Abstract
BackgroundWe reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251) mutants with a K65R mutation in reverse transcriptase (RT), and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. Because of significant sequence differences between SIV and HIV-1 RT that affect drug susceptibilities and mutational patterns, it is unclear to what extent findings with SIV can be extrapolated to HIV-1 RT. Accordingly, to model HIV-1 RT responses, 12 macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, and started on prolonged tenofovir therapy 5 months later.ResultsThe early virologic response to tenofovir correlated with baseline viral RNA levels and expression of the MHC class I allele Mamu-A*01. For all animals, sensitive real-time PCR assays detected the transient emergence of K70E RT mutants within 4 weeks of therapy, which were then replaced by K65R mutants within 12 weeks of therapy. For most animals, the occurrence of these mutations preceded a partial rebound of plasma viremia to levels that remained on average 10-fold below baseline values. One animal eventually suppressed K65R viremia to undetectable levels for more than 4 years; sequential experiments using CD8+ cell depletion and tenofovir interruption demonstrated that both CD8+ cells and continued tenofovir therapy were required for sustained suppression of viremia.ConclusionThis is the first evidence that tenofovir therapy can select directly for K70E viral mutants in vivo. The observations on the clinical implications of the K65R RT-SHIV mutants were consistent with those of SIVmac251, and suggest that for persons infected with K65R HIV-1 both immune-mediated and drug-dependent antiviral activities play a role in controlling viremia. These findings suggest also that even in the presence of K65R virus, continuation of tenofovir treatment as part of HAART may be beneficial, particularly when assisted by antiviral immune responses.
Highlights
We reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251) mutants with a K65R mutation in reverse transcriptase (RT), and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy
While the K65R mutation reduces replication fitness of HIV-1 in vitro relative to wild-type virus [13], it is unclear to which extent this can be extrapolated to virus replication fitness in vivo, especially when K65R is accompanied by other mutations in RT; some mutations may be compensatory, while the combination of K65R with certain other drug-selected mutations may be deleterious for viral replicative capacity (e.g., L74V, certain thymidine-analogue mutations), or may restore viral susceptibility to other compounds of the drug regimen [14,15,16,17]
In vivo passage of RT-SHIV and establishment of persistent infection the molecular clone of RT-SHIV is virulent in macaques, earlier studies found that infection resulted in a variable peak and set-point of viral RNA levels in plasma [24,26,27,28]
Summary
We reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251) mutants with a K65R mutation in reverse transcriptase (RT), and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. While the K65R mutation reduces replication fitness of HIV-1 in vitro relative to wild-type virus [13], it is unclear to which extent this can be extrapolated to virus replication fitness in vivo, especially when K65R is accompanied by other mutations in RT; some mutations may be compensatory (to improve replicative capacity), while the combination of K65R with certain other drug-selected mutations may be deleterious for viral replicative capacity (e.g., L74V, certain thymidine-analogue mutations), or may restore viral susceptibility to other compounds of the drug regimen [14,15,16,17] It is unclear whether the detection of K65R HIV-1 mutants is a valid criterion for withdrawing tenofovir from the patient's regimen, as it is possible that tenofovir still exerts some residual antiviral activity in vivo against replication of K65R HIV-1
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