Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques

Abstract

To determine the role of CD8(+) T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8(+) T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo.

Figure 1

Temporal association between CD8 decline and viral load increase. The impact of OKT8 (dark blue arrows) on viral load (red circles) and CD8⁺ T cell counts (green squares) was examined in six chronically infected macaques (AT-02, AT-22, AR-68, AR-71, AR-90, and AR-93) and one uninfected animal (AT-03). The injection of a control antibody (light blue arrows), P1.17, to an infected macaque (AT-48) is also shown. The dotted line denotes the level of sensitivity of the viral load assay.

Figure 2

The impact of OKT8F, or the control antibody, on the total number of CD3⁺ (orange squares), CD4⁺ (blue triangles), and CD4⁺Ki67⁺ (purple circles) cells.

Figure 3

Plasma viral load data from two monkeys together with theoretical predictions based on a standard model of HIV-1 dynamics. The theoretical predictions model changes in the death rate of infected cells, δ, the viral production rate, p, or the infection rate constant, k, after anti-CD8 treatment. The theoretical curves shown were generated using nonlinear least-squares regression to find the new value of δ, k, or p that gave the best fit to the data.