The Effect of TRIM5 Allelic Polymorphisms on Primary SIV/DeltaB670 Infections in Rhesus Macaques
Angela Amedee*1, H Michael2, N Lacour1, H Aamer2, and M Murphey-Corb2
1Louisiana State Univ Hlth Sci Ctr, New Orleans, US and 2Univ of Pittsburgh Sch of Med, PA, US
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 SIVmac251 and SIVmacE660
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.