Adaptive evolution of simian immunodeficiency viruses isolated from 2 conventional-progressor macaques with encephalitis

Abstract

Simian immunodeficiency virus-infected macaques may develop encephalitis, a feature more commonly observed in macaques with rapid progressive disease than in those with conventional disease. In this report, an analysis of 2 conventional progressors with encephalitis is described. Phylogenetic analyses of viruses isolated from the cerebrospinal fluid and plasma of both macaques demonstrated compartmentalization. Furthermore, these viruses appear to have undergone adaptive evolution to preferentially replicate in their respective cell targets of monocyte-derived macrophages and peripheral blood mononuclear cells. A statistically significant loss of potential N-linked glycosylation sites in glycoprotein 160 was observed in viruses isolated from the central nervous system.

Fig. 1

Clinical and pathological features. (A) Plasma and (B) CSF viral RNA levels. Samples were obtained at sequential time points post inoculation. Y axis represents viral RNA load (copies/ml) and the X axis represents weeks post inoculation. Macaques H631 (square symbol) and H636 (circle symbol) are shown in red and the rapid progressor macaque H635 is shown in blue. (C) SIV-specific in situ hybridization and immunohistochemistry of infiltrating cell populations in the brain of conventional progressor macaques with SIVE, H631 and H636. Prominent perivascular mononuclear infiltrates stained specifically with antibodies to CD3 (H631), CD8 (H631), and CD20 (H636) on the left identified by DAB substrate (brown). The right panels show the infiltration of macrophages as evident by staining with HAM56 in red (H636), with an inset of a characteristic HAM56⁺ multinucleated giant cell. A serial section shows the expression of SIV RNA in these infiltrating cells in blue. The bottom right panel shows confocal microscopy of the brain of H636 showing that SIV-expressing cells (green), co-expressed HAM56 (white) consistent with their identification as macrophages although uninfected CD3⁺ T cells (red) were also present.

Fig. 2

Sequence analysis of the V1/V2 region of gp120 clones directly from CSF and plasma viral RNA in H631 (A) and H636 (B) obtained from weeks 32 and 76 post inoculation. In addition, samples obtained at week 116 (death) for H631 are shown in (A). Amino acid numbering is based on SIVsmE543-3 sequence. Amino acid substitutions are indicated, dashes indicate deletions, a dot indicates identity, and potential N-linked glycosylation sites are underlined.