Simian Immunodeficiency Virus-Infected Memory CD4⁺T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS

Abstract

Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4+ T cells (CD4) and macrophages (MΦs) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4+ memory T cells (Br-mCD4), brain-MΦs (Br-MΦs), and brain B cells (Br-B cells). Both Br-mCD4s and Br-MΦs harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-MΦs. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain. IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4+ T cells harbor replication-competent SIV DNA; however, only brain CD4+ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.

Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice

“…Thus, to the best of our knowledge, this is the first report directly comparing two different HIV-1 Tat induction methods to evaluate changes in behavior and gene expression in a rodent model. We showed that Tat induction in iTat mice led to mild behavioral deficits when compared to WT controls including one or more of the following trends [1] higher anxiety levels depicted by reduced time spent in the open arms of EPM [2] altered ambulation during LMA [3] higher swim speeds in MWM [4] altered learning in T-maze. Simultaneously, we also depicted that gene expressions of [1] select inflammatory cytokines were unchanged, [2] MMPs were elevated, [3] TIMPs were altered depending on the duration of Tat exposure, subsequently impacting the brain MMP/TIMP balance.…”

“…During each trial, the mouse was allowed to swim until it climbed on the platform or for a maximum of 60 s, whichever was earlier. This pre-training was done so that the mice could learn the motor components of the task such as swimming and climbing onto a platform, and to reduce the bias of anxiety to a new environment during the subsequent phases [2] Acquisition phase: mice were then tested for their ability to locate a hidden platform using spatial cues around the room over four sessions (one session/day). Each session consisted of five trials, at 2-min intervals.…”

“…During the antiretroviral therapy (ART) era, the brain remains a viral reservoir for HIV (1)(2)(3), and milder forms of HIV-associated neurocognitive disorders (HAND) affect nearly 18 million HIVinfected individuals lowering the quality of life (4)(5)(6)(7). Patients suffering from these milder forms of HAND exhibit difficulty with working memory, executive functioning, and speed of information processing (6).…”

Central Nervous System (CNS) Viral Seeding by Mature Monocytes and Potential Therapies To Reduce CNS Viral Reservoirs in the cART Era

“…These researchers found HIV within the brains of these ToM mice, thus showing that T cells can traffic and establish viral reservoirs in the CNS in the absence of macrophages ( 46 ). A recent study using macaques infected with a neuropathogenic SIV clone, CL757, that results in progression to SIV-induced encephalitis (SIVE) in 50% of those infected, showed increased numbers of memory CD4 + T cells (mCD4s) and macrophages in the brains of macaques with SIVE ( 47 ). In addition, these researchers found replication-competent virus in macrophages of animals with SIVE and in mCD4s of animals with or without SIVE ( 47 ).…”

“…A recent study using macaques infected with a neuropathogenic SIV clone, CL757, that results in progression to SIV-induced encephalitis (SIVE) in 50% of those infected, showed increased numbers of memory CD4 + T cells (mCD4s) and macrophages in the brains of macaques with SIVE ( 47 ). In addition, these researchers found replication-competent virus in macrophages of animals with SIVE and in mCD4s of animals with or without SIVE ( 47 ). Given that only mCD4s harbored replication-competent virus in the absence of encephalitis, these authors suggest that mCD4s may be a potential viral reservoir within the brain ( 47 ).…”