Neuropathogenesis of Chimeric Simian/Human Immunodeficiency Virus infection In Pig‐tailed and Rhesus Macaques

Abstract

We recently reported that a chimeric simian/human immunodeficiency virus (SHIVKU-1) developed in our laboratory caused progressive depletion of CD4+ T lymphocytes and AIDS within 6 months of inoculation into pig-tailed macaques (M. nemestrina). None of the pig-tailed macaques showed productive SHIV infection in the central nervous system (CNS). In this report, we show that by further passage of the pathogenic virus in rhesus macaques [M. mulatta], we have derived a new strain of SHIV (SHIVKU-2) that has caused AIDS and productive CNS infection in 3 of 5 rhesus macaques infected with the virus. Productive replication of SHIV in the CNS was clearly shown by high infectivity titers and p27 protein levels in brain homogenates, and in 2 of the 3 rhesus macaques this was associated with disseminated, nodular, demyelinating lesions, including focal multinucleated giant cell reaction, largely confined to the white matter. These findings were reminiscent of HIV-1 associated neurological disease, and our immunohistochemical and in situ hybridization data indicated that the neuropathological lesions were associated with the presence of SHIV-specific viral antigens and nucleic acid respectively. However, the concomitant reactivation of opportunistic infections in these macaques suggested that such pathogens may have influenced the replication of SHIV in the CNS, or modified the neuropathological sequelae of SHIV infection in the rhesus species, but not in pig-tailed macaques. Our findings in the two species of macaques highlight the complexities of lentiviral neuropathogenesis, the precise mechanisms of which are still elusive.

Neutralization-Sensitive R5-Tropic Simian-Human Immunodeficiency Virus SHIV-2873Nip, Which Carries env Isolated from an Infant with a Recent HIV Clade C Infection

“…We observed loss of memory CD4 ϩ CD29 ϩ T cells in peripheral blood and depletion of CD4 ϩ T cells in the gut tissues of all SHIV2873Nip-infected RMs. This SHIV-C targets memory CD4 ϩ T cells, whereas the acutely pathogenic, X4-or dual-tropic SHIVs that have been used frequently in vaccine efficacy studies in nonhuman primate models predominantly affect naive CD4 ϩ T cells (16,39) and induce precipitous drops in peripheral blood CD4 ϩ T cells that are irreversible in most RMs (43,45,53). In contrast, SHIV-2873Nip does not induce acute, severe lymphocyte depletion, suggesting that this new R5-tropic SHIV-C exhibits biological characteristics that mimic HIV disease progression in humans.…”

Neuroimmunity and the Blood–Brain Barrier: Molecular Regulation of Leukocyte Transmigration and Viral Entry into the Nervous System with a Focus on NeuroAIDS

“…The HIV-1 env gene was the first gene replaced to study its protein product in nonhuman primates (Shibata et al 1991;Shibata and Adachi 1992). Many strains of SHIV have been developed; the highly neuropathic SHIV-KU2 strain was produced by passaging an earlier neurovirulent strain (Raghavan et al 1997;Liu et al 1999). Another study examined the role of PDGF, which induces CCL2, in SHIV-KU2-infected cell lines and encephalitic macaques ).…”

Generation of Lineage-Related, Mucosally Transmissible Subtype C R5 Simian-Human Immunodeficiency Viruses Capable of AIDS Development, Induction of Neurological Disease, and Coreceptor Switching in Rhesus Macaques

“…The development of central nervous system (CNS) disorders during AIDS has been documented for HIV-1-infected individuals and for SIV-and X4 and R5X4 SHIV-infected macaques (49)(50)(51)(52). We recently observed severe, multifocal SHIV-induced giant cell encephalitis (S/HIVE) in macaques infected with the pathogenic subtype B R5 SHIV SF162P3N , with several unique and classical HIVE features, including expansive lesions with spongiosis and necrosis, deep gray matter involvement, microglial infection with high levels of HLA-DR expression, and burnt-out lesions (Westmoreland et al, presented at the 2012 Conference on HIV in the Nervous System).…”