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. 2024 Jan 27;34(1):e2519. doi: 10.1002/rmv.2519

TABLE 2.

Studies reporting the association between HIV‐associated neuroinflammation and neurocognitive impairment/HIV encephalitis in PLWH.

References Sampling technique Brain section Markers Major findings
33 Enzyme‐linked immunosorbent assay (ELISA) Frontal cortex (FC), caudate nucleus, insular cortex, basal ganglia (BG), thalamus, hypothalamus, hippocampus, superior cerebellum (CB), midbrain (MB), pons (PN) and medulla (MED) Interleukin (IL)‐1, IL‐3, IL‐6, and tumour necrosis factor (TNF)‐α

  1. All cytokine concentrations in the extracted tissues were uniformly low except for an occasional modest level of TNF‐α.

  2. Regional analysis of cytokines showed higher concentrations of TNF‐α in the BG of people living with HIV (PLWH) and HIV encephalitis (HIVE).

  3. Regional analysis of cytokines in cases with minimal HIVE showed a gradient of TNF‐α with the highest concentration in BG.

  4. A similar analysis in cases with severe HIVE showed a uniform elevation of TNF‐α in all three regions (cortical grey, cortical white, and deep grey matter).
34 Immunohistochemistry (IHC) Temporal cortex (TC), BG, and brain stem Major histocompatibility class II (MHC‐II) antigen, human Leucocyte antigen – DR isotype (HLA‐DR), IL‐1 and TNF‐α

  1. Microglial activation was identified by higher levels of HLA‐DR, TNF‐α and IL‐1 expression.

  2. Severe microglial activation was only found in AIDS participants.

  3. Microglial activation was less pronounced but obvious in pre‐AIDS cases and weak or absent in seronegative patients.

  4. There was no clear distinction in the level of microglia activation between the HIVE/HIV‐associated dementia (HAD) compared to HIV non‐encephalitis (HIVnE) cases.
35 (IHC) Cortex and white matter (WM) TNF‐α, IL‐1α, IL‐4 and IL‐6

  1. IL‐1α, IL‐4, IL‐6 and TNF‐α were higher in pre‐AIDS brains compared to HIV‐negative controls

  2. Neurocognitively impaired (NCI)/HIVE AIDS brains had lower levels of TNF‐α, and IL‐4 compared to pre‐AIDS brains.

  3. HIVE brains had higher levels of IL‐1α compared to pre‐AIDS brains.

  4. No differences were found for IL‐6 when comparing HIVE to pre‐AIDS brains.
36 Immunocytochemistry (ICC) Frontal lobe Glial fibrillary acidic protein (GFAP)

  1. HIVE cases had significantly higher values of white and grey matter GFAP positivity, than all other case groups (all p < 0.05).

  2. The severity of NCI correlated positively with the number of GFAP‐positive astrocytes both for WM (Spearman rank order, RS = 0.537, t = 2.29, p = 0.02) and grey matter (RS = 0.633, t = 2.95, p < 0.006).
37 IHC BG and hippocampus Cluster of differentiation (CD)68, CD3, CD8, CD20, GFAP and MHC‐II

  1. In the BG, CD68 levels were similar in highly active antiretroviral therapy (HAART)‐treated brains, AIDS, and pre‐symptomatic and HIVE brains however, all of these cases demonstrated higher levels compared to HIV‐negative controls (p = 0.004).

  2. No significant differences in BG CD68 levels were found between HIVE and AIDS/pre‐symptomatic brains.

  3. In the hippocampus, CD68 levels in HAART cases were similar to HIVE and significantly higher than those seen in AIDS, pre‐symptomatic, or control brains (p = 0.01).

  4. BG CD68 levels were higher in HIVE brains compared to AIDS, pre‐symptomatic, or control brains.

  5. HIVE cases show the highest levels of GFAP compared to all other groups; however, this was not significant.

  6. CD3, CD8, CD20 and MHC‐II were not significantly different between HIVE and HIVnE groups.
38 IHC Frontal, temporal lobes and the thalamus CD68

  1. HIVE groups displayed more CD68‐positive microglia in the grey matter than the HIVnE groups (p < 0.001).

  2. No difference was detected between the HIVE and HIVnE groups in terms of CD68 positivity in the frontal lobe.
39 IHC and polymerase chain reaction (PCR) FC IL‐1β and IL‐10

  1. IL‐1β gene expression was detected in the HIV‐associated dementia (HAD) group at significantly higher levels than in the group of neurocognitive normal (NCN) group (p < 0.025) and in the control group (p < 0.025).

