In a prior post from last year, I reported on some controversy regarding the mechanisms by which CD8 T cells inhibit HIV and SIV replication. Two studies had been published suggesting that the main mechanism is not direct killing of infected cells--as generally believed--but rather the release of soluble antiviral factors such as chemokines. But as mentioned at the time, the authors of both papers noted there was evidence indicating that CD8 T cells can kill virus-infected cells prior to the release of new virions, which would render their direct cytotoxic activity invisible in the particular experimental systems that were used in these studies.
In a paper published last month in PLoS One, Christian Althaus and Rob De Boer explicitly model this scenario mathematically. The model shows that, indeed, early CD8 T cell killing is entirely compatible with the previously reported results. The authors write:
“Here we have formally demonstrated that when CTL-mediated killing occurs early during the intracellular eclipse phase it can control HIV replication very efficiently, while remaining consistent with current observations on the up-slopes and down-slopes of the viral load observed during CD8+ T cell depletion experiments and antiretroviral treatment.”
PLoS One. 2011 Feb 7;6(2):e16468.
Althaus CL, De Boer RJ.
Theoretical Biology, Utrecht University, Utrecht, The Netherlands.
Abstract
Patients infected with HIV exhibit orders of magnitude differences in their set-point levels of the plasma viral load. As to what extent this variation is due to differences in the efficacy of the cytotoxic T lymphocyte (CTL) response in these patients is unclear. Several studies have shown that HIV-infected CD4+ T cells also present viral epitopes that are recognized by CTLs before the productive stage of infection, i.e., during the intracellular eclipse phase before the infected cell starts to produce new viral particles. Here, we use mathematical modeling to investigate the potential impact of early killing of HIV-infected cells on viral replication. We suggest that the majority of CTL-mediated killing could occur during the viral eclipse phase, and that the killing of virus-producing cells could be substantially lower at later stages due to MHC-I-down-regulation. Such a mechanism is in agreement with several experimental observations that include CD8+ T cell depletion and antiretroviral drug treatment. This indicates a potentially important role of CTL-mediated killing during the non-productive stage of HIV-infected cells.
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