Abstract
Central nervous system (CNS) invasion during acute-stage HIV-infection has been demonstrated in a small number of individuals, but there is no evidence of neurological impairment at this stage and virus infection in brain appears to be controlled until late-stage disease. Using our reproducible SIV macaque model to examine the earliest stages of infection in the CNS, we identified immune responses that differentially regulate inflammation and virus replication in the brain compared to the peripheral blood and lymphoid tissues. SIV replication in brain macrophages and in brain of SIV-infected macaques was detected at 4 days post-inoculation (p.i.). This was accompanied by upregulation of innate immune responses, including IFNβ, IFNβ-induced gene MxA mRNA, and TNFα. Additionally, IL-10, the chemokine CCL2, and activation markers in macrophages, endothelial cells, and astrocytes were all increased in the brain at four days p.i. We observed synchronous control of virus replication, cytokine mRNA levels and inflammatory markers (MHC Class II, CD68 and GFAP) by 14 days p.i.; however, control failure was followed by development of CNS lesions in the brain. SIV infection was accompanied by induction of the dominant-negative isoform of C/EBPβ, which regulates SIV, CCL2, and IL6 transcription, as well as inflammatory responses in macrophages and astrocytes. This synchronous response in the CNS is in part due to the effect of the C/EBPβ on virus replication and cytokine expression in macrophage-lineage cells in contrast to CD4+ lymphocytes in peripheral blood and lymphoid tissues. Thus, we have identified a crucial period in the brain when virus replication and inflammation are controlled. As in HIV-infected individuals, though, this control is not sustained in the brain. Our results suggest that intervention with antiretroviral drugs or anti-inflammatory therapeutics with CNS penetration would sustain early control. These studies further suggest that interventions should target HIV-infected individuals with increased CCL2 levels or HIV RNA in the CNS.
Highlights
HIV infection of the brain is thought to occur during acute infection based on a limited number of case reports and studies [1,2,3]
Based on our previous studies, SIV viral load is detectable at 7 days p.i. in the plasma and cerebrospinal fluid (CSF) of infected macaques, while SIV mRNA in the brain is observed at 7 and 10 day p.i. [9,36,37,42,43]
We examined the brain of SIVinfected macaques at 4 days p.i. to determine when virus infection in the brain occurs compared to the peripheral blood
Summary
HIV infection of the brain is thought to occur during acute infection based on a limited number of case reports and studies [1,2,3]. It has been postulated that HIV infection is cleared from the brain after acute infection, and that CNS deficits occur because of reentry of virus into the CNS during late-stage disease—when there is high viral load in peripheral blood and immune impairment [4,5]. This is relevant in the current HAART-era, when patients frequently maintain suppression of virus replication in the peripheral blood.
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