  2. IL‐10 gene expression was also expressed at significantly higher levels in the HAD group compared with the control (p < 0.01) and NCN group (p < 0.01).
40 Western blot Occipital lobes Osteopontin (OPN)

  1. OPN levels were higher in PLWH with more severe NCI compared to HIV‐infected individuals without or with mild NCI (p = 0.0387).
41 IHC Hippocampus, putamen, and internal capsule, FC HLA‐DR, GFAP, and ionised calcium‐binding adapter molecule (Iba)‐1

  1. NCI was not associated with Iba‐1, GFAP or HLA‐DR in any of the investigated brain regions.
42 In situ hybridisation FC, hippocampus, and brain stem C‐C chemokine ligand (CCL)2

  1. Cells expressing CCL2 RNA were often observed in perivascular regions. No CCL2‐positive cells were seen in normal brain tissue or tissue from patients without dementia and only found in brains with dementia.
43 Immunostaining, IHC and ICC Cerebral WM and adjacent cortex and/or BG CD14, CD45, and CD68

  1. In HIV‐negative control brains, CD14 expression was limited to macrophages in the perivascular and meningeal locations and parenchymal microglia were CD14‐negative.

  2. In HIV‐seropositive control brains, a spectrum of parenchymal microglial CD14 expression was seen ranging from normal levels to those seen in HIVE cases.

  3. In HIVE cases, microglial CD14 expression was the most robust.

  4. CD45 expression was further upregulated in microglia and macrophages in HIVE.

  5. No data were reported for comparing CD68 levels between groups.
8 IHC Frontal lobe CD45, CD45RA, CRB, CD45RB, CD45RC, CD45RO, CD68, CD3, and CD8

  1. αCD45RA and αRC‐reactive cells were rare averaging—one cell per 400× field in HIVE and even fewer in control brains.

  2. Neither CD45RA nor CD45RC counts were significantly different among the groups investigated.

  3. CD45RB parenchymal counts were uniformly high in all three groups (p > 0.05), HIV‐positive, HIV‐negative and HIVE.

  4. Perivascular CD45RB counts were significantly elevated in HIVE compared with HIV−negative (p < 0.001) or HIV‐positive (p < 0.01) groups.

  5. When CD45RO counts were compared between groups, the parenchymal (but not perivascular) CD45RO counts in HIVE were significantly elevated compared with the HIVnE group.

  6. The total CD45RO counts were also significantly elevated in HIVE compared with HIVnE.
44 Immunofluorescence Mid‐frontal cortex (MFC), caudate nucleus, insular cortex, BG, thalamus, hippocampus, CB, MB, PN, MED, and spinal cord (SPC). CD68 and HLA‐DR

  1. HIV‐1 sections demonstrated a mild increase in CD68‐positive cells and cell processes within both the cortex and CB.

  2. No overall increase between HIVE and HIVnE of HLA‐DR expression was observed in any region compared to the same region in the control section.

  3. Compared to both HIV‐1 and control sections, HIVE sections demonstrated a marked increase in parenchymal and perivascular CD68‐positive cells, including CD68‐reactive microglial nodules, within the cortical WM, the deep grey matter, and, to a lesser extent, the cortical grey matter.

  4. Cerebellar sections, on the other hand, contained only a slightly greater number of immunoreactive cells than that observed in all HIV‐1 sections.
45 PCR and IHC FC IL‐1, IL‐6 and TNF‐α

  1. IL‐1 transcription levels were significantly higher in PLWH, and latent HIV compared to HIVE (p < 0.05).

  2. Significant upregulation of IL‐6 transcript was observed in latent HIV cases compared to HIV and HIVE cases.

  3. TNF‐α transcript levels were not significantly different between groups.

  4. IL‐6 immunoreactivity was also higher in the astroglial cells in the latent and HIVE group compared to the HIV group.
46 IHC Frontal lobe WM, FC and BG Iba‐1

  1. Iba1‐immunoreactive cells were higher in sections from subjects with NCI compared to the NCN groups (p < 0.05).

  2. Iba1 expression levels were found to be higher in the NCI group without HIVE.
47 PCR and ELISA FC Transforming growth factor (TGF)‐β1 and TGF‐β2

  1. TGF‐β1 messenger (m)RNA levels were higher in NCI brains when compared to NCN brains and to nearly negligible amounts in control brain tissue (p < 0.05).

