The relationship between simian immunodeficiency virus RNA levels and the mRNA levels of alpha/beta interferons (IFN-alpha/beta) and IFN-alpha/beta-inducible Mx in lymphoid tissues of rhesus macaques during acute and chronic infection

Abstract

To define the role of alpha/beta interferons (IFN-alpha/beta) in simian immunodeficiency virus (SIV) infection, IFN-alpha and IFN-beta mRNA levels and mRNA levels of Mx, an antiviral effector molecule, were determined in lymphoid tissues of rhesus macaques infected with pathogenic SIV. IFN-alpha/beta responses were induced during the acute phase and persisted in various lymphoid tissues throughout the chronic phase of infection. IFN-alpha/beta responses were most consistent in tissues with high viral RNA levels; thus, IFN-alpha/beta responses were not generally associated with effective control of SIV replication. IFN-alpha/beta responses were differentially regulated in different lymphoid tissues and at different stages of infection. The most consistent IFN-alpha/beta responses in acute and chronic SIV infection were observed in peripheral lymph nodes. In the spleen, only a transient increase in IFN-alpha/beta mRNA levels during acute SIV infection was observed. Further, IFN-alpha and IFN-beta mRNA levels showed a tissue-specific expression pattern during the chronic, but not the acute, phase of infection. In the acute phase of infection, SIV RNA levels in lymphoid tissues of rhesus macaques correlated with mRNA levels of both IFN-alpha and IFN-beta, whereas during chronic SIV infection only increased IFN-alpha mRNA levels correlated with the level of virus replication in the same tissues. In lymphoid tissues of all SIV-infected monkeys, higher viral RNA levels were associated with increased Mx mRNA levels. We found no evidence that monkeys with increased Mx mRNA levels in lymphoid tissues had enhanced control of virus replication. In fact, Mx mRNA levels were associated with high viral RNA levels in lymphoid tissues of chronically infected animals.

FIG. 1.

Virologic and immunologic parameters of chronically SIV-infected monkeys. (A) Plasma vRNA levels of chronically SIV-infected monkeys, expressed as log₁₀ plasma vRNA levels per milliliter of plasma, throughout the course of the study. (B) Serum anti-SIVmac251 IgG antibody titers (reported as endpoint dilutions). (C) Absolute CD4 T-cell number per microliter of blood in each individual monkey. Individual animals are represented by a distinct symbol in all panels.

FIG. 2.

vRNA levels in lymphoid tissues of chronically SIV-infected rhesus macaques. Tissue vRNA levels are reported as log₁₀ vRNA copies per microgram of total tissue RNA. Each bar represents an individual monkey. The same bar pattern for an individual monkey is used for results from each of the tissues.

FIG. 3.

Plasma vRNA levels, IFN-α/β, and Mx mRNA levels in PBMC of SIV-infected rhesus macaques. The relationships between plasma vRNA levels and PBMC IFN-α, IFN-β, and Mx mRNA levels are shown for weeks 1, 2, 5, and 24 p.i. For each individual monkey (labels on x axis), the plasma vRNA level (black bar) and mRNA levels for IFN-α (green bar), IFN-β (blue bar), and Mx (red bar) are shown. Plasma vRNA levels are reported as log₁₀ vRNA copies per milliliter of plasma. The mRNA levels of IFN-α, IFN-β, and Mx are reported as fold increase (FI) versus mRNA levels in matched PBMC of uninfected animals. Note that due to the different mRNA expression levels, the scales differ for each of the parameters assessed. Also, data for the rapid progressor monkey are on the far left on the x axis, and data for nonprogressor monkeys are on the far right.

FIG. 4.

vRNA levels, IFN-α/β, and Mx mRNA levels in lymphoid tissues of chronically SIV-infected rhesus macaques. The relationships between tissue vRNA levels (black bars) and tissue IFN-α, IFN-β, and Mx mRNA levels are shown for spleen, for peripheral, mesenteric, and genital lymph nodes, and for the thymus. Tissue vRNA levels are reported as log₁₀ vRNA copies per microgram of total tissue RNA. The figure is organized as described in the legend for Fig. 3.

FIG. 5.

vRNA levels, IFN-α/β, and Mx mRNA levels in lymphoid tissues of acutely SIV-infected rhesus macaques. The relationships between tissue vRNA levels and tissue IFN-α, IFN-β, and Mx mRNA levels are shown for spleen, peripheral lymph nodes, and thymus on day 7 and day 14 p.i. Tissue vRNA levels are reported as log₁₀ vRNA copies per 10 mg of tissue. The figure is organized as described in the legend for Fig. 3.