CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production

Abstract

Whether CD8+ T lymphocytes control human immunodeficiency virus infection by cytopathic or non-cytopathic mechanisms is not fully understood. Multiple studies highlighted non-cytopathic effects, but one hypothesis is that cytopathic effects of CD8+ T cells occur before viral production. Here, to examine the role of CD8+ T cells prior to virus production, we treated SIVmac251-infected macaques with an integrase inhibitor combined with a CD8-depleting antibody, or with either reagent alone. We analyzed the ensuing viral dynamics using a mathematical model that included infected cells pre- and post- viral DNA integration to compare different immune effector mechanisms. Macaques receiving the integrase inhibitor alone experienced greater viral load decays, reaching lower nadirs on treatment, than those treated also with the CD8-depleting antibody. Models including CD8+ cell-mediated reduction of viral production (non-cytolytic) were found to best explain the viral profiles across all macaques, in addition an effect in killing infected cells pre-integration (cytolytic) was supported in some of the best models. Our results suggest that CD8+ T cells have both a cytolytic effect on infected cells before viral integration, and a direct, non-cytolytic effect by suppressing viral production.

Comparative Analysis of Within-Host Dynamics of Acute Infection and Viral Rebound Dynamics in Postnatally SHIV-Infected ART-Treated Infant Rhesus Macaques

“…Furthermore, viral production rates were higher in the absence of CD8+ cells. These results suggest that CD8+ cells have both a noncytolytic effect in suppressing viral production, as well as a cytolytic effect before viral integration [87]. Recent studies in vitro have also pointed to a noncytolytic effect of CD8+ T cells by preventing viral production rather than viral infectivity, which is consistent with Policicchio et al [87], as well as with our observation for a tendency toward increased infectivity during rebound [101].…”

“…We observe an increase in the killing rate of infected cells, although the estimated death rate is generally lower compared to the adult rebound values [57,86] and the variability among rebounding RMs, some of whom display values consistent with acute infection (Supplementary Fig 5). In addition, we find a decrease in the product of scaled viral production rate, which can be attributed to a reduced viral production due to noncytolytic effects of CD8+ T cells [87]. Recent modeling works also provides support for a dual function of CD8+ T cells in HIV-1 infection [87].…”

“…In addition, we find a decrease in the product of scaled viral production rate, which can be attributed to a reduced viral production due to noncytolytic effects of CD8+ T cells [87]. Recent modeling works also provides support for a dual function of CD8+ T cells in HIV-1 infection [87]. Indeed, CD8+ T cell responses are a hallmark of control.…”

Antibody-mediated depletion of select leukocyte subsets in blood and tissue of nonhuman primates

“…We believe this is likely due to the promiscuous expression of CD8α by activated CD4+ T cells. However, we do not know the mechanism; we note that others have similarly observed this transient off-target depletion with CD8α-depleting antibodies ( 1 , 3 , 30 , 32 – 34 ).…”

Incorporating Intracellular Processes in Virus Dynamics Models

“…These models have been expanded further and used for other scientific investigations. In particular, together with macaques data, they hypothesized that CD8+ T cells have both a cytolytic effect on infected cells before viral integration, and a direct, noncytolytic effect by suppressing viral production [117]. This result was an important contribution in our understanding of the role of CD8+ T cells [118,119].…”