  2. TGF‐β2 mRNA was increased in NCI brains by 10‐fold (p < 0.01) compared to NCN brains and control brains.

  3. It is noteworthy that TGF‐β2 protein levels in NCI brain tissue were also significantly higher compared to the control group (p < 0.01).
48 PCR microarray FC All differential regulated genes due to HIVE

  1. Genes involved in several categories were dysregulated in HIVE.

  2. Neuroinflammation genes were upregulated in HIVE compared to cognitively normal (CN) controls.

  3. Upregulation of interferon‐inducible genes in the HIVE with methamphetamine using group (and not HIVE alone), which together as a gene group was highly statistically significant (p = 0.0064).
49 IHC FC GFAP and Iba‐1

  1. GFAP and Iba‐1 were increased brain tissue from aged HIVE patients compared to young HIVE patients.

  2. GFAP immunoreactivity and signal were elevated in young and aged HIVE tissues versus young and aged HIV positive samples; however, GFAP signal was most intense in tissues from aged HIVE patients.

  3. Iba‐1 signal intensity was increased in brain tissues of young and aged HIVE patients compared to HIV positive patients from both groups, with cells from HIVE tissues having more extended processes in greater numbers.
19 PCR FC TNF‐α

  1. TNF‐α mRNA levels were significantly higher in the brains of Hispanics diagnosed with mild neurocognitive disorder (MND), compared to NCN controls (p < 0.05).

  2. Significantly higher levels of TNF‐α mRNA were found for the Hispanic group compared to the non‐Hispanic group (p < 0.01).
50 IHC N/A CD14, CD16, and HLA‐DR

  1. Compared to HIV‐negative controls, there were increased numbers of perivascular CD14+ and CD16+ mononuclear phagocytes in HIVE brains.

  2. The majority of these cells identified in microglial nodules and the perivascular infiltrate were CD14+/CD16+.

  3. CD14+/CD16+ and HLA‐DR were higher in HIVE compared to HIVnE brains.
51 IHC N/A CD68, CD14 and CD16,

  1. Higher levels of CD68 cells were found in HIVE brain tissue sections when compared to brain tissue from HIVnE (p = 0.016) and seronegative controls (p = 0.002).

  2. The total number of parenchymal CD68 cells was also significantly increased in HIVE brains.

  3. Increases in parenchymal macrophages in HIVE were observed with tissue sections stained for CD16, relative to HIV infected/HIVnE (p = 0.03) or normal controls (p = 0.005).

  4. CD14 levels were not significantly different between HIVE and HIVnE brains.
52 IHC Cortex (mostly frontal), BG, and MB or PN GFAP, and HLA‐DR

  1. HIV infection without encephalopathy showed a clear increase in GFAP and HLA‐DR immunoreactivity when compared with normal tissues.

  2. GFAP and HLA‐DR were not significantly different between HIV and HIVnE groups.
53 IHC and PCR MFG and the BG HAM‐56

  1. The mean summary score for HAM‐56 was significantly higher in the severely demented group compared with the non‐demented group (p = 0.04)
54 IHC MFG, parietal cortex and CB GFAP and HLA‐DR

  1. HLA‐DR and GFAP were increased in the MFG and CB of NCI brains compared to NCN brains

  2. No differences for HLA‐DR were found in the parietal cortex.
55 PCR and IHC FC IL‐1β and IL‐33

  1. IL‐1β (10‐fold) transcript levels were increased in the brains of PLWH with NCI and HIVE compared to the brains of NCN and HIV‐uninfected controls.

