Nonhuman primate models of NeuroAIDS

Williams, Rachel; Bokhari, Sirosh; Silverstein, Peter S.; Pinson, David M.; Kumar, Anil; Buch, Shilpa

doi:10.1080/13550280802074539

Cited by 62 publications

(51 citation statements)

References 75 publications

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“…Infection of rhesus macaques with pathogenic simian immunodeficiency virus (SIV) clones and/or viral swarms is a widely used model for HIV/AIDS (13) as well as neuroAIDS (14). SIV-infected macaques exhibit clinical manifestations similar to those of HIV-1-infected humans, albeit on a shorter time scale of approximately 1 to 3 years (13), and the incidence (Ͻ25%) of SIV-associated encephalitis (SIVE), the pathological hallmark of neuroAIDS, is similar to that of untreated seropositive patients (Ͻ30%) (15).…”

mentioning

confidence: 99%

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Rife

Nolan

Lamers³

et al. 2016

J Virol

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The emergence of a distinct subpopulation of human or simian immunodeficiency virus (HIV/SIV) sequences within the brain (compartmentalization) during infection is hypothesized to be linked to AIDS-related central nervous system (CNS) neuropathology. However, the exact evolutionary mechanism responsible for HIV/SIV brain compartmentalization has not been thoroughly investigated. Using extensive viral sampling from several different peripheral tissues and cell types and from three distinct regions within the brain from two well-characterized rhesus macaque models of the neurological complications of HIV infection (neuroAIDS), we have been able to perform in-depth evolutionary analyses that have been unattainable in HIV-infected subjects. The results indicate that, despite multiple introductions of virus into the brain over the course of infection, brain sequence compartmentalization in macaques with SIV-associated CNS neuropathology likely results from late viral entry of virus that has acquired through evolution in the periphery sufficient adaptation for the distinct microenvironment of the CNS. IMPORTANCEHIV-associated neurocognitive disorders remain prevalent among HIV type 1-infected individuals, whereas our understanding of the critical components of disease pathogenesis, such as virus evolution and adaptation, remains limited. Building upon earlier findings of specific viral subpopulations in the brain, we present novel yet fundamental results concerning the evolutionary patterns driving this phenomenon in two well-characterized animal models of neuroAIDS and provide insight into the timing of entry of virus into the brain and selective pressure associated with viral adaptation to this particular microenvironment. Such knowledge is invaluable for therapeutic strategies designed to slow or even prevent neurocognitive impairment associated with AIDS. Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain a persistent complication despite the success of highly active antiretroviral therapy (HAART) in prolonging the progression to AIDS in HIV-1-infected patients (1). Although the post-HAART era has witnessed a decrease in the prevalence of the most severe form of HAND, HIV-associated dementia (HAD), an increase in prevalence has been observed for the milder forms, referred to as asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) (2, 3). Moreover, these assessments have been reported to be an underestimation of the true prevalence, based on a study in which approximately 64% of HIV-1-infected patients classified as "noncomplainers," self-reporting no symptoms of cognitive impairment, tested positive for HAND using comprehensive neurocognitive testing criteria (4). Furthermore, with the life expectancy for patients receiving HAART now projected to be greater than 70 years (5, 6), the reported prevalence estimations can only be expected to increase, whereas our understanding of the critical components of disease pathogenesis, such as t...

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confidence: 99%

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Rife

Nolan

Lamers³

et al. 2016

J Virol

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“…Although combination antiretroviral therapy (cART) has markedly diminished the incidence of overt HAD, a milder-to-moderate form of neurocognitive impairment known collectively as HIV-1-associated neurocognitive disorders (HAND) developed in an estimated 50% of treated patients (1)(2)(3). Lentiviral neuroinvasion involves the recruitment of infected monocytes/macrophages and/or T cells to the central nervous system (CNS) from circulation, with activation and productive infection of resident microglia and a more restricted/latent infection of astrocytes (4)(5)(6)(7)(8)(9). HIV-1 infection of mononuclear phagocytes in the CNS has been suggested to be the critical driving force of HIV-induced encephalitis (HIVE), as well as HAND (10,11).…”

