The dynamics of simian immunodeficiency virus after depletion of CD8+ cells

Abstract

Human immunodeficiency virus infection is still one of the most important causes of morbidity and mortality in the world, with a disproportionate human and economic burden especially in poorer countries. Despite many years of intense research, an aspect that still is not well understood is what (immune) mechanisms control the viral load during the prolonged asymptomatic stage of infection. Because CD8+ T cells have been implicated in this control by multiple lines of evidence, there has been a focus on understanding the potential mechanisms of action of this immune effector population. One type of experiment used to this end has been depleting these cells with monoclonal antibodies in the simian immunodeficiency virus-macaque model and then studying the effect of that depletion on the viral dynamics. Here we review what these experiments have told us. We emphasize modeling studies to interpret the changes in viral load observed in these experiments, including discussion of alternative models, assumptions and interpretations, as well as potential future experiments.

The CD8+T Cell Noncytotoxic Antiviral Responses

“…Subsequently, a similar observation was made in macaques infected with SIV ( 53 , 54 ) as well as with a live attenuated SIV (SIVmac239Δnef) used to protect macaques against pathogenic SIVmac251 challenge ( 55 ). Some of these early experiments used different depleting antibodies that targeted the CD8α subunit of the CD8 molecule over the course of several years ( 56 ). Those studies demonstrated as well that when the CD8α + cell compartment was reduced, the viral load, previously under control in the NHP, rose from undetectable to up to 10 million RNA copies of SIV/ml of plasma.…”

“…In addition to the in vivo studies described above, mathematical modeling has permitted further evaluation of the potential impact of different CD8 + cell functions (e.g., cytotoxic and noncytotoxic) on viral dynamics under various conditions, including the use of antiviral drugs ( 56 ). For example, in studies of a successful SIV/HIV (SHIV) vaccination approach in NHP, the peak viral loads and the resulting decay rates of virus observed were compared to the dynamics expected from mathematical models of cytotoxic cell clearance versus noncytotoxic cell control.…”

Modeling the immune response to HIV infection

“…The second theme is related to the primary role of CD8+ T-cells in HIV infection: are responses primarily lytic or non-lytic? [84] This debate was spurred on by contradictory experimental observations, well summarized in [84,85], including CD8+ cell depletion experiments in SIV infected macaques [86–89]. While overall the support for nonlytic responses seemed stronger, the evidence is indirect and mathematical modeling is the best platform to gain insight into the primary mechanism of CD8 effect, and to resolve these contradictions.…”

Thresholds for post-rebound SHIV control after CCR5 gene-edited autologous hematopoietic cell transplantation

“…A fraction f of these cells become SHIV-specific CD8 + effector T cells, E h , that are removed at a rate d h ( De Boer, 2007 ; Wodarz and Nowak, 1999 ; Wodarz et al, 2000 ). These effector cells may reduce virus production ( π ) or increase infected cell clearance ( δ I ) by 1/ (1+ θE h ) or by (1+ κE h ), respectively ( Elemans et al, 2011 ; Klatt et al, 2010 ; Wong et al, 2010 ; Borducchi et al, 2016 ; Cardozo et al, 2018 ). We assumed that non-susceptible CD4 + T cells may upregulate CCR5 and replenish the susceptible pool during infection ( Okoye et al, 2007 ; Okoye et al, 2012 ; Okoye and Picker, 2013 ) with rate ω 4 .…”