Neuropathology of wild-type and nef-attenuated T cell tropic simian immunodeficiency virus (SIVmac32H) and macrophage tropic neurovirulent SIVmac17E-Fr in cynomolgus macaques

Abstract

The neuropathology of simian immunodeficiency (SIV) infection in cynomolgus macaques (Macaca fascicularis) was investigated following infection with either T cell tropic SIVmacJ5, SIVmacC8 or macrophage tropic SIVmac17E-Fr. Formalin fixed, paraffin embedded brain tissue sections were analysed using a combination of in situ techniques. Macaques infected with either wild-type SIVmacJ5 or neurovirulent SIVmac17E-Fr showed evidence of neuronal dephosphorylation, loss of oligodendrocyte and CCR5 staining, lack of microglial MHC II expression, infiltration by CD4⁺ and CD8⁺ T cells and mild astrocytosis. SIVmacJ5-infected animals exhibited activation of microglia whilst those infected with SIVmac17E-Fr demonstrated a loss of microglia staining. These results are suggestive of impaired central nervous system (CNS) physiology. Furthermore, infiltration by T cells into the brain parenchyma indicated disruption of the blood brain barrier (BBB). Animals infected with the Δnef-attenuated SIVmacC8 showed microglial activation and astrogliosis indicative of an inflammatory response, lack of MHC II and CCR5 staining and infiltration by CD8⁺ T cells. These results demonstrate that the SIV infection of cynomolgus macaque can be used as a model to replicate the range of CNS pathologies observed following HIV infection of humans and to investigate the pathogenesis of HIV associated neuropathology.

Fig. 1

Representative images from frontal lobe showing results obtained following either SIVmacJ5 (a, c) or SIVmac17E-Fr (b) infection for a in situ hybridisation (×40), b anti-SIV env (×40) and c anti-SIV nef (×40)

Fig. 2

Representative images showing immunohistochemical staining results for a–d astrocytes (GFAP × 10), e–h oligodendrocytes (CNPase1 × 10) and i–l neuronal phosphorylation (FF-1 × 20) within a–h frontal lobe and i–l cerebellum of either SIV naive or SIV-infected brain samples

Fig. 3

Representative images showing immunohistochemical staining results for a–d macrophage (CD68, ×40), E-H: microglia (iba-1, ×20), and i–l SIV-infected microglia (CD163, ×40) within frontal lobe of either SIV naive or SIV-infected brain samples

Fig. 4

Representative images showing immunohistochemical staining results for a–d MHCII (×20) and e–h CCR5 (×20); a–d frontal lobe and e–h cerebellum of either SIV naive or SIV-infected brain samples