Increased IL-6 expression precedes reliable viral detection in the rhesus macaque brain during acute SIV infection.

Raja Mohan Gopalakrishnan,Emma Geiger,Caitlin Davis,Shaily Malik,Steven E Bosinger,Rhianna Jones,Noe B Mercado,R Keith Reeves,Amanda J Martinot,Cesar Piedra-Mora,Dan H Barouch,Valerie Varner,C Sabrina Tan,Malika Aid

doi:10.1172/jci.insight.152013

Abstract

Knowledge of immune activation in the brain during acute HIV infection is crucial for the prevention and treatment of HIV-associated neurological disorders. We determined regional brain (basal ganglia, thalamus, and frontal cortex) immune and virological profiles at 7 and 14 days post infection (dpi) with SIVmac239 in rhesus macaques. The basal ganglia and thalamus had detectable viruses earlier (7 dpi) than the frontal cortex (14 dpi) and contained higher quantities of viruses than the latter. Increased immune activation of astrocytes and significant infiltration of macrophages in the thalamus at 14 dpi coincided with elevated plasma viral load, and SIV colocalized only within macrophages. RNA signatures of proinflammatory responses, including IL-6, were detected at 7 dpi in microglia and interestingly, preceded reliable detection of virus in tissues and were maintained in the chronically infected macaques. Countering the proinflammatory response, the antiinflammatory response was not detected until increased TGF-β expression was found in perivascular macrophages at 14 dpi. But this response was not detected in chronic infection. Our data provide evidence that the interplay of acute proinflammatory and antiinflammatory responses in the brain likely contributed to the overt neuroinflammation, where the immune activation preceded reliable viral detection.

Highlights

Despite the success of antiretroviral therapy, people with HIV still experience some form of neurocognitive impairment [1]
Frontal cortex sections from all animals at 14 dpi, except one, had cells containing detectable SIV RNA. Both at 7 (P = 0.045) and 14 dpi (P = 0.010), the number of SIV+ cells, was significantly higher in the basal ganglia when compared with the frontal cortex (Figure 1A)
To understand the pathogenesis associated with acute SIV infection in the macaque brains, we examined H&Estained sections of the basal ganglia, thalamus, and frontal cortex from animals euthanized at 7 and 14 dpi

Summary

Introduction

Despite the success of antiretroviral therapy, people with HIV still experience some form of neurocognitive impairment [1]. CD8+ T cells exert some control of viral infection by cytotoxicity-mediated killing [5] In one study, these cytotoxic CD8+ and helper CD4+ T lymphocytes independently correlated directly with HIV RNA levels in cerebrospinal fluid (CSF) and in plasma during acute infection, suggesting that peripheral immune response may modulate CNS viral infection [6]. The severity of CNS lesions did not correlate with the corresponding plasma viral load, despite the correlation between CSF and plasma viral loads [6,7,8]. These data suggest that distinct viral immune responses may be compartmentalized in the CNS. Better understanding of HIV pathogenesis and the associated myeloid or lymphoid cell dynamics in the CNS during acute infection will elucidate factors leading to viral persistence in the brain [9]

Methods

Results

Conclusion