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Comparative Study
. 1998 Dec;72(12):9597-611.
doi: 10.1128/JVI.72.12.9597-9611.1998.

Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques

A Kaur  1 , R M Grant, R E Means, H McClure, M Feinberg, R P Johnson
Affiliations
Comparative Study

Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques

A Kaur et al. J Virol. 1998 Dec.

Abstract

Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) do not develop immunodeficiency despite the presence of viral loads of 10(5) to 10(7) RNA copies/ml. To investigate the basis of apathogenic SIV infection in sooty mangabeys, three sooty mangabeys and three rhesus macaques were inoculated intravenously with SIVmac239 and evaluated longitudinally for 1 year. SIVmac239 infection of sooty mangabeys resulted in 2- to 4-log-lower viral loads than in macaques and did not reproduce the high viral loads observed in natural SIVsmm infection. During acute SIV infection, polyclonal cytotoxic T-lymphocyte (CTL) activity coincident with decline in peak plasma viremia was observed in both macaques and mangabeys; 8 to 20 weeks later, CTL activity declined in the macaques but was sustained and broadly directed in the mangabeys. Neutralizing antibodies to SIVmac239 were detected in the macaques but not the mangabeys. Differences in expression of CD38 on CD8(+) T lymphocytes or in the percentage of naive phenotype T cells expressing CD45RA and CD62L-selection did not correlate with development of AIDS in rhesus macaques. In macaques, the proportion of CD4(+) T lymphocytes expressing CD25 declined during SIV infection, while in mangabeys, CD25-expressing CD4(+) T lymphocytes increased. Longitudinal evaluation of cytokine secretion by flow cytometric analysis of unstimulated lymphocytes revealed elevation of interleukin-2 and gamma interferon in a macaque and only interleukin-10 in a concurrently infected mangabey during acute SIV infection. Differences in host responses following experimental SIVmac239 infection may be associated with the divergent outcome in sooty mangabeys and rhesus macaques.

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Figures

FIG. 1
FIG. 1
SIV-specific CTL activity and plasma SIV RNA during acute SIVmac239 infection in three sooty mangabeys (FYg, FLg, and FWl) and three rhesus macaques (RFi-1, RLk-1, and RGa-3). Adjacent pairs were infected concurrently.
FIG. 2
FIG. 2
Dynamics of primary SIV viremia in the first 100 days following SIVmac239 infection in three rhesus macaques and three sooty mangabeys. Plasma SIV viremia was quantitated by competitive RNA PCR at 2, 5, 7, 9, 12, 14, 16, 19, 21, 28, 63, and 98 days following SIV infection. Each data point with error bars represents the mean and standard error of the mean viral load. The differences in level of viremia between the rhesus macaques and sooty mangabeys at each measured time point were statistically significant (P value by Student’s t test = 0.0005 at days 5 and 9 and <0.05 after day 14). The slope of rise and decay in plasma viremia was calculated from data points in the linear portions of the curve (days 2 to 7 and 16 to 21 in the macaques; days 7 to 12 and 19 to 28 in the rhesus macaques). The slope of rise was 0.636 ± 0.015 log10 RNA copies/day (mean ± SD) in the macaques and 0.449 ± 0.075 log10 RNA copies/day in the mangabeys (P value by Student’s t test = 0.066). The slope of decay was −0.093 ± 0.031 log10 RNA copies/day (mean ± SD) in the macaques and −0.213 ± 0.029 log10 RNA copies/day in the mangabeys (P value by Student’s t test = 0.014).
FIG. 3
FIG. 3
SIV-specific CTL activity and plasma SIV RNA during acute and chronic SIVmac239 infection in three sooty mangabeys (FYg, FLg, and FWl) and three rhesus macaques (RFi-1, RLk-1, and RGa-3). Arrows denote the time at which an animal died. SIV-specific CTL activity to Gag, Pol, Env, and Nef is shown as columns. The absence of a column(s) at a particular time point denotes that CTL activity was not tested at that time point. Undetectable CTL activity is depicted by 0.5% specific lysis. Viral loads below the threshold of detection (1,000 RNA copies/ml) are plotted as 1,000 copies/ml.
FIG. 4
FIG. 4
Neutralizing antibodies to SIVmac239 in SIV-infected sooty mangabeys and rhesus macaques. (a) Representative assay in one sooty mangabey and one rhesus macaque. (b) Percent inhibition of 1:20 dilution sera in three sooty mangabeys and three rhesus macaques during SIV infection.
FIG. 5
FIG. 5
T-cell homeostasis during acute and chronic SIVmac239 infection in sooty mangabeys and rhesus macaques. The percentage of circulating T-lymphocyte subsets was determined longitudinally during SIV infection in all six animals by three-color flow cytometry. In the pair of animals FYg and RFi-1, immunophenotyping was performed only after 13 weeks of SIV infection.
FIG. 6
FIG. 6
Surface expression of CD38 on CD3+ CD8+ T lymphocytes in peripheral blood during SIV infection in two sooty mangabeys (FLg and FYg) and two rhesus macaques (RLk-1 and RFi-1). PBMC were immunophenotyped with CD38, CD3, and CD8 and analyzed by three-color flow cytometry. (a) Analysis of CD38 on gated CD3+ CD8+ T lymphocytes. (b) Longitudinal evaluation of the proportion of CD38-expressing CD3+ CD8+ T lymphocytes. Data points from day 0 to week 34 are available for FLg and RLk-1 and from week 30 to week 50 for FYg and RFi-1. The last data point reflects the time of death of RLk-1 and RFi-1. The mean normal values were obtained from immunophenotyping uninfected sooty mangabeys (n = 7) and uninfected rhesus macaques (n = 7).
FIG. 7
FIG. 7
Longitudinal analysis of association between SIV infection and peripheral T lymphocytes expressing CD25, HLA DR, or CD69 in SIV infection. Regression plots were generated by simple regression analysis using time after SIV infection as the independent variable and the mean and 95% confidence intervals of the proportion of CD4+ or CD8+ T lymphocytes expressing the activation marker as the dependent variable. The data were generated from three sooty mangabeys and three rhesus macaques.
FIG. 8
FIG. 8
Longitudinal analysis of naive and memory phenotype of CD4+ and CD8+ T lymphocytes in two rhesus macaques and two sooty mangabeys during SIV infection. PBMC were immunophenotyped and analyzed on a FACSVantage (BDIS), using four-color flow cytometry. The animal pairs FLg plus RLk-1 and FYg plus RFi-1 were infected concurrently. Data points from day 0 to week 34 are available for FLg plus RLk-1 and from week 10 to week 50 for FYg plus RFi-1. The last data point reflects the time of death of RLk-1 and RFi-1. The mean normal values were obtained from immunophenotyping uninfected sooty mangabeys (n = 7) and uninfected rhesus macaques (n = 7).
FIG. 9
FIG. 9
Longitudinal comparison of intracellular cytokine secretion in PBMC during SIV infection in one sooty mangabey (FWl) and a concurrently infected rhesus macaque (RGa-3). Contour plots showing intracellular IL-2, IL-4, IL-10, and IFN-γ in unstimulated PBMC at days 0, 7, 82, and 148 following SIV infection. The numbers in the right upper quadrant of each plot are the values for the percentage/geometric mean channel fluorescence of cytokine-positive cells in the lymphocyte gate.
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