  2. No significant differences were found in IL‐33 transcript levels between the groups.
56 IHC Frontal lobe and BG TNF‐α and GFAP

  1. TNF‐α ‐positive cell density was significantly high in the frontal cerebral cortex and BG in NCI brains compared with that in NCN brains (p < 0.01) and also with that HIV‐negative controls (p < 0.01).

  2. There was no statistical significance in the density of TNF‐α‐positive cells between NCN brains and HIV‐negative controls.

  3. The BG also showed a significant difference in the density of TNF‐α‐positive cells between NCI brains compared with that in NCN brains (p < 0.01) and also with that HIV‐negative controls (p < 0.01).

  4. The GFAP‐positive astrocyte density in NCI brains tended to be increased compared with NCN brains, but no significant difference between them was obtained.
57 ICC MFC C‐X‐C motif chemokine ligand (CXCL)12

  1. In the MFC, CXCL12‐immunoreactive astroglia cells were most abundant in the subpial region and WM.

  2. In the astroglial cells, levels of immunoreactive CXCL12 were not significantly different among the four groups and did not correlate with the presence/absence of HIVE and/or neuronal damage (ND).

  3. In the brains of control cases, CXCL12 immunoreactivity was primarily localised to astrocytes and microglial cells whereas, in HIVE cases intense CXCL12 immunoreactivity was observed in microglia and neurons.
58 PCR and IHC OC Microtubule‐associated protein‐2 (MAP‐2), HLA‐DR and GFAP.

  1. MAP2 was significantly correlated with global neurocognitive functioning and HIV‐associated neurocognitive disorder (HAND) severity.

  2. GFAP levels in the putamen were associated with motor, (r = 0.24, p = 0.034), and HLA‐DR in the FC with learning (r = 0.27, p = 0.017) outcomes. These correlations were not significant after correction using the FDR.
59 PCR and IHC Right dorsolateral and MFC. HLA‐DR, Iba‐1 and GFAP

  1. None of the histopathological nor genetic markers besides MAP2 (at an FDR of 0.05) was associated with neurocognitive outcomes.
60 Cytokine labelling MFC, cortical and subcortical regions IL‐1β, IL‐2 and TGF‐β1

  1. IL‐1β and TGF‐β1 were higher in cases with moderate HIVE in the FC compared to HIVnE.

  2. IL‐2 was not significantly different between HIVE and HIVnE brains.
61 PCR and IHC FC All differentially expressed genes, GFAP and CD45

  1. In the HIVE brain, neuroinflammatory genes such as IgG heavy constant‐g3, major histocompatibility complex (MHC) classes 1A, C, F, h2‐ microglobulin and bone marrow stromal cell antigen‐2 (also known as B‐cell growth factor) were significantly upregulated.

  2. No significant differences in GFAP and CD45 between HIVE and HIVnE cases.
62 PCR Frontal lobe TNF‐α and IL‐1β

  1. mRNA of both cytokines TNF‐α and IL‐1β showed significant up‐regulation in HAD brains compared with non‐dementia HIV/AIDS patients.
63 PCR Brain and SPC tissue (cerebrum, CB, and brain stem) TNF‐α, MIP‐1α and MIP‐1β

  1. Expression of TNF‐α, MIP‐ 1α, and MIP‐ 1β strongly correlated with NCI and occurred in regions where HIV‐ 1‐infected cells were most plentiful and were localised primarily to the viral negative cells.
64 PCR and IHC FC CX3CL1

  1. CX3CL1 mRNA levels were found to be significantly higher in the brains of NCI compared with the NCN and HIV‐negative controls (p < 0.05).

  2. CX3CL1 proteins levels were found to be overexpressed in the brains of NCI compared with the NCN.

  3. CX3CL1 protein immunoreactivity was found to be associated with astrocytes but not with neurons.
65 PCR Cortex, BG, WM, and CB TNF‐α, IL‐1β, IL‐6, and CD14

  1. TNF‐α mRNA levels were higher in all brain tissue of PLWH than in controls.

  2. TNF‐α mRNA levels were the highest in HIVE brain tissue (p < 0.05).

  3. IL‐1β mRNA levels were higher in the brains of PLWH compared to negative controls but no significant differences were found between HIVE and NCN brains.

