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Objective: HIV-1 invades the brain within days post-transmission. This study quantitated cerebrospinal fluid (CSF) white blood cell count (WBC) and investigated whether it associated with plasma and CSF HIV-1 RNA during untreated acute HIV infection (AHI)., Design: Seventy participants underwent lumbar puncture during Fiebig stages I-V AHI., Method: WBC and HIV-1 RNA with a lower limit of quantification (LLQ) of 80 copies/ml were measured in CSF., Results: Sixty-nine (99%) participants were men, with a median age of 26. Their blood CD4 + and CD8 + T-cell counts were 335 [interquartile range (IQR) 247-553) and 540 (IQR 357-802) cells/μl, respectively. Forty-five (64%) were in Fiebig stages III-V whereas 25 (36%) were in Feibig stages I-II. Fifty-two (74%) experienced acute retroviral syndrome. Median plasma and CSF HIV-1 RNA were 6.10 (IQR 5.15-6.78) and 3.15 (IQR 1.90-4.11) log 10 copies/ml, respectively. Sixteen (23%) CSF samples had HIV-1 RNA below LLQ. Median CSF WBC was 2.5 (IQR 1-8) cells/μl. CSF pleocytosis (WBC >5) was observed in 33% and was only present in CSF samples with detectable HIV-1 RNA. The frequencies of CSF pleocytosis during Fiebig stages III-V and among CSF samples of higher viral load (>1000 copies/ml) were 42 and 45%, respectively. Pleocytosis independently associated with CSF HIV-1 RNA in multivariate analysis [adjusted coefficient: 0.79, 95% confidence interval (CI) 0.41-1.14), P  < 0.001] and a lower plasma to CSF HIV-1 RNA ratio ( P  < 0.001)., Conclusion: CSF pleocytosis was present in one-third of participants with AHI. It associated with higher CSF HIV-1 RNA and a lower plasma to CSF HIV-1 RNA ratio, suggesting a potential association with HIV-1 neuroinvasion., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: HIV-associated neuroinflammation persists in the brain despite suppressive combination antiretroviral therapy (cART). We evaluated associations between a subset of CD8 + T cells, termed CD4 dim CD8 bright T cells, and soluble markers of immune activation and/or neuroinflammation in the cerebrospinal fluid (CSF) and plasma of people with HIV (PWH)., Design: Fifteen cART-naive PWH were enrolled and underwent blood draw, lumbar puncture for CSF collection, and neuropsychological tests at week 0 (pre-cART) and 24 weeks after cART initiation., Methods: CSF and peripheral blood T cells were evaluated with flow cytometry and soluble markers of immune activation were measured by multiplex and singleplex assays. Spearman bootstrap correlation coefficients with 10 000 resamples were computed and reported with corresponding 95% confidence intervals (CIs) for each marker of interest and T-cell type., Results: The frequency of CSF CD4 dim CD8 bright T cells at week 0 was inversely related with CSF neopterin. In contrast, at week 24, CSF CD4 - CD8 + T cells were positively correlated with CSF s100β, a marker of brain injury. In the blood, at week 0, CD4 dim CD8 bright T cells were inversely correlated with MCP-1, IP-10, IL-8, IL-6, G-CSF, and APRIL and positively correlated with plasma RANTES and MMP1. At week 0, the frequency of blood CD4 - CD8 + were positively correlated with CRP and BAFF., Conclusion: CD4 dim CD8 bright T cells are associated with some anti-inflammatory properties, whereas CD4 - CD8 + T cells may contribute to inflammation and injury. Assessing the contrast between these two cell populations in neuroHIV may inform targeted therapeutic intervention to reduce neuroinflammation and associated neurocognitive impairment., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: People with chronic HIV exhibit lower regional brain volumes compared to people without HIV (PWOH). Whether imaging alterations observed in chronic infection occur in acute HIV infection (AHI) remains unknown., Design: Cross-sectional study of Thai participants with AHI., Methods: One hundred and twelve Thai males with AHI (age 20-46) and 18 male Thai PWOH (age 18-40) were included. Individuals with AHI were stratified into early (Fiebig I-II; n  = 32) and late (Fiebig III-V; n  = 80) stages of acute infection using validated assays. T1-weighted scans were acquired using a 3 T MRI performed within five days of antiretroviral therapy (ART) initiation. Volumes for the amygdala, caudate nucleus, hippocampus, nucleus accumbens, pallidum, putamen, and thalamus were compared across groups., Results: Participants in late Fiebig stages exhibited larger volumes in the nucleus accumbens (8% larger; P  = 0.049) and putamen (19%; P  < 0.001) when compared to participants in the early Fiebig. Compared to PWOH, participants in late Fiebig exhibited larger volumes of the amygdala (9% larger; P  = 0.002), caudate nucleus (11%; P  = 0.005), nucleus accumbens (15%; P  = 0.004), pallidum (19%; P  = 0.001), and putamen (31%; P  < 0.001). Brain volumes in the nucleus accumbens, pallidum, and putamen correlated modestly with stimulant use over the past four months among late Fiebig individuals ( P s < 0.05)., Conclusions: Findings indicate that brain volume alterations occur in acute infection, with the most prominent differences evident in the later stages of AHI. Additional studies are needed to evaluate mechanisms for possible brain disruption following