Abstract
HIV cerebrospinal fluid (CSF) escape is defined by a concentration of HIV-1 RNA in CSF above the lower limit of quantification of the employed assay and equal to or greater than the plasma HIV-1 RNA level in the presence of treatment-related plasma viral suppression, while CSF discordance is similarly defined by equal or higher CSF than plasma HIV-1 RNA in untreated individuals. During secondary CSF escape or discordance, disproportionate CSF HIV-1 RNA develops in relation to another infection in addition to HIV-1. We performed a retrospective review of people living with HIV receiving clinical care at Sahlgrenska Infectious Diseases Clinic in Gothenburg, Sweden who developed uncomplicated herpes zoster (HZ) and underwent a research lumbar puncture (LP) within the ensuing 150 days. Based on treatment status and the relationship between CSF and plasma HIV-1 RNA concentrations, they were divided into 4 groups: i) antiretroviral treated with CSF escape (N = 4), ii) treated without CSF escape (N = 5), iii) untreated with CSF discordance (N = 8), and iv) untreated without CSF discordance (N = 8). We augmented these with two additional cases of secondary CSF escape related to neuroborreliosis and HSV-2 encephalitis and analyzed these two non-HZ cases for factors contributing to CSF HIV-1 RNA concentrations. HIV-1 CSF escape and discordance were associated with higher CSF white blood cell (WBC) counts than their non-escape (P = 0.0087) and non-discordant (P = 0.0017) counterparts, and the CSF WBC counts correlated with the CSF HIV-1 RNA levels in both the treated (P = 0.0047) and untreated (P = 0.002) group pairs. Moreover, the CSF WBC counts correlated with the CSF:plasma HIV-1 RNA ratios of the entire group of 27 subjects (P = <0.0001) indicating a strong effect of the CSF WBC count on the relation of the CSF to plasma HIV-1 RNA concentrations across the entire sample set. The inflammatory response to HZ and its augmenting effect on CSF HIV-1 RNA was found up to 5 months after the HZ outbreak in the cross-sectional sample and, was present for one year after HZ in one individual followed longitudinally. We suggest that HZ provides a ‘model’ of secondary CSF escape and discordance. Likely, the inflammatory response to HZ pathology provoked local HIV-1 production by enhanced trafficking or activation of HIV-1-infected CD4+ T lymphocytes. Whereas treatment and other systemic factors determined the plasma HIV-1 RNA concentrations, in this setting the CSF WBC counts established the relation of the CSF HIV-1 RNA levels to this plasma set-point.
Highlights
Hiv infects various compartments in the body including the central nervous system (CNS)
We identified 25 HIV-1-infected individuals who underwent lumbar punctures (LPs) within 150 days after the onset of Herpes zoster (HZ) rash: 9 on and 16 off antiretroviral therapy (ART) (Table 1)
In order to better understand the reversal of cerebrospinal fluid (CSF):plasma HIV-1 RNA ratios by HZ in some, but not all, of the identified individuals, we examined a number of other variables, including the CSF white blood cell (WBC) count, CSF neopterin concentration, blood CD4+ T-lymphocyte counts, CSF neurofilament light (NfL) concentration, time between the HZ rash outbreak and CSF sampling, and distance between the HZ outbreak and the site of LP (Fig 2)
Summary
Hiv infects various compartments in the body including the central nervous system (CNS). HIV-1 RNA is detected in the cerebrospinal fluid (CSF) throughout the course of untreated systemic infection, beginning early after initial exposure [1,2,3] and continuing until suppressed by antiretroviral therapy (ART) [4,5,6,7]. Combination ART is generally very effective in suppressing CNS HIV-1 infection, so that treatment that reduces plasma HIV-1 to below the clinical LLoQ is effective in eliminating ‘clinically detectable’ CSF HIV-1 RNA. Even when more sensitive assays have been used to measure HIV-1 RNA, detection in the CSF was less common and at lower levels than that in plasma, consistent with the general treatment effectiveness on CNS infection [9, 14]
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