Abstract
Infection of macaques with live attenuated simian immunodeficiency virus (SIV) usually results in long-lasting efficient protection against infection with pathogenic immunodeficiency viruses. However, attenuation by deletion of regulatory genes such as nef is not complete, leading to a high viral load and fatal disease in some animals. To characterize immunological parameters and polymorphic host factors, we studied 17 rhesus macaques infected with attenuated SIVmac239ΔNU. Eight animals were able to control viral replication, whereas the remaining animals (non-controllers) displayed variable set-point viral loads. Peak viral load at 2 weeks post-infection (p.i.) correlated significantly with set-point viral load (P<0.0001). CD4+ T-cell frequencies differed significantly soon after infection between controllers and non-controllers. Abnormal B-cell activation previously ascribed to Nef function could already be observed in non-controllers 8 weeks after infection despite the absence of Nef. Two non-controllers developed an AIDS-like disease within 102 weeks p.i. Virus from these animals transmitted to naïve animals replicated at low levels and the recipients did not develop immunodeficiency. This suggested that host factors determined differential viral load and subsequent disease course. Known Mhc class I alleles associated with disease progression in SIV WT infection only marginally influenced the viral load in Δnef-infected animals. Protection from SIVmac251 was associated with homozygosity for MHC class II in conjunction with a TLR7 polymorphism and showed a trend with initial viral replication. We speculated that host factors whose effects were usually masked by Nef were responsible for the different disease courses in individual animals upon infection with nef-deleted viruses.
Highlights
Infection or immunization with live attenuated human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) protects efficiently against symptoms of AIDS or infection with pathogenic immunodeficiency viruses (Daniel et al, 1992; Gorry et al, 2007; Koff et al, 2006; Whitney & Ruprecht, 2004)
Variation of viral load and disease progression in rhesus monkeys infected with nef-deleted SIVmac
The protective immune responses induced by infection with nef-deleted SIVs have been considered to be instructive for the development of an effective AIDS vaccine (Daniel et al, 1992; Koff et al, 2006; Whitney & Ruprecht, 2004)
Summary
Infection or immunization with live attenuated human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) protects efficiently against symptoms of AIDS or infection with pathogenic immunodeficiency viruses (Daniel et al, 1992; Gorry et al, 2007; Koff et al, 2006; Whitney & Ruprecht, 2004). The commonly used live attenuated viruses for experimental immunization of macaques harbour deletions in the viral nef gene. As early as 3 weeks and as late as 2 years after immunization, juvenile and adult macaques can be protected against superinfection with pathogenic SIV (Sharpe et al, 2004; Stebbings et al, 2004). Several reports have shown that protection can be obtained in the presence of low or even absent cellular or humoral immune responses (Mansfield et al, 2008; Nilsson et al, 1998; Stahl-Hennig et al, 2007; Stebbings et al, 2005)
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