Abstract
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 us understand CTL-mediated viral control and the fitness cost extracted by immune escape mutation. Traditional methods for following CTL escape and reversion are, however, insensitive to minor viral quasispecies. We developed sensitive quantitative real-time PCR assays to track the viral load of SIV Gag164–172 KP9 wild-type (WT) and escape mutant (EM) variants in pigtail macaques. Rapid outgrowth of EM virus occurs during the first few weeks of infection. However, the rate of escape plateaued soon after, revealing a prolonged persistence of WT viremia not detectable by standard cloning and sequencing methods. The rate of escape of KP9 correlated with levels of vaccine-primed KP9-specific CD8+ T cells present at that time. Similarly, when non-KP9 responder (lacking the restricting Mane-A*10 allele) macaques were infected with SHIVmn229 stock containing a mixture of EM and WT virus, rapid reversion to WT was observed over the first 2 weeks following infection. However, the rate of reversion to WT slowed dramatically over the first month of infection. The serial quantitation of escape mutant viruses evolving during SIV infection shows that rapid dynamics of immune escape and reversion can be observed in early infection, particularly when CD8 T cells are primed by vaccination. However, these early rapid rates of escape and reversion are transient and followed by a significant slowing in these rates later during infection, highlighting that the rate of escape is significantly influenced by the timing of its occurrence.
Highlights
CD8þ cytotoxic T lymphocyte (CTL) responses during acute HIV-1 and simian immunodeficiency virus (SIV) infection in humans and macaques, respectively, correlate with effective control of acute viremia [1,2,3,4]
To further elucidate CTL escape and reversion kinetics, we recently studied the in vivo effectiveness of different SIV Gag– restricted T cell responses in pigtail macaques [15]
We found that prior immunization of macaques resulted in very rapid immune escape during acute infection
Summary
CD8þ cytotoxic T lymphocyte (CTL) responses during acute HIV-1 and simian immunodeficiency virus (SIV) infection in humans and macaques, respectively, correlate with effective control of acute viremia [1,2,3,4]. Many CTL escape mutations evolve to select a single common escape motif, including the Mane-A*10-restricted KP9 SIV Gag epitope in pigtail macaques, which selects the K165R mutation to escape this response [11]. Reversion of CTL EM variants upon transmission to MHCmismatched hosts have been widely documented in both human and macaque settings [12,13,14]. These studies imply a significant fitness cost to the evolution of some Gag CTL escape mutations. Rapid reversion of the K165R escape mutant (EM) KP9 virus is observed in Mane-A*10 negative pigtail macaques infected with EM challenge stock SHIVmn229, suggesting a significant fitness cost of the K165R mutation [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
