TY - JOUR
T1 - Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation
AU - Cheng, Da
AU - Luo, Zhenwu
AU - Fu, Xiaoyu
AU - Stephenson, Sophie
AU - Di Germanio, Clara
AU - Norris, Philip J.
AU - Fuchs, Dietmar
AU - Ndhlovu, Lishomwa C.
AU - Li, Quan Zhen
AU - Zetterberg, Henrik
AU - Gisslen, Magnus
AU - Price, Richard W.
AU - Peng, Shifang
AU - Jiang, Wei
N1 - Publisher Copyright:
© 2022 Cheng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
PY - 2022/2
Y1 - 2022/2
N2 - The mechanisms of persistent central nervous system (CNS) inflammation in people with HIV (PWH) despite effective antiretroviral therapy (ART) are not fully understood. We have recently shown that plasma anti-CD4 IgGs contribute to poor CD41 T cell recovery during suppressive ART via antibody-mediated cytotoxicity (ADCC) against CD41 T cells, and that plasma anti-CD4 IgG levels are associated with worse cognitive performance and specific brain area atrophy. However, the role of anti-CD4 IgGs in neuroinflammation remains unclear. In the current study, plasma and cerebrospinal fluid (CSF) samples from 31 ART-naive and 26 treated, virologically suppressed PWH, along with 16 HIV-seronegative controls, were evaluated for CSF levels of antiCD4 IgG, white blood cell (WBC) counts, soluble biomarkers of neuroinflammation, and neurofilament light chain (NfL). We found that 37% of the PWH exhibited elevated CSF anti-CD4 IgG levels, but few or none of the PWH were observed with elevated CSF antiCD4 IgM, anti-CD8 IgG, or anti-double-strand DNA IgG. CSF anti-CD4 IgG levels in PWH were directly correlated with neuroinflammation (WBC counts, neopterin, and markers of myeloid cell activation), but not with CSF NfL levels. Using cells from one immune nonresponder to ART, we generated a pathogenic anti-CD4 monoclonal IgG (JF19) presenting with ADCC activity; JF19 induced the production of soluble CD14 (sCD14) and interleukin-8 (IL-8) in human primary monocyte-derived macrophages via CD4 binding in vitro. This study demonstrates for the first time that elevated CSF anti-CD4 IgG levels present in a subgroup of PWH which may play a role in neuroinflammation in HIV. IMPORTANCE This study reports that an autoantibody presents in the CNS of HIV patients and that its levels in the CSF correlate with some markers of neuroinflammation.
AB - The mechanisms of persistent central nervous system (CNS) inflammation in people with HIV (PWH) despite effective antiretroviral therapy (ART) are not fully understood. We have recently shown that plasma anti-CD4 IgGs contribute to poor CD41 T cell recovery during suppressive ART via antibody-mediated cytotoxicity (ADCC) against CD41 T cells, and that plasma anti-CD4 IgG levels are associated with worse cognitive performance and specific brain area atrophy. However, the role of anti-CD4 IgGs in neuroinflammation remains unclear. In the current study, plasma and cerebrospinal fluid (CSF) samples from 31 ART-naive and 26 treated, virologically suppressed PWH, along with 16 HIV-seronegative controls, were evaluated for CSF levels of antiCD4 IgG, white blood cell (WBC) counts, soluble biomarkers of neuroinflammation, and neurofilament light chain (NfL). We found that 37% of the PWH exhibited elevated CSF anti-CD4 IgG levels, but few or none of the PWH were observed with elevated CSF antiCD4 IgM, anti-CD8 IgG, or anti-double-strand DNA IgG. CSF anti-CD4 IgG levels in PWH were directly correlated with neuroinflammation (WBC counts, neopterin, and markers of myeloid cell activation), but not with CSF NfL levels. Using cells from one immune nonresponder to ART, we generated a pathogenic anti-CD4 monoclonal IgG (JF19) presenting with ADCC activity; JF19 induced the production of soluble CD14 (sCD14) and interleukin-8 (IL-8) in human primary monocyte-derived macrophages via CD4 binding in vitro. This study demonstrates for the first time that elevated CSF anti-CD4 IgG levels present in a subgroup of PWH which may play a role in neuroinflammation in HIV. IMPORTANCE This study reports that an autoantibody presents in the CNS of HIV patients and that its levels in the CSF correlate with some markers of neuroinflammation.
KW - Anti-CD4 IgG
KW - Anti-CD4 autoantibody
KW - Cerebrospinal fluid
KW - HIV
KW - HIV-1 infection
KW - Neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=85124267075&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124267075&partnerID=8YFLogxK
U2 - 10.1128/spectrum.01975-21
DO - 10.1128/spectrum.01975-21
M3 - Article
C2 - 34985329
AN - SCOPUS:85124267075
SN - 2165-0497
VL - 10
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 1
M1 - e01975-21
ER -