  4. IL‐6 mRNA levels were lower in HIVE brains compared to PLWH, however, not significantly.

  5. CD14 mRNA levels were uniformly higher in patients with HIVE than in controls (p < 0.05).
66 IHC N/A MIP‐1α, MIP‐1β, CCL2, and RANTES (CCL5), CD68, HLA‐DR and GFAP

  1. Severe HIVE brains had pronounced infiltration of CD68‐positive MDM into the brain parenchyma compared to mild HIVE.

  2. Severe HIVE brains had strong positive immunostaining for HLA‐DR in white matter microglia compared to a lower level of HLA‐DR found in mild HIVE.

  3. GFAP was found in different areas but was especially prominent in zones most affected by MDM infiltration and microglial nodule formation in severe HIVE, whereas astrocyte reaction was less obvious in mild HIVE.

  4. All chemokines were higher in severe HIVE compared to milder HIVE.

  5. Chemokines were not detected in HIV‐negative brains.

  6. HIVE was associated with viral infection, microglial activation, monocyte‐derived macrophage (MDM) brain infiltration, astrogliosis, and β‐chemokine expression.
67 IHC Hippocampus GFAP and HLA‐DR (LN3)

  1. The number of GFAP reactive astrocytes increased in the 2 AIDS groups and was greatest in the HIVE group (p < 0.05).

  2. The increase in GFAP reactive astrocytes for both NCN HIV and HIVE was greatest in the CA4 region where it was 4‐fold and 6‐fold greater than controls

  3. LN3‐positive microglia were rare or absent in controls and increased in AIDS brains.
68 IHC Hippocampus CD45RO and CD68

  1. Parenchymal CD45RO+ and CD3+T lymphocytes were abundant in seven of the eight hippocampal regions with local HIVE but were rare or absent in the hippocampus of the NCN group and the HIVEnE.

  2. The higher mean number of hippocampal CD45RO + T‐ lymphocytes in the HIVE patient group (n = 10) than in the NCN group (n = 11) and the control group (n = 7),

  3. A highly significant increase in T lymphocytes in those hippocampal regions with HIVE inflammatory nodules (p < 0.001).

  4. CD68+ macrophages significantly increased in all three hippocampal regions of the HIVE group but not in the NCN group.
69 ICC FC GFAP, HLA‐DR, CD45 and CD68

  1. GFAP immunostaining of subcortical WM revealed increased astrogliosis in tissue from demented and nondemented AIDS brains compared to HIV‐negative control and pre‐AIDS brains.

  2. There was a statistically significant increase in the mean number of GFAP‐positive cells detected in tissue from the two AIDS groups compared to the control group (p = 0.04).

  3. The increased numbers of immunodetectable astrocytes were accompanied by hypertrophy of the astrocyte cell body and elongation of cell processes in the AIDS groups compared to the control group.

  4. There were no significant differences in GFAP between demented versus non‐demented groups.

  5. Microglial hypertrophy and increased expression of LCA (CD45), EBM‐I 1 (CD68), and HLA‐DR were observed in HIV‐infected brains compared to controls. However, no differences were found between demented and non‐demented brains.
70 PCR and IHC Frontal lobe, neocortex, WM, and neostriatum Galectin (Gal)‐9

  1. Gal‐9 gene expression was significantly higher only in the FWM brain region of HIVE donors compared to controls (p = 0.016).

  2. Although the intensity of Gal‐9 staining did not significantly differ among groups, an increase in the number of Gal‐9 positive cells in HIVnE samples as compared to uninfected controls was observed (p = 0.037).
71 Immunofluorescence FC CD40 and CD68

  1. CD68‐positive cells were more in the perivascular spaces of HIVE compared to HIV‐negative control cases. No data were reported comparing HIVE compared to HIVnE brains.

  2. CD40 was expressed higher in HIVE compared to normal HIV brains and HIV‐negative control brains.

  3. Microglia in severe HIVE cases were positive for CD40 and no immunostaining was detected in HIV‐negative controls.
72 IHC WM, BG (GP and the FC TNF‐α

  1. For TNF‐α, the degree of staining in the frontal deep WM and the BG correlated with the stage of AIDS dementia complex (p = 0.0001 and p = 0.0017 respectively).
73 IHC and PCR (FC) with adjacent deep white matter (DWM) and (BG), including the globus pallidus and frontal region CXCL12

  1. A greater number of positive CXCL12 staining astrocytes tended to be observed in the BG of subjects with moderate/severe HIVE when compared to those with mild HIVE (p = 0.12) and HIV‐negative controls (unadjusted p‐value = 0.04).

