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

Abstract

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...

Insights into the Impact of CD8+Immune Modulation on Human Immunodeficiency Virus Evolutionary Dynamics in Distinct Anatomical Compartments by Using Simian Immunodeficiency Virus-Infected Macaque Models of AIDS Progression

“…Sequences were aligned as previously described (41), and approximately 20 gp120 sequences per tissue per time point were obtained after removal of potential recombinants. Detailed information regarding sample collection, sequencing protocols, and the sequence alignment procedure has been reported previously (2,43). All sequences used in this study are accessible in GenBank under accession numbers JF765272 to JF766081 (Mac251-DEP cohort) and accession numbers KR998525 to KR999900, KX081185 to KX081229, and KX081254 to KX082629 (Mac251-NP cohort and inoculating viral swarm).…”

“…Maximum likelihood (ML) reconstruction of phylogenetic trees for both macaque cohorts was performed in RAxML v8.0.25 (69; http://sco.h-its.org/exelixis/web/software/raxml/index.html), using the general time-reversible (GTR) model of nucleotide substitution (70) with gamma-distributed rate variation across sites and 1,000 bootstrap replicates. Trees were viewed and modified in FigTree v1.4.0 (http://tree.bio.ed.ac.uk/software/figtree/) and can be found in previously published studies (2,41).…”

“…1). Viral genomic RNA was extracted from these samples and the SIVmac251 inoculum as previously described (2,41,43,61). Viral genomic material was also extracted from meninges and brain tissue sections from the parietal, frontal, and temporal lobes at necropsy, when available.…”

“…KEYWORDS AIDS, HIV, SIV, evolution, phylodynamics, tissue V iral evolutionary changes often have a profound impact on human immunodeficiency virus type 1 (HIV-1) disease progression (reviewed in reference 1), with the most well-characterized changes involving shifts in coreceptor usage and adaptation to specific tissues and cell types (2). Cellular and receptor tropism shifts have been linked to faster AIDS progression (3) as well as to the onset and progression of AIDS-related neuropathology (4).…”

Brain tissue transcriptomic analysis of SIV-infected macaques identifies several altered metabolic pathways linked to neuropathogenesis, and Poly (ADP-ribose) polymerases (PARPs) as potential therapeutic targets

“…Frontal cortex tissue samples were collected from two cohorts of animals intravenously infected with SIVmac251 [24], which originally consisted of five CD8+ lymphocyte-depleted (D) and six non-CD8-depleted (N = naturally progressing to SAIDS) Rhesus macaques, as previously described (Table S1) [43]. Procedures on the CD8+ lymphocyte-depleted and naturally progressing cohort were conducted with the approval of New England Regional Primate Center at Harvard [19] and University Tulane University's Institutional Animal Care and Use Committee [43], respectively. Animals were kept in the same facility under similar conditions to minimize batch effects.…”