Cerebrospinal fluid signs of neuronal damage after antiretroviral treatment interruption in HIV-1 infection

Abstract

BackgroundThe neurofilament is a major structural component of myelinated axons. Increased cerebrospinal fluid (CSF) concentrations of the light chain of the neurofilament protein (NFL) can serve as a sensitive indicator of central nervous system (CNS) injury. To assess whether interrupting antiretroviral treatment of HIV infection might have a deleterious effect on the CNS, we measured NFL levels in HIV-infected subjects interrupting therapy.We identified subjects who had CSF HIV RNA concentrations below 50 copies/mL at the time combination antiretroviral therapy was interrupted, and for whom CSF samples were available before and after the interruption.ResultsA total of 8 subjects were studied. The median (range) CSF NFL level at baseline was <125 (<125–220) ng/L (normal <250 ng/L). All 8 subjects exhibited an increase in CSF and plasma HIV RNA after stopping therapy, accompanied by intrathecal immunoactivation as evidenced by CSF lymphocytic pleocytosis (7/8 patients) and increased CSF neopterin concentration (5/6 patients). Three subjects showed a consistent increase in CSF NFL, rising from <125 ng/L to a maximum of 880 (at day 148), 1,010 (day 58) and 10,930 ng/L (day 101). None exhibited new neurological symptoms or signs, or experienced functional deterioration during the period off treatment; of 5 who underwent brief quantitative neurological testing, none showed worsening performance.ConclusionThese findings suggest that resurgence of active HIV replication may result in measurable, albeit subclinical, CNS injury. Further studies are needed to define the frequency and pathobiological importance of the increase in CSF NFL.

Discordant CSF/plasma HIV-1 RNA in patients with unexplained low-level viraemia

“…Intermittent reseeding of virus into the CNS during periods of systemic replication due to another cause (e.g. non-declared poor adherence) may also establish compartmentalised CNS infection (Gisslen et al 2005; Eden et al 2010). Regardless of the origin of CSF virus, targeting LP to patients with unexplained blips or persistent LLV in plasma may represent a useful strategy in clinical practice and warrants further investigation.…”

Factors in AIDS Dementia Complex Trial Design: Results and Lessons from the Abacavir Trial

“…Thus, markers that allow “real time” evaluation of ADC activity, as opposed to its retrospective identification by history, are urgently needed. In this regard, emerging data on the CSF concentrations of the neuronal markers neurofilament and perhaps t-tau are promising [37–39]. …”

Paving the path to HIV neurotherapy: Predicting SIV CNS disease

“… * Previously unreported data 1 Wactman et al, 2006 2 Njamnshi et al, 2009 3 Ragin et al, 2011 4 Sanchez-Ramon et al, 2003 5 Burdo et al, 2011 6 Marcondes et al, 2009 7 Winston et al, 2010 8 Zink et al, 1999 9 Cysique et al, 2005; McArthur et al, 2004; Sevigny et al, 2004 10 Mankowski et al, 2004; Zink et al, 2001 11 Sevigny et al, 2004 12 Mankowski et al, 2004 13 Fredrikson et al, 1987; Fuchs et al, 1989; Hagberg et al, 2010 14 Bonneh-Barkay et al, 2008 15 Meulendyke et al, 2014 16 Gisslen et al, 2005; Mellgren et al, 2007 …”

“…In the context of HIV, CSF neurofilament light chain decreases with cART and increases with interruption of cART treatment, implying that cART is able to interrupt the neurodegenerative processes associated with chronic HIV-1 infection (Gisslen et al, 2005; Mellgren et al, 2007). CSF neurofilament light chain has been rarely reported in SIV primate models of HIV infection.…”