The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment

Abstract

Highly active antiretroviral therapy has been effective in lowering viral loads in the peripheral blood, restoring immune function and reducing the incidence of opportunistic infections and dementia in human immunodeficiency virus (HIV)-infected individuals. However, motor and cognitive deficits and peripheral neuropathy continue, with some studies reporting an increase in prevalence of nervous system disease. The authors developed an accelerated, consistent simian model of HIV infection in which pigtailed macaques are dual inoculated with a neurovirulent simian immunodeficiency virus (SIV) clone and an immunosuppressive SIV strain. Infected animals invariably develop acquired immunodeficiency syndrome (AIDS) and over 90% develop central nervous system disease as well as peripheral nervous system disease with neurodegeneration by 3 months postinoculation. This model provides outstanding opportunities to delineate the pathogenesis of infection, to study the regulation of virus gene expression, and to identify host immune responses throughout the acute, clinically silent and late stages of infection. Using this model, the authors have demonstrated that the virus enters the brain within days after inoculation, that CCL2 (monocyte chemoattractant protein [MCP]-1) plays a major role in recruiting monocytes/macrophages to the brain, and that type I interferons are critical in suppressing early virus replication and inducing viral latency. This model provides a rigorous platform for the testing of potential antiretroviral, immune reconstituting, and/or neuroprotective agents and already has been used to confirm the neuroprotective properties of minocycline, which now is being tested in clinical trials of HIV-infected individuals.

Figure 1

Viral, inflammatory, and immune parameters in the accelerated, consistent SIV/macaque model of HIV-associated neurological disease. (A) Viral RNA levels in plasma increase rapidly during the first 7 to 10 days after virus inoculation, decline by approximately 1 log, then increase again and remain at 10⁷ to 10⁸ for the remainder of the infection period. Viral RNA levels in CSF increase during acute infection, decline by several logs during the next 2 weeks, then increase again only in macaques that will develop moderate to severe encephalitis. CD4+ cell counts in peripheral blood decline during acute infection, recover briefly, then begin to decline again during the asymptomatic stage of infection. (B) CCL2 production in the CNS, expressed as the ratio of CCL2 in CSF:plasma rises during acute infection, declines by day 21 p.i., then increases again in macaques that will develop moderate to severe encephalitis. Markers of macrophage infiltration and activation (CD68 and MHC class II) are elevated in brain tissue during acute and terminal infection. In contrast, activation of astrocytes as measured by expression of GFAP in brain tissue increases gradually throughout infection. (C) During acute infection, when there is an increase in viral RNA in the brain, IFNβ and MX RNA are elevated in the brain. Viral RNA declines rapidly after expression of IFNβ and MX and rises again late in infection in conjunction with immunosuppression. IFNβ and MX RNA are again expressed at high levels during late-stage infection.