  2. RNA levels of CXCL12 in the FC were compared and similar levels were detected in subjects with HIVE compared to those HIVnE.

  3. No difference in the number of CXCL12 ‐positive neurons was found in the FC between groups

  4. In HIV subjects with moderate to severe disease, the number of CXCL12 ‐positive neurons and astrocytes in the BG was increased compared to that in subjects with mild disease and controls
74 IHC FC and BG Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL)

  1. TRAIL was associated with mononuclear phagocytes (MP) (by colocalisation with HAM‐56) in both the FC and BG regions of HIVE brains.

  2. The percentage of macrophages expressing TRAIL in HIVE brain tissue (the ratio of dual HAM‐56‐ and TRAIL‐stained cells to total HAM‐56‐stained cells) was increased (69.4 ± 19% as compared to 52.9 ± 10%, p < 0.01) when compared to PLWH without neurological disease.

  3. Additionally, several of the macrophages expressing TRAIL were HIV‐1 infected as detected by co‐localization with HIV‐1 p24 antibodies).
75 PCR N/A TNF2 and HLA‐DR3

  1. TNF2 and HLA‐DR3 did not associate with the presence of HIVE/leukoencephalopathy.
76 IHC MFG, superior temporal and cingulate gyri, hippocampus, occipital cortex, nucleus basalis of Meynert, head of the caudate nucleus, pallidum, WM of the centrum ovale, dentate nucleus, SC at cervical, thoracic and lumbar levels GFAP

  1. GFAP‐positive astrocytes in the WM of the frontal lobe were higher in AIDS brains (U = 4, p = 0.0027) than in controls.

  2. AIDS patients with cognitive disorders did not differ significantly from others for GFAP.
77 IHC

  • Cortical

  • WM (from the BG including the putamen and pallidum, and from the deep WM of the centrum ovale)

 TNF‐α and GFAP

  1. The density of TNF‐α positive cells was correlated with the mini‐mental state examination (MMSE) score in the deep WM (p = 0.022), and the BG and MFC (p = 0.037 for each).

  2. AIDS patients with myelin pallor (n = 5) had significantly higher numbers of TNF‐α‐positive cells in the deep‐white matter than other AIDS patients (p = 0.0045).

  3. A low density of TNF‐α positive cells, most of which were in close contact with the vessels, was found in normal controls and the density of TNF‐α positive cells was significantly higher in AIDS patients (p = 0.0012 for the deep WM; p = 0.0016 for the subcortical WM; p = 0.0007 for the MFC and BG).

  4. TNF‐α was significantly higher in HIVE (n = 3) compared to poliodystrophy (n = 6), in two regions: The deep WM and the MFC (p = 0.039; and p = 0.0201, respectively).

  5. No significant difference was found in the density of GFAP‐positive cells among the neuropathological subgroups of AIDS patients.
78 ICC Occipital lobe OPN, CD68, Iba‐1, and GFAP

  1. Compared to the HIV‐negative group, OPN levels did not differ significantly compared to the groups (NCN, NCI).

  2. Not significant, but there was a trend of increased OPN in the NCI group.

  3. There were significantly higher levels of OPN between PLWH and the NCI groups compared to the amyotrophic lateral sclerosis (ALS) group (p = 0.011).

  4. CD68 was significantly lower in certain cases when comparing NCI brains to normal controls, however, the levels between NCN and NCI brains were not reported.

  5. GFAP were not significantly different between NCN and NCI brains.

  6. Iba‐1 levels normalised to OPN intensity were significantly lower in NCI brains compared to normal controls, however, the levels between NCN and NCI brains were not reported.
79 PCR and IHC Frontal lobe and subcortical WM Tumour necrosis factor receptor (TNFR)I, TNFRII and TNF‐α

  1. The TNFRI and TNFRII gene expression were significantly higher in PLWH compared to HIV‐negative controls in the cerebral WM (p < 0. 01).

