Effect of Single Housing on Innate Immune Activation in Immunodeficiency Virus-Infected Pigtail Macaques ( Macaca nemestrina ) as a Model of Psychosocial Stress in Acute HIV Infection

Abstract

Objective: Simian immunodeficiency virus (SIV) infection of macaques recapitulates many aspects of HIV pathogenesis and is similarly affected by both genetic and environmental factors. Psychosocial stress is associated with immune system dysregulation and worse clinical outcomes in people with HIV. This study assessed the impact of single housing, as a model of psychosocial stress, on innate immune responses of pigtailed macaques ( Macaca nemestrina ) during acute SIV infection.

Methods: A retrospective analysis of acute SIV infection of 2- to si6-year-old male pigtailed macaques was performed to compare the innate immune responses of socially ( n = 41) and singly ( n = 35) housed animals. Measures included absolute monocyte count and subsets, and in a subset ( n ≤ 18) platelet counts and activation data.

Results: SIV infection resulted in the expected innate immune parameter changes with a modulating effect from housing condition. Monocyte number increased after infection for both groups, driven by classical monocytes (CD14 + CD16 - ), with a greater increase in socially housed animals (227%, p < .001, by day 14 compared with preinoculation time points). Platelet numbers recovered more quickly in the socially housed animals. Platelet activation (P-selectin) increased by 65% ( p = .004) and major histocompatibility complex class I surface expression by 40% ( p = .009) from preinoculation only in socially housed animals, whereas no change in these measures occurred in singly housed animals.

Conclusions: Chronic psychosocial stress produced by single housing may play an immunomodulatory role in the innate immune response to acute retroviral infection. Dysregulated innate immunity could be one of the pathways by which psychosocial stress contributes to immune suppression and increased disease severity in people with HIV.

FIGURE 1

Monocyte response to acute SIV infection in singly compared with socially housed macaques. Housing groups were compared from baseline (three time points) to 7, 10, and 14 days after inoculation with SIV (for n for each time point, see Supplemental Digital Content, Table S4, http://links.lww.com/PSYMED/A873). ART was started on day 12 for all animals. A, White blood cell counts in whole blood CBCs were compared. Using a linear mixed-effects regression model, differences between housing groups over time were significant (F(5,406) = 4.27, p < .001). B–D, CD14 and CD16 monocytes expression profiles were compared using flow cytometry, and total monocyte count was used to calculate absolute numbers of each subtype. Error bars display the standard error of estimated least squares means generated by a linear mixed-effects regression model. * p < .05; ** p < .01; *** p < .001. SIV = simian immunodeficiency virus; ART = antiretroviral therapy; CBC = complete blood count.

FIGURE 3

Correlation of housing status and immune parameters with viral load at day 7 after inoculation. Housing group and monocyte subsets at day 7 were correlated with previously reported data on CD4 T-cell count and plasma and CSF viral load (33). A least squares regression model was generated by using a sum-of-squares F test to determine if one line or individual lines best fit each data set. A, When directly compared, CD4 T-cell count did not correlate with plasma or CSF viral load overall, or in each housing subset. B, The line of best fit comparing CD14⁺CD16⁻ monocytes and viral load was different between housing groups (p = .03 plasma, p = .004 CSF), but showed no correlation with viral load. C, The line of best fit for CD14⁺CD16⁺ monocytes was different between housing groups (p < .001), and socially housed animals only showed a positive correlation with CSF viral load (p = .03, Spearman r = 0.33). D, Plasma and CSF viral load showed no relationship with CD14⁻CD16⁺ monocytes. CSF = cerebrospinal fluid.

FIGURE 2

Platelet response to acute SIV infection in singly compared with socially housed macaques. Housing groups were compared at baseline (two time points) against day 10 after inoculation with SIV (for n for each time point, see Supplemental Digital Content, Table S4, http://links.lww.com/PSYMED/A873). ART was started on day 12 for all animals. A, Platelet counts in whole blood CBCs were compared. Singly housed animals showed a delayed recovery from thrombocytopenia during acute infection, failing to return to baseline by day 14. Differences between housing groups over time were significant (F(4,64) = 8.26, p < .001). B, Platelet P-selectin expression in singly housed macaques was less than in socially housed both at baseline and at day 10. C, The effects of housing (F(2,41) = 47.03, p < .001) and housing over time (F(2,41) = 53.29, p = .009) were significant. Platelet CD40L expression was not different between groups at day 10; however, a difference was present in a single baseline time point. In addition, the effect of housing over time was significant (F(2,41) = 10.03, p < .001). D, Platelet MHC-I expression was not as upregulated at day 10 in singly housed animals. In addition, the effect of housing over time was significant (F(2,39) = 4.18, p = .023). Error bars display the standard error of estimated least squares means generated by a linear mixed-effects regression model. * p < .05; ** p < .01; *** p < .001. SIV = simian immunodeficiency virus; ART = antiretroviral therapy; CBC = complete blood count.