Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation
Laura P. Kincer, … , Paola Cinque, Sarah B. Joseph
Laura P. Kincer, … , Paola Cinque, Sarah B. Joseph
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e176358. https://doi.org/10.1172/JCI176358.
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Research Article AIDS/HIV

Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation

Abstract

During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.

Authors

Laura P. Kincer, Ameet Dravid, Mattia Trunfio, Andrea Calcagno, Shuntai Zhou, Riccardo Vercesi, Serena Spudich, Magnus Gisslen, Richard W. Price, Paola Cinque, Sarah B. Joseph

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Figure 6

Model of the emergence of NSE during treatment with an ART regimen representative of those used in this cohort.

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Model of the emergence of NSE during treatment with an ART regimen repre...
(i) Most drugs are at lower concentrations in the CSF (86). Despite the overall low levels of protein in the CSF, most ATV in the CSF is protein bound (54), thus reducing the amount of available ATV (54) to noninhibitory levels (86). In contrast, TDF and 3TC are primarily unbound in the CSF. In this drug regimen (TDF/3TC/ATV/r, the most common regimen in our cohort), 3TC is likely the only drug at inhibitory levels in CSF. During a period of poor adherence, the concentration of drug falls and the CSF HIV-1 RNA rises. Upon returning to adherence, drug levels rise and HIV-1 RNA decreases. Return to adherence will select for the M184V mutation (conveying resistance to 3TC). (ii) Resistant virus can reach the CNS as a migrating CD4+ T cell carrying a provirus with the M184V mutation or (iii) evolve in the CNS during replication when all 3 drugs are at noninhibitory levels. (iv) HIV-1 RNA in the CSF remains detectable and may increase as the drug-resistant virus replicates. (v and vi) Replication increases genetic diversity, CSF HIV-1 RNA, and inflammatory biomarkers. Both v and vi are associated with the spread of drug resistant virus and an elevation in CSF WBC. (vii) Optimization of ART to a regimen with good CNS penetration and to which the NSE virus is sensitive will (viii) stop replication and improve symptoms. Created with BioRender.