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HIV-1 persists in CSF cells in half of individuals on long-term ART
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Program Abstract- These findings highlight the need to develop interventions in addition to ART to clear persistently infected cells from the CSF compartment.” from Jules: in my next email I am reporting on neurocognitive impairment associated with CSF HIV DNA.
25th Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2018, Boston
Mark Mascolini
Almost half of people taking multiyear effective antiretroviral therapy (ART) had detectable HIV DNA in cells collected from cerebrospinal fluid (CSF) [1]. In this AIDS Clinical Trials Group (ACTG) analysis, detectable HIV DNA in CSF cells did not correlate with HIV DNA in blood or with inflammation in blood or CSF.
Previous work turned up evidence of HIV persistence in the central nervous system (CNS). But the ACTG team noted that this work did not answer some key questions about HIV in the CNS, including (1) prevalence during ART, (2) the relationship of CNS HIV to system-wide and CNS immune activation, and (3) the relationship of CNS HIV to HIV-related neurocognitive disorders.
To begin answering these questions, ACTG A5321 investigators compared paired CSF and blood samples from trial participants who started ART during chronic HIV infection. All participants had lumbar puncture to give a 20-mL CSF sample. The ACTG team measured (1) cell-associated HIV DNA and RNA in CSF and peripheral blood mononuclear cells (PBMCs) and (2) cell-free HIV RNA measured by a single-copy assay in CSF supernatant and blood plasma. They also measured an array of inflammatory markers in cell-free CSF and plasma: IL-6, IP-10, neopterin, MCP-1, sCD14, sCD163, and TNF-alpha.
The 69 people in the study group (67 of them men) had a median age 50, compared with 49 in 19 HIV-negative controls. Median ART duration measured 8.6 years and ranged from 5.4 to 16.4. Median CD4 count stood at 696, and 67 of 69 participants had a current viral load below 40 copies.
The researchers detected cell-free RNA in CSF of only 3 participants (4%). But 6 of 69 participants (9%) had cell-associated RNA in CSF and 33 of 69 (48%) had cell-associated DNA. In people with detectable CSF cell-associated HIV DNA, median level stood at 2.1 copies per 1000 cells. By comparing the 33 people with CSF cell-associated DNA and the 36 people without HIV DNA in CSF cells, the researchers found no significant differences in blood cell-associated DNA, blood cell-associated RNA, or plasma RNA by the single-copy assay. Detection of cell-associated HIV DNA in CSF cells had no clear link to HIV DNA in blood.
Compared with HIV-negative controls, people with HIV had significantly higher levels of inflammatory markers like sCD163 and IP-10 in CSF, and in blood, despite years of effective ART. But measures of inflammatory markers in CSF did not differ between people with detectable and undetectable CSF cell-associated DNA, cell-associated RNA, or cell-free RNA by the single-copy assay. Levels of inflammatory CSF markers did correlate with each other, marker levels correlated between CSF and plasma, and all CSF inflammatory markers correlated with age (r = 0.29 to 0.42, P < 0.016).
The ACTG team concluded that almost half of these people on long-term ART had HIV-infected mononuclear cells in CSF. But persistence of HIV-infected cells in CSF could not be linked to HIV DNA levels in blood or to inflammation in blood or CSF. The investigators believe their findings "underscore the need for further investigation of HIV persistence in the CNS."
Reference
1. Spudich SS, Gandhi RT, Cyktor JC, et al. HIV-1 persists in CSF cells in half of individuals on long-term ART. 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 119.
WEBCAST: http://www.croiwebcasts.org/console/player/37285?mediaType=slideVideo&&crd_fl=1&ssmsrq=1520538548868&ctms=5000&csmsrq=914
In the Q&A the question came up, where this HIV in CSF is coming from, does this have something to do with the reservoir, asked by Dr Richard Price; is what we see in CSF coming from a reservoir, I do nothing it is a reservoir, the most important question is where these cells are trafficking from. Later in this session is a study I just reported by Mankowski where he suggests its coming from spinal cord, a reservoir he newly anoints after this study as a reservoir perhaps; are they trafficking from the blood - we don’t know even though blood levels were higher here. Are these cells getting infected by some active replicating virus in the CNS in the brain, or are they cells actually leaking from the brain that are infected or are they dimly enhanced by their collection in the CSF vs in the blood or are they coming directly from the blood.
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