Background:  Recent studies indicate that host genetic factors may play a major role in controlling HIV infection in humans. Determining how these factors affect SIV infection in the macaque model for AIDS is critical to the development of effective therapies and vaccines. Allelic variation in the gene encoding the viral resistance factor, TRIM5 has been shown to affect HIV replication in vitro and disease progression in vivo induced by both SIV_mac251 and SIV_macE660 isolates. Here we examine the relationship of TRIM5 with virus burden and response to the antiviral drug PMPA in macaques infected with the primary rhesus-grown isolate, SIV/DeltaB670.
Methods:  The major allelic variations of TRIM5, TFP, CypA, and Q were determined in 48 rhesus macaques in a therapeutic vaccine trial. Macaques were intravenously infected with SIV/DeltaB670 and 6 weeks later, daily therapy with PMPA was initiated and continued for 10 months. One month after the start of therapy, monkeys were divided into 3 groups, with one serving as a drug-treated control and the other 2 given 8 monthly immunizations with 2 different DNA vaccines. The relationship between the TRIM5 haplotype and acute (7 and 14 days) and set-point (42 days) plasma viral load, and viral rebound when drug was stopped was analyzed by nonparametric Mann-Whitney. The relationship between TRIM5 and PMPA responsiveness was analyzed using Fisher’s exact and log rank tests.
Results:  The plasma viral load at 7 days post-infection was significantly lower in animals with the restrictive genotype TFP/TFP when compared to those with TFP/Q and all genotypes (p = 0.003 and 0.001). This difference resolved by 14 days, however, with plasma viral loads at all time points thereafter similar among the groups. No association between TRIM5 genotypes and PMPA response was observed. Protection from viral rebound by either therapeutic vaccine, one of which significantly reduced rebound, was also not associated with a specific allele.
Conclusions:  Although the first rounds of SIV/DeltaB670 replication (>7 days) in vivo are apparently affected by specific TRIM5 alleles, this effect is overridden by other, more dominant factors, as infection proceeds. The response to PMPA and the ability of a therapeutic vaccine to control viral rebound when therapy is stopped are also independent of TRIM5. Virus-specific immunity, and not an inherent difference in the resistance factor, TRIM5, plays a more dominant role in controlling SIV/DeltaB670 infection in vivo.