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Comprehensive study of cerebrospinal fluid β2-microglobulin, a marker of central nervous system immune activation in individuals with HIV
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In our previous work we have demonstrated that most untreated NA individuals have elevated CSF neopterin and although levels decline markedly after ART initiation, nearly half retain elevated CSF neopterin levels.[35, 36] We find the same pattern for CSF β 2 M. More than 90% of untreated NA participants, especially those with low CD4 + T-cell counts, had elevated levels. Among virally suppressed NA participants, 37% remained elevated…... Individuals with a low CD4 + T-cell nadir prior to ART might not be expected to normalize inflammatory markers to the same extent as those with higher CD4+ T-cell counts, underscoring the importance of early ART.
Interestingly, one third of the controls also showed increased CSF β 2 M and neopterin levels. This is consistent with a recent study reporting higher CSF β 2 M levels in controls on PrEP compared with individuals without PrEP, suggesting that non-HIV factors, including lifestyle (e.g. drug use) and viral co-infections (e.g. cytomegalovirus), may contribute to CSF inflammation.[22, 37] After three years on ART, the proportion of NA individuals with elevated CSF β 2 M levels was similar to that of controls. Given that the majority of controls in our study were on PrEP and considering the similarities between NA individuals and those on PrEP, these findings further support the contributions of factors other than HIV to CSF inflammation.
In conclusion CSF β 2 M shows decay characteristics similar to neopterin, with substantial reduction after ART and normalization in many PWH. The association with BBB disruption and neuronal injury supports its value as a marker of HIV-related CNS involvement and it may serve as a clinical alternative to neopterin, used together with other inflammatory or dementia-related markers, when evaluating cognitive difficulties in PWH.
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Comprehensive study of cerebrospinal fluid β2-microglobulin, a marker of central nervous system immune activation in individuals with HIV
Anesten, Birgittaa,b; Zetterberg, Henrikc,d,e,f,g,h; Nilsson, Staffani; Fuchs, Dietmarj; Gisslén, Magnusa,b; Yilmaz, Aylina,b
AIDS March 06, 2026
Objective:
Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has not been fully characterized in people with HIV (PWH) in different categories of disease.
Design:
Retrospectively, we determined levels of β2M, neopterin, HIV RNA, albumin ratio, IgG index, CD4+ T cell count, neurofilament light chain protein (NfL), and leukocyte counts (WBC), in CSF and blood in PWH with and without antiretroviral treatment (ART). Persons without HIV served as controls.
Methods:
Participants were grouped as: 1) neuroasymptomatic HIV (NA), 2) NA CSF escape, 3) symptomatic CSF escape, 4) secondary CSF escape, 5) HIV-associated dementia (HAD), 6) opportunistic infections in the central nervous system (CNS) (OI), and 7) elite controllers.
Results:
We included 638 individuals: NA (N = 556); NA CSF escape (N = 33); symptomatic CSF escape (N = 4); secondary CSF escape (N = 5); HAD (N = 16); OI (N = 18); elite controllers (N = 6) and 59 controls. Highest CSF β2M levels were found in HAD, OI and symptomatic CSF escape. In 112 longitudinally followed NA participants, elevated CSF β2M levels (89%) were found at baseline, and (96%) for CSF neopterin. After ART initiation CSF β2M levels decreased by 10% per month and CSF neopterin by 17%. After three years 39% had CSF β2M and 44% had CSF neopterin levels above the reference values, similar to the controls (39%).
Conclusion:
CSF β2M levels were elevated in the majority of individuals across HIV stages. Suppressive ART decreases β2M toward control levels, although neuroinflammation persists, most likely driven by non-HIV factors.
Longitudinal follow-up of β 2 M and neopterin after ART initiation
Of 342 untreated NA participants, 112 were followed before and after ART initiation. At baseline, 89% had elevated CSF β2 M and 96% had elevated CSF neopterin levels. After ART initiation, CSFβ 2 M levels declined by 10% per month during the first three months (p < 0.0001), 10% per year at one year (p < 0.01) and 5% per year at three years (p < 0.05), with no further decline thereafter (Figure 3). Three months after ART initiation, 78% (73/93) still had elevated CSF β 2 M levels, 58% (49/85) at one year, 39% (22/56) at three years, 40% (17/42) at five years, and 57% (12/21) at ten years.
Serum β 2 M declined by 8% per month in the early phase (p < 0.0001), 9% per year at one year (p < 0.0001), 4% per year at three years (p < 0.05), with no further significant decline thereafter.
CSF neopterin levels declined by 17% per month during the early phase (p < 0.0001), 27% per year at one year (p < 0.0001) and 2% per year at three years (not significant), with no further decline thereafter (Figure 3). After three months on ART 80% (75/94) had elevated CSF neopterin levels, 56% (48/85) at one year, 44% (25/57) at three years in, 27% (12/44) at five years, and 62% (13/21) at ten years.
Serum neopterin declined by 16% per month in the early phase (p < 0.0001) and by 17% per year at one year (p < 0.001), with no statistically significant changes thereafter.
All five participants with HAD had abnormal baseline CSF β 2 M and neopterin levels. After ART initiation, CSF β 2 M declined by 21% per month (not significant) and serum β 2 M by 15% (p < 0.05) during the early phase (Figure 3). At three months, 3/3 had CSF β2 M levels above the reference values, 2/3 after one year, and none at three (0/2) years. CSF neopterin levels declined by 32% per month (not significant) and serum neopterin by 29% (p < 0.05) in the early phase. At three months, 3/3 had elevated CSF neopterin, 2/3 at one year, and none at three (0/1) years.
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