play in regulation of pathogenesis of HIV infection.