chemokines and HIV-1 Neuropathogenesis

Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins. FASEB J. 2007 Mar;21(3):777-89. Epub 2006 Dec 28. Chauhan A, Hahn S, Gartner S, Pardo CA, Netesan SK, McArthur J, Nath A.

Human Immune Deficiency Virus-1 (HIV-1) infection can induce severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction, and dementia. HIV can persistently infect astrocytes, during which viral accessory proteins are produced that are unaffected by current antiretroviral therapy. The effect of these proteins on astrocyte function remains unknown. Astrocytes are the predominant cells within the brain; thus, disruption of astrocyte function could influence the neuropathogenesis of HIV infection. To explore further these effects, we constitutively expressed HIV-Tat protein in astrocytes. Since the nuclear presence of Tat protein leads to alteration of host gene expression, we further analyzed the effects of Tat on host gene transcripts. Endothelin-1 (ET-1) was a significantly elevated transcript as verified by reverse transcription-polymerase chain reaction (RT-PCR), and it was subsequently released extracellularly   in Tat-expressing and HIV-infected astrocytes. ET-1 expression was also prominent in reactive astrocytes and neurons in brain tissues from basal ganglia and frontal lobes of HIV encephalitic patients. HIV-Tat regulated ET-1 at the transcriptional level through NF-kappaB (NF-kappaB)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 microM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-kappaB in astrocytes. Our findings suggest that ET-1 may be critical in mediating the neuropathogenesis of HIV dementia and that statins may have therapeutic potential in these patients.

Reddy PV, Pilakka-Kanthikeel S, Saxena SK, Saiyed Z, Nair MP. Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder.2012;2012:953678. Epub 2012 May 20.

Abstract

HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB). Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population

Fraga D, Raborn ES, Ferreira GA, Cabral GA. Cannabinoids inhibit migration of microglial-like cells to the HIV protein Tat. 2011 Dec;6(4):566-77. Epub 2011 Jul