Checkmating HIV - trapping immune escape HIV strains
CD8+ cytotoxic T lymphocytes (CTL) can be effective at controlling HIV-1 in humans and SIV in macaques, but their utility is partly offset by mutational escape. The kinetics of CTL escape, and reversion of escape mutant viruses upon transmission to MHC-mismatched hosts can help understand CTL-mediated viral control and the fitness cost extracted by immune escape mutation. Traditional methods to follow CTL escape and reversion cannot, however, detect minor viral quasispecies. We recently developed sensitive quantitative real-time PCR assays to track the viral load of wild-type and escape mutant SIV variants in pigtail macaques. Rapid outgrowth of escape mutant virus occurs during the first few weeks on infection. However, the rate of escape plateaus soon after, revealing a prolonged persistence of wild type virus in blood. The rate of reversion to wild type slows dramatically after the first month of infection. Both vaccination ( Loh et al, PloS Pathogens, 2008) and the make-up of the infecting virus (Loh et al, PloS Pathogens, 2009) affect the rate of escape and reversion. This work has implications for how best to control HIV during early infection.
We are now applying similar techniques to the study of the integrated virus reservoir. Formation of integrated virus is a key blockade to curing HIV. The precise timing of when reservoir viruses are laid down has however been difficult to study in humans since the infecting isolate is usually not known and serial samples are rarely available during the first 1-2 weeks of acute infection prior to symptoms. This work was recently highlighted in The University of Melbourne Voice (Vol.5, No.2 May 2009).
Together with our collaborators Drs Miles Davenport and Janka Petravic at UNSW, we are defining when and how much wild-type and escape mutant virus is replicating during infection, this effectively provides a "molecular clock" to track when the We find that there is rapid turnover of viral DNA in resting CD4 T cells during active replication with high viral loads - this has implications for new strategies to reduce or eliminate the latent reservoir and approaches to cure HIV. This work was recently published in Plos Pathogens. We are now evaluating escape variants in the latent reservoir when antiretroviral therapy is initiated.
Dr Stephen Kent, Dr Jeanette Reece, Shayarana Gooneratne, Thakshila Amaresena
NHMRC Project Grant #454553, AmfAR Award #106849-42-RGRL, ARC Discovery Project #DP0987339
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