CD8+ Lymphocytes Control Viral Replication in SIVmac239-Infected Rhesus Macaques without Decreasing the Lifespan of Productively Infected Cells

Abstract

While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.

Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

“…The finding that escape rates are generally slow [7] and other observations [42,43] have lead to a controversy in the field as to what extent CTLs are important in controlling HIV replication [44,46 -48]. Our results provide some insights into this ongoing debate as we show that slow escape rates do not necessarily imply a weak selection pressure of CTL clones.…”

“…k P ¼ 0) [41]. Such a mechanism can serve as an explanation for recent experiments that have shown that CTLs do not substantially contribute to the clearance of cells during the virusproducing stage [42,43]. We attempt to make a fair comparison between the two stages by restricting the total death rate at each stage to reflect the death rate of infected cells that is observed during antiretroviral drug treatment ( [24]).…”

HIV-1 Pathogenesis: The Virus

“…The ability to kill CD4 þ T cells in culture is consistent with the short half-life of virus in the blood after the initiation of therapy Wei et al 1995). That this is in large part a virologic effect is seen by the fact that the decay of virus in the blood goes on at a similar rate in the presence or absence of CD8 þ cytotoxic T cells (Klatt et al 2010). In addition to the direct killing of infected cells, a number of mechanisms have been proposed that result in indirect killing of uninfected cells because of their proximity to infected cells and the general state of immune activation (Lackner et al 2011).…”

HIV/AIDS: 30 Years of progress and future challenges

“…Healthy asymptomatic individuals, particularly LTSs, exhibit increased frequencies of the CD8 1 cells that mediate CNAR in comparison to those who progress to AIDS [46,47]. Moreover, studies of SIV-infected rhesus monkeys depleted of CD8 1 cells in vivo suggest that the virus level is maintained by a CD8 1 cell noncytotoxic process [48,49]. Also, CNAR appears to protect HESNs from infection via sexual contact [50] and children born to infected mothers [51].…”