  2. TNFRI and TNFRII were not significantly different between HIVnE and HIVE brain tissue.

  3. TNF‐α immunoreactivity was significantly higher in the brain tissue of PLWH compared to HIV‐negative controls (p < 0.05).

  4. There were no significant differences in TNF‐α immunoreactivity between HIVnE and HIVE.
80 PCR and ELISA FC and BG (CB, and WM) IL‐1β, Matrix metalloproteinases (MMP)2 and tissue inhibitors of metalloproteinases (TIMP)

  1. TIMP‐1 protein levels in brain tissue were significantly lower in PLWH and NCI PLWH when compared to controls (p < 0.001)

  2. MMP‐2 protein levels showed the opposite trend and were significantly higher in PLWH (p < 0.01) and NCI/HIVE brains (p < 0.0001).

  3. IL‐1β RNA was upregulated in PLWH and NCI PLWH as compared to seronegative controls (p < 0.001).
20 PCR FC IL‐1β

  1. IL‐1β levels were significantly higher in all brains with NCI compared to NCN brains, despite ART regimens.
81 IHC FWM and BG CD16, CD163, CD68, HLA‐DR and GFAP

  1. Significant accumulation of MΦs/microglia in HIVE and HIVnE, as compared to control tissues, revealed by CD68 immunopositivity.

  2. Significant CD16 expression was observed on MΦs/microglia that accumulated within the brain parenchyma, as well as those that comprise perivascular cuffs and nodular lesions, in the brains of patients with HIVE and was absent in seronegative brains.

  3. CD16 expression was also seen in the CNS of the HIVnE group although this was generally to a much lesser extent than that observed in HIVE.

  4. Significant accumulation of CD163+ MΦs and microglia were observed in the CNS of patients with HIVE within the parenchyma, perivascular cuffs, and nodular lesions. In normal brain, CD163+ expression was seen on perivascular MΦs, but not parenchymal microglia consistent with normal CD163 expression in the CNS.

  5. HIVnE subjects showed some accumulation of CD163+ perivascular MΦs but not to the same degree as HIVE.

  6. There were no significant differences between HIVnE and HIVE brains for CD68 and CD16.

  7. HIVE, HLA‐DR expression in the brains of subjects with none‐encephalitis was, for the most part, not observed on cells in the parenchyma, however, when present, parenchymal HLA‐DR was observed, it was seen on aggregates of cells, or what we've termed, ‘soft nodules’ because they appear as mild cell aggregates, rather than the distinct large nodular lesions seen in HIVE.

  8. In seronegative brains, HLA‐DR was predominantly limited to rare expression by perivascular MΦ.

  9. Increased frequency of GFAP + astrocytes was observed in WM of subjects with none‐encephalitis and HIVE, as compared to those without HIV, which corresponded with greater astrocyte hypertrophy.

  10. In cortical grey matter (GM), GFAP expression by astrocytes in areas away from blood vessels was only observed in HIVE.
82 IHC Frontal lobe GFAP

  1. GFAP was not significantly different between HIVE and HIVnE groups.
83 IHC Entorhinal cortex, hippocampus, subcortical WMFC and BG GFAP

  1. Mean GFAP values were significantly greater in the HAD entorhinal cortex, hippocampus and subcortical WM than those recorded in NCN controls, while differences in FC and BG proved negligible.
84 PCR Cortex, subcortical, and deep WM from the right frontal lobe and GP from the BG IL‐1β, IL‐6, IFN‐γ, TGF‐ β1, TGF‐ β2, TNF‐α, IL‐2, IL‐4, IL‐10 and monokine induced by gamma interferon (MIG)‐2

  1. TGF‐β1 was easily detectable in most brains while amounts of TNF‐α, IL‐1β, and IL‐6 were more variable.

  2. TNF‐α was significantly higher in NCI AIDS patients, while IL‐1β tended to be lower.

  3. No differences between the NCI and NCN AIDS groups were detected for IFN‐γ, IL‐6, TGF‐β1, or TGF‐ β2.

  4. IL‐2, MIG‐2 and IL‐10 transcripts were undetectable in all brains.

  5. IL‐4 transcripts were undetectable in the brains of NCI PLWH but were detected in the brains of many CN and control subjects.
85 ICC FC GFAP