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confidence: 99%

Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis

Zhuang

Léda

Tsai

et al. 2014

J Virol

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Human immunodeficiency virus type 1 (HIV-1) infection in the central nervous system (CNS) is characterized by replication in macrophages or brain microglia that express low levels of the CD4 receptor and is the cause of HIV-associated dementia and related cognitive and motor disorders that affect 20 to 30% of treatment-naive patients with AIDS. Independent viral envelope evolution in the brain has been reported, with the need for robust replication in resident CD4 low cells, as well as CD4-negative cells, such as astrocytes, proposed as a major selective pressure. We previously reported giant-cell encephalitis in subtype B and C R5 simian-human immunodeficiency virus (SHIV)-infected macaques (SHIV-induced encephalitis [SHIVE]) that experienced very high chronic viral loads and progressed rapidly to AIDS, with varying degrees of macrophage or microglia infection and activation of these immune cells, as well as astrocytes, in the CNS. In this study, we characterized envelopes (Env) amplified from the brains of subtype B and C R5 SHIVE macaques. We obtained data in support of an association between severe neuropathological changes, robust macrophage and microglia infection, and evolution to CD4 independence. Moreover, the degree of Env CD4 independence appeared to correlate with the extent of astrocyte infection in vivo. These findings further our knowledge of the CNS viral population phenotypes that are associated with the severity of HIV/SHIV-induced neurological injury and improve our understanding of the mechanism of HIV-1 cellular tropism and persistence in the brain. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection of astrocytes in the brain has been suggested to be important in HIV persistence and neuropathogenesis but has not been definitively demonstrated in an animal model of HIV-induced encephalitis (HIVE).Here, we describe a new nonhuman primate (NHP) model of R5 simian-human immunodeficiency virus (SHIV)-induced encephalitis (SHIVE) with several classical HIVE features that include astrocyte infection. We further show an association between severe neuropathological changes, robust resident microglia infection, and evolution to CD4 independence of viruses in the central nervous system (CNS), with expansion to infection of truly CD4-negative cells in vivo. These findings support the use of the R5 SHIVE models to study the contribution of the HIV envelope and viral clades to neurovirulence and residual virus replication in the CNS, providing information that should guide efforts to eradicate HIV from the body.

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“…15,20 MRI scans were performed on a Siemens 3T Trio scanner with the CP extremity coil (Siemens Medical Solutions, Malvern, PA) before SIV inoculation and in 2,4,8,12,16, and 20 weeks post-inoculation (WPI). Blood samples were collected from each animal for monitoring CD4 + and CD8 + T cells before each MRI scan.…”

Section: Methodsmentioning

confidence: 99%

“…The simian immunodeficiency virus (SIV)-infected macaque models exhibit neuropathological symptoms similar to those seen in HIV-infected humans, and have been widely used for studying the cognitive and neuropathological sequelae of AIDS [14][15][16][17] or vaccine development. 18,19 SIVsmmFGb is a novel simian lentivirus strain inducing neuropathology in over 90% of infected pig-tailed macaques.…”

Section: Introductionmentioning

confidence: 99%

A Longitudinal Magnetization Transfer Imaging Evaluation of Brain Injury in a Macaque Model of NeuroAIDS

Herndon

Novembre

et al. 2015

AIDS Research and Human Retroviruses

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Magnetization transfer (MT) imaging has been explored in prior studies of HIV patients and showed the potential capacity to assess brain injury after HIV infection. In the present study, adult pig-tailed macaques were infected with a highly neuropathogenic virus SIVsmmFGb. MT imaging was exploited to examine the monkey brains before simian immunodeficiency virus (SIV) inoculation and 2, 4, 8, 12, 16, and 20 weeks post-SIV inoculation. Blood samples were collected from each animal for monitoring CD4+ and CD8 + T cells before each MRI scan. The MT ratios (MTR) in several brain regions of interest were evaluated longitudinally. Significant reductions of MTR were observed in whole brain and selected regions of interest (genu, splenium, thalamus, caudate, centrum semiovale, frontal white matter, frontal gray matter, and putamen) in the SIV-infected monkeys, consistent with those reported previously in HIV patients. In particular, the longitudinal results indicate that abnormal MTR reduction can be detected as early as in 2 weeks and MTR may be more sensitive to the brain injury in cortical regions than in subcortical regions during acute SIV infection. In addition, MTR reduction in genu, centrum semiovale, and thalamus significantly correlated with the CD4 + T cell percentage decrease. Also, the MTR reduction in thalamus correlated with the CD8 + T cell percentage elevation. Taken together, this study reported the longitudinal evolution of MTR in different brain regions during SIV infection and further validates previous findings in HIV patients. The preliminary results suggest that MT imaging could be a robust and sensitive approach to characterize the neurodegeneration after SIV or HIV infection.

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Nonhuman primate models of NeuroAIDS

Cited by 62 publications

References 75 publications

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis

A Longitudinal Magnetization Transfer Imaging Evaluation of Brain Injury in a Macaque Model of NeuroAIDS

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