Macaque species susceptibility to simian immunodeficiency virus: increased incidence of SIV central nervous system disease in pigtailed macaques versus rhesus macaques

Abstract

Immune pressure exerted by MHC class I-restricted cytotoxic T cells drives the development of viral escape mutations, thereby regulating HIV disease progression. Nonetheless, the relationship between host immunity and HIV central nervous system (CNS) disease remains poorly understood. The simian immunodeficiency virus (SIV) macaque model recapitulates key features of HIV infection including development of AIDS and CNS disease. To investigate cell-mediated immunity regulating SIV CNS disease progression, we compared the incidence of SIV encephalitis and the influence of MHC class I allele expression on the development of CNS disease in rhesus macaques (Macaca mulatta) versus pigtailed macaques (Macaca nemestrina). After inoculation with the immunosuppressive swarm SIV/DeltaB670 and the neurovirulent molecular clone SIV/17E-Fr, pigtailed macaques progressed more rapidly to AIDS, had higher plasma and cerebrospinal fluid (CSF) viral loads, and were more likely to progress to SIV-associated encephalitis (SIVE) compared to rhesus macaques. In addition, MHC class I alleles were neuroprotective in both species (Mamu-A*001 in rhesus macaques and Mane-A1*084:01:01 in pigtailed macaques); animals expressing these alleles were less likely to develop SIV encephalitis and correspondingly had lower viral replication in the brain. Species-specific differences in susceptibility to SIV disease demonstrated that cell mediated immune responses are critical to SIV CNS disease progression.

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

“…With this inoculation combination, approximately two-thirds of macaques develop SIV encephalitis within 84 days 156,157 . Of interest is the fact that, though most studies of SIV pathogenesis use rhesus macaques, pigtailed macaques develop CNS disease more often than do rhesus macaques that receive the same SIV inoculum 158 . Key features of the pigtailed macaque SIV model include development of CNS inflammation that correlates with high viral load in the brain, cognitive and motor deficits typical of HIV, and the classic lesions of HIV encephalitis 156,159–163 .…”

Non-human primate models of SIV infection and CNS neuropathology

“…Additionally, using SIVsm804E the authors demonstrated both MHC-I and TRIM5alpha as restrictive host genotypes, underscoring both the role of viral sequences as well as host viral restriction factors in SIVE development[10]. Similar restrictive host genetic MHC I alleles, were reported by Beck et al, in pig tail macaques [8]. These factors underscore the importance of innate anti-viral factors within macrophages, as well as CTL responses most likely against SIV-gag proteins.…”

“…Historically early models used rhesus macaques (RM) or pigtail macaques (PM) and different viral clones or swarms that resulted in immune suppression (AIDS) macrophage tropism for CNS infection, and SIV encephalitis (SIVE) in approximately 30 percent of the animals in RM and higher percentages of PM [8](Table 1). More recently, immune modulation (depletion) of CD4 and CD8 T lymphocytes, and/or serial passage of virus through monkeys for enhanced macrophage replication and neurotropism have been used [6,9–11] (Table 1).…”

Tracking Epidermal Nerve Fiber Changes in Asian Macaques

“…, 2002), specific end points were predetermined according to stage of disease [acute phase at 7 and 10 days post infection (dpi), asymptomatic phase at 21, 35, 42, and 56 dpi, and terminal AIDS at 84 dpi]. Because the course of disease progression is more variable in rhesus macaques, these animals were euthanized when two or more AIDS-defining criteria were met (mean length of infection 213 days)(Beck et al , 2015). …”