CSF/plasma HIV-1 RNA discordance even at low levels is associated with up-regulation of host inflammatory mediators in CSF

Abstract

HighlightsDiscordant HIV in CSF is associated with raised inflammatory mediators in CSF.CSF mediators are raised with discordance both at high and low levels.Discordance on ultrasensitive testing can also be also associated with raised mediators.

Diffuse White Matter Signal Abnormalities on Magnetic Resonance Imaging Are Associated With Human Immunodeficiency Virus Type 1 Viral Escape in the Central Nervous System Among Patients With Neurological Symptoms

“…Diffuse white matter signal abnormalities occur more commonly in the HIV-infected population compared with the HIV-uninfected population and become more extensive with duration of infection [ 18 ]. The presence of HIV in the CSF is proinflammatory as evidenced by raised levels of CSF neopterin [ 3 ] and cytokine profiles [ 17 ]. Nightingale et al [ 17 ], using CSF samples from the penetration of antiretroviral therapy into the nervous system study, showed the presence of higher levels of inflammatory cytokines in the CSF of individuals with discordance when compared with matched controls.…”

“…An elevated HIV-1 CSF VL compared to plasma has been associated with NCI [ 15 ] and dementia in untreated patients [ 16 ]. More recently, the presence of HIV in CSF was associated with an inflammatory response [ 17 ] and low-level peripheral viremia in cART-treated patients [ 17 ]. Two case series [ 4 , 12 ] have identified cases of CSF discordance with neurological symptoms.…”

HIV Cerebrospinal Fluid Escape and Neurocognitive Pathology in the Era of Combined Antiretroviral Therapy: What Lies Beneath the Tip of the Iceberg in Sub-Saharan Africa?

“…Markers of BBB dysfunction are evident with elevation of the matrix metalloproteinases MMP-2, 3 and 9 and subsequent elevation of their inhibitors TIMP-1 and 2 [ 80 ]. Other inflammatory mediators are elevated such a sCD14—a marker of macrophage activation [ 80 ]; chemokines—CCL3, CCL4, CCL5 and CXCL10; cytokines—IL-1α/β, IL-1RA, IL-8, IL-10; TNF related proteins—TNFα, TNFR1, TNFR2 and TRAIL; adhesion molecules; VCAM and ICAM [ 5 , 80 ]. The presence of these inflammatory mediators show that CSF escape/discordance is associated with neuroinflammation, which is occurring in the context of a reconstituted immune system, which may be responsible for both the inflammation and viral replication by attracting HIV infected immune cells or activating latent reservoirs [ 81 ].…”

“…The definitions of these terms are based on the quantification of CSF HIV RNA in paired CSF and plasma specimens (see Table 1 ). CSF discordance is defined as CSF viral load (VL) greater than 0.5 or 1log 10 of the plasma VL and CSF escape is defined as any VL in the CSF above the limit of detection of the assay used (usually 50 copies/mL) when the VL in the plasma is undetectable by the same assay [ 3 , 4 , 5 ]. Although CSF HIV VL does correlate well with brain HIV RNA levels [ 6 ], the causal relationship between CSF escape/discordance and HAND is unclear.…”

Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

“…Though the frequency of HAD has significantly decreased with HAART, approximately half of all HIV-infected individuals develop some form of HAND (34,55,56). One plausible explanation for HAND is decreased, but incompletely suppressed, viral replication within the central nervous system (CNS) (54,57). Indeed, the blood-brain barrier is thought to decrease the penetrance of antiretroviral medication into the CNS (55,58).…”