Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts

Abstract

In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue.

Figure 1

Reduced CCR5 expression on peripheral blood– and LN-derived CD4⁺ T cells in natural hosts of SIV. (A) Representative contour plots showing CD4 and CCR5 staining of peripheral blood–derived T cells of healthy uninfected individuals belonging to 5 nonnatural/recent hosts of HIV/SIV—humans (Hu), rhesus macaques (RM), pigtail macaques (PTM), cynomolgus macaques (CYM), and baboons (Bab)—and 5 natural hosts of SIV—sooty mangabeys (SM), Caribbean African green monkeys (AGM), mandrills (MND), sun-tailed monkeys (SUN), and chimpanzees (Cy). (B) Representative contour plots showing CD4 and CCR5 staining of T cells isolated from the LNs of RMs, baboons, SM, AGM, and mandrills. (C) Summary of CCR5 expression on blood-derived CD4⁺ T cells of the primate species listed in panel A. Statistically significant differences in CCR5 expression on CD4⁺ T cells from natural and nonnatural hosts of SIV was determined by one-way nonparametric ANOVA (Kruskal-Wallis) followed by the Dunn multiple comparison test. For nonnatural human hosts of SIV versus natural AGM hosts of SIV, P < .05; for all other nonnatural hosts versus natural hosts, P < .001.

Figure 2

Similar levels of CCR5 are expressed on the surfaces of CD8⁺ T cells from natural and nonnatural hosts of SIV. (A) Representative contour plots showing CD8 and CCR5 staining of peripheral blood–derived T cells of healthy humans, RMs, PTMs, cynomolgus macaques, baboons, SMs, Caribbean AGMs, mandrills, sun-tailed monkeys, and chimpanzees. (B) Representative contour plots showing CD8 and CCR5 staining of T cells isolated from the LNs of RMs, baboons, SMs, AGMs, and mandrills. (C) Summary of CCR5 expression on peripheral blood–derived CD8⁺ T cells of the primate species listed in panel A. One-way nonparametric ANOVA (Kruskal-Wallis) followed by the Dunn multiple comparison test found no statistically significant differences (P > .05) in CCR5 expression on CD8⁺ T cells obtained from natural and nonnatural hosts of SIV. The only exception was SMs with lower levels of CD8⁺CCR5⁺ T cells than RMs (P < .05).

Figure 3

CCR5 expression on T cells derived from MALT in natural and nonnatural hosts. (A) Representative contour plots showing CD4 and CCR5 staining of T cells isolated from the gastrointestinal tract of healthy uninfected RMs, baboons, SMs, and AGMs (top) and the lung (through bronchial alveolar lavage) of healthy uninfected RMs and SMs (bottom). (B) Summary of CCR5 expression on CD4⁺ T cells isolated from the gastrointestinal tract of the species listed in panel A. Statistically significant differences in CCR5 expression on CD4⁺ T cells from natural and nonnatural hosts of SIV were observed with the use of one-way nonparametric ANOVA (Kruskal-Wallis) followed by the Dunn multiple comparison test and the Mann-Whitney U test. For nonnatural RM hosts of SIV versus natural SM hosts of SIV, P < .001; and versus natural SGM hosts of SIV, P < .01. For nonnatural BAB hosts versus natural SM and AGM hosts, P < .05. (C) Representative contour plots showing CD8 and CCR5 staining of T cells isolated from the gastrointestinal tract of healthy uninfected RMs, baboons, SMs, and AGMs (top) and the lung (through bronchial alveolar lavage) of healthy uninfected RMs and SMs (bottom).

Figure 4

Limited CCR5 expression on CD4⁺ T cells in SIV-infected natural hosts. (A) Representative contour plots showing CD4 and CCR5 staining of peripheral blood–derived T cells of chronically SIV-infected SMs, AGMs, mandrills, and sun-tailed monkeys. (B) Summary of CCR5 expression on CD4⁺ T cells from the blood of the species listed in panel A. (C) Representative contour plots showing CD8 and CCR5 staining of T cells isolated from the gastrointestinal tract of chronically SIV-infected SMs and AGMs (left) and the lung (through bronchial alveolar lavage) of an SIV-infected SM (right).

Figure 5

Reduced CCR5 expression on monocytes in natural hosts of SIV. (A) Representative contour plots showing CCR5 expression on monocytes in healthy uninfected individuals belonging to progressing (RMs and PTMs) and nonprogressing (SMs and AGMs) NHPs. (B) Summary of CCR5 expression on monocytes of the primate species listed in panel A. One-way nonparametric ANOVA (Kruskal-Wallis) followed by the Dunn multiple comparison test and the Mann-Whitney U test. For nonnatural RM hosts of SIV versus natural SM and AGM hosts, P > .05; for nonnatural PTM hosts of SIV versus natural SM and AGM hosts, P < .001.