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HIV-1 replication within the central nervous system (CNS) impairs neurocognitive function and has the potential to establish persistent, compartmentalized viral reservoirs. The origins of HIV-1 detected in the CNS compartment are unknown, including whether cells within the cerebrospinal fluid (CSF) produce virus. We measured viral RNA+ cells in CSF from acutely infected macaques longitudinally and people living with early stages of acute HIV-1. Active viral transcription (spliced viral RNA) was present in CSF CD4+ T cells as early as four weeks post-SHIV infection, and among all acute HIV-1 specimens (N = 6; Fiebig III/IV). Replication-inactive CD4+ T cell infection, indicated by unspliced viral RNA in the absence of spliced viral RNA, was even more prevalent, present in CSF of >50% macaques and human CSF at ~10-fold higher frequency than productive infection. Infection levels were similar between CSF and peripheral blood (and lymph nodes in macaques), indicating comparable T cell infection across these compartments. In addition, surface markers of activation were increased on CSF T cells and monocytes and correlated with CSF soluble markers of inflammation. These studies provide direct evidence of HIV-1 replication in CD4+ T cells and broad immune activation in peripheral blood and the CNS during acute infection, likely contributing to early neuroinflammation and reservoir seeding. Thus, early initiation of antiretroviral therapy may not be able to prevent establishment of CNS viral reservoirs and sources of long-term inflammation, important targets for HIV-1 cure and therapeutic strategies., Competing Interests: The authors have declared that no competing interests exist.

Background: Central nervous system (CNS) infiltration by CD8 T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8 T cells in the CNS during acute HIV infection (AHI) is unknown., Methods: We analyzed the phenotype, gene expression, T cell receptor (TCR) repertoire, and HIV specificity of CD8 T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of AHI (n = 26), chronic (n = 23), and uninfected (n = 8)., Results: CSF CD8 T cells were elevated in AHI compared with uninfected controls. The frequency of activated CSF CD8 T cells positively correlated to CSF HIV RNA and to markers of CNS inflammation. In contrast, activated CSF CD8 T cells during chronic HIV infection were associated with markers of neurological injury and microglial activation. CSF CD8 T cells in AHI exhibited increased functional gene expression profiles associated with CD8 T cells effector function, proliferation, and TCR signaling, a unique restricted TCR Vbeta repertoire and contained HIV-specific CD8 T cells directed to unique HIV epitopes compared with the periphery., Conclusions: These results suggest that CSF CD8 T cells in AHI expanding in the CNS are functional and directed against HIV antigens. These cells could thus play a beneficial role protective of injury seen in chronic HIV infection if combination antiretroviral therapy is initiated early.

ObjectiveTo evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment.DesignSoluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-naïve individuals (25 men and 35 women) with chronic HIV infection and 18 HIV-uninfected controls (9 men and 9 women) from Thailand. Following enrollment, participants began combination antiretroviral therapy and were evaluated for expression of these markers after 48 weeks.MethodsPlasma and CSF levels of 19 soluble biomarkers (IFN-γ, TNFα, TNF-RII, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFNα, I-FABP, and sCD14) were measured using either a multiparameter or standard ELISA assay.ResultsPrior to combination antiretroviral therapy, women with impaired cognition had elevated levels of neopterin and TNF-RII compared with women with normal cognition in both the plasma and CSF; however, levels did not differ between cognitively impaired or normal men. In a secondary outcome-hypothesis generating analysis, sex differences were also pronounced in plasma levels of MCP-1, IL-10, I-FABP, and sCD14 in response to treatment. Neopterin, IP-10, TNFα, TNF-RII, IFNα, MCP-1, IL-8, I-FABP, and sCD14 plasma levels remained elevated following 48 weeks of therapy in both sexes compared with uninfected controls.ConclusionWe provide evidence of sustained immune activation after 48 weeks of treatment and identify possible sex differences in biomarkers previously linked to cognitive impairment, chronic inflammation, and gut integrity that may contribute to immunological differences between sexes in relationship to disease progression and response to therapy.

Background: Chronic immune activation in the blood and central nervous system is a consequence of human immunodeficiency virus (HIV) infection that contributes to disease morbidity and can occur despite virally suppressive antiretroviral therapy (ART). The trajectory of HIV-related inflammation may vary with the timing of ART initiation. We examined immune activation markers in cerebrospinal fluid (CSF) and blood specimens collected over 96 weeks from participants who initiated ART during acute HIV infection (AHI).Methods: RV254/SEARCH010 study participants with AHI underwent CSF (n = 89) and plasma (n = 146) sampling before initiating ART and at weeks 24 and 96 of treatment. A majority participants (64.4%) received a standard ART regimen (hereafter, "standard ART"), with some (34.7%) also receiving maraviroc and raltegravir for the first 24 weeks (hereafter, "ART plus"). We compared neopterin, CXCL10, CCL2, and interleukin 6 (IL-6) levels in the AHI group to those in 18 healthy, uninfected controls.Results: Following 24 and 96 weeks of treatment, levels of all CSF markers normalized while levels of several plasma markers remained elevated in the AHI group (P < .001). Participants receiving the ART-plus regimen had lower median plasma CCL2 levels at week 24 and lower plasma neopterin levels at week 96.Conclusions: ART initiation during AHI differentially impacts the brain compartment, with markers of inflammation returning to normal levels in the CSF, where they were sustained at week 96, but not in plasma. [ABSTRACT FROM AUTHOR]

Background: Myeloid activation contributes to cognitive impairment in chronic human immunodeficiency virus (HIV) infection. We explored whether combination antiretroviral therapy (cART) initiation during acute HIV infection impacts CD163 shedding, a myeloid activation marker, and in turn, implications on the central nervous system (CNS).Methods: We measured soluble CD163 (sCD163) levels in plasma and cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay in Thais who initiated cART during acute HIV infection (Fiebig stages I-IV). Examination of CNS involvement included neuropsychological testing and analysis of brain metabolites by magnetic resonance spectroscopy. Chronic HIV-infected or uninfected Thais served as controls.Results: We examined 51 adults with acute HIV infection (Fiebig stages I-III; male sex, >90%; age, 31 years). sCD163 levels before and after cART in Fiebig stage I/II were comparable to those in uninfected controls (plasma levels, 97.9 and 93.6 ng/mL, respectively, vs 99.5 ng/mL; CSF levels, 6.7 and 6.4 ng/mL, respectively, vs 7.1 ng/mL). In Fiebig stage III, sCD163 levels were elevated before cART as compared to those in uninfected controls (plasma levels, 135 ng/mL; CSF levels, 10 ng/mL; P < .01 for both comparisons) before normalization after cART (plasma levels, 90.1 ng/mL; CSF levels, 6.5 ng/mL). Before cART, higher sCD163 levels during Fiebig stage III correlated with poor CNS measures (eg, decreased N-acetylaspartate levels), but paradoxically, during Fiebig stage I/II, this association was linked with favorable CNS outcomes (eg, higher neuropsychological test scores). After cART initiation, higher sCD163 levels during Fiebig stage III were associated with negative CNS indices (eg, worse neuropsychological test scores).Conclusion: Initiation of cART early during acute HIV infection (ie, during Fiebig stage I/II) may decrease inflammation, preventing shedding of CD163, which in turn might lower the risk of brain injury. [ABSTRACT FROM AUTHOR]

Objectives: Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury. Methods: We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). Results: The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. Interpretation: Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. [ABSTRACT FROM AUTHOR]