  1. GFAP was significantly higher in HIVE compared to HIVnE brains.
86 IHC Frontal lobe and PN IL‐1β and TNF‐α

  1. IL‐1β was detected only in the cells of the inflammatory lesions in all 11 cases with HIVE.

  2. TNF‐α was also detected in the inflammatory lesions of 7 cases with HIVE.

  3. Without HIVE, IL‐1β and TNF‐ α were detected in very few perivascular cells.
87 PCR FC and BG IL‐8

  1. Expression levels of IL‐8 were 2.8‐fold higher in HIVE individuals compared with controls (p < 0.05) and 2.6‐fold higher compared with HIV‐1‐seropositive individuals (p < 0.05).
88 PCR Caudate and ACC CCL2, CCR5 and CXCR4

  1. In the caudate and ACC: none of the marker's transcript levels were significantly different when comparing NCI and NCN PLWH.

  2. CCL2 transcript levels were significantly higher in PLWH in both caudate and ACC compared to HIV‐negative controls.
97 ICC FC or BG (putamen) IL‐1

  1. IL‐1 immunoreactivity was higher in all cases of HIVE compared to HIVnE cases.

  2. IL‐1 staining in control brains was minimal.

  3. IL‐1 is strongly expressed in activated microglia and macrophages in HIVE.
90 IHC Frontal lobe, Parietal lobe, temporal lobe occipital lobe, BG, hippocampus, CB, MB, PN, MED, thalamus, corpus callosum, pituitary, Mamlliary bodies, choroid plexus and putamen CD8, CD68, S100 calcium‐binding protein MRP‐8 (S100A8)

  1. CD8 was significantly higher in HAD compared to non‐dementia patients in the BG and parietal regions (p < 0.05).

  2. CD68 was significantly higher between HAD and NCN the difference was observed in BG, parietal and MB (p < 0.05).

  3. S‐100A8 immunohistochemical staining was also pronounced in the deeper midline and mesial temporal structure in HAD brains.

Note: p values were reported in this table for studies that reported the p values.

Abbreviations: ACC, anterior cingulate cortex; AIDS, acquired immunodeficiency syndrome; AM, amygdala; BG, Basal ganglia; CB, cerebellum; CCL, C‐C chemokine ligand; CCR, chemokine receptor; CD, Cluster of differentiation CXCL, Chemokine (C‐X‐C motif) ligand; CXCR, C‐X‐C chemokine receptor type; ELISA, Enzyme‐linked immunosorbent assay; FC, frontal cortex; FWM, frontal white matter; Gal, Galectin; GFAP, Glial fibrillary acidic protein GP, globus pallidus; HAART, Highly active antiretroviral therapy; HAD, HIV‐associated dementia; HIVE, HIVE encephalitis; HIVnE, HIV no encephalitis; HLA‐DR, Human Leucocyte Antigen – DR isotype (HLA‐DR); HO, Heme oxygenase; Iba‐1, ionised calcium‐binding adapter molecule; ICC, Immunocytochemistry; IHC, Immunohistochemistry; IL, Interleukin; MB, midbrain; MC, motor cortex; MED, medulla; MFC, Midfrontal cortex; MHC‐II, Major histocompatibility class II; MIP, macrophage inflammatory protein; MMP, Matrix metalloproteinases; MMSE, mini‐mental state examination; MND, mild neurocognitive disorder; MP, mononuclear phagocytes; mRNA, messenger RNA; NCI, neurocognitive(ly) impaired; NCN, cognitive/cognitively normal; ND, Neuronal damage; OC, occipital cortex; OPN, Osteopontin; PCC, posterior cingulate cortex; PCR, Polymerase chain reaction; PLWH, people living with HIV; PN, pons; RNA, ribonucleic acid; SC, sensory cortex; SPC, spinal cord; TC, temporal cortex; TGF, Transforming growth factor; TIMP, tissue inhibitors of metalloproteinases; TNF, Tumour necrosis factor; TNFR, Tumour necrosis factor receptor; WM, White matter.