ART, including viral factors and markers of neuroinflammation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We examined individual differences in CD4/CD8 T-cell ratio trajectories and associated risk profiles from acute HIV infection (AHI) through 144 weeks of antiretroviral therapy (ART) using a data-driven approach., Methods: A total of 483 AHI participants began ART during Fiebig I-V and completed follow-up evaluations for 144 weeks. CD4+, CD8+, and CD4/CD8 T-cell ratio trajectories were defined followed by analyses to identify associated risk variables., Results: Participants had a median viral load (VL) of 5.88 copies/ml and CD4/CD8 T-cell ratio of 0.71 at enrollment. After 144 weeks of ART, the median CD4/CD8 T-cell ratio was 1.3. Longitudinal models revealed five CD4/CD8 T-cell ratio subgroups: group 1 (3%) exhibited a ratio >1.0 at all visits; groups 2 (18%) and 3 (29%) exhibited inversion at enrollment, with normalization 4 and 12 weeks after ART, respectively; and groups 4 (31%) and 5 (18%) experienced CD4/CD8 T-cell ratio inversion due to slow CD4+ T-cell recovery (group 4) or high CD8+ T-cell count (group 5). Persistent inversion corresponded to ART onset after Fiebig II, higher VL, soluble CD27 and TIM-3, and lower eosinophil count. Individuals with slow CD4+ T-cell recovery exhibited higher VL, lower white blood cell count, lower basophil percent, and treatment with standard ART, as well as worse mental health and cognition, compared with individuals with high CD8+ T-cell count., Conclusions: Early HIV disease dynamics predict unfavorable CD4/CD8 T-cell ratio outcomes after ART. CD4+ and CD8+ T-cell trajectories contribute to inversion risk and correspond to specific viral, immune, and psychological profiles during AHI. Adjunctive strategies to achieve immune normalization merit consideration., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Objective: People with HIV continue to exhibit cognitive symptoms after suppressive antiretroviral therapy (ART). It remains unclear if initiating ART during acute HIV-1 infection (AHI) uniformly improves cognitive outcomes., Methods: Sixty-seven individuals (96% men, median age 28 years) initiated ART immediately after AHI diagnosis and maintained viral suppression for 6 years. They underwent a four-test neuropsychological battery that measured fine motor speed and dexterity, psychomotor speed, and executive functioning at baseline (pre-ART AHI), weeks 12, 24 and 96, and annually thereafter through week 288. Performances were standardized to calculate an overall (NPZ-4) score and frequencies of impaired cognitive performance (≤-1 SD on at least two tests, or ≤-2 SD on at least one test). Group-based trajectory analysis (GBTA) was applied to identify distinct neuropsychological trajectories modelled from baseline to week 288. Posthoc analyses examined HIV-1 and demographic factors that differed between trajectory subgroups., Results: NPZ-4 scores improved from baseline to week 96 (P < 0.001) and from weeks 96 to 288 (P < 0.001), with frequencies of impaired performance of 30, 6 and 2% at the respective time-points. The amplitude of NPZ-4 improvement throughout the period was more than 0.5 SD and beyond practice effects. GBTA identified three NPZ-4 trajectory subgroups that all showed improvement over-time. The subgroup with lowest baseline performance exhibited worse depressive symptoms at baseline (P = 0.04) and the largest improvement among the three. HIV-1 indices did not differ between the subgroups., Conclusion: Cognitive performance improved in a sustained and stable manner after initiating ART during AHI. Largest improvements were seen in participants with worst baseline cognitive performance., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Despite suppression of HIV-1 replication in the periphery by antiretroviral therapy (ART), up to 10% of treated individuals have quantifiable HIV-1 in the CSF, termed CSF escape. CSF escape may be asymptomatic but has also been linked to progressive neurological disease, and may indicate persistence of HIV in the central nervous system (CNS). CSF escape has not yet been assessed after initiation of ART during acute HIV-1 infection (AHI)., Design: Prospective cohort study., Setting: Major voluntary counseling and testing site in Bangkok, Thailand., Participants: Participants identified and initiated on ART during AHI who received an optional study lumbar puncture at pre-ART baseline or after 24 or 96 weeks of ART., Main Outcome Measures: Paired levels of CSF and plasma HIV-1 RNA, with CSF greater than plasma HIV-1 RNA defined as CSF escape., Results: Two hundred and four participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. Twenty-nine participants had CSF sampling at all three visits. CSF escape was detected in 1/90 at week 24 (CSF HIV-1 RNA 2.50 log10 copies/ml, plasma HIV-1 RNA <50 copies/ml), and 0/55 at week 96., Conclusion: Although levels of CSF HIV-1 RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first 2 years of treatment. Early treatment may improve control of HIV-1 within the CNS compared with treatment during chronic infection, which may have implications for long-term neurological outcomes and CNS HIV-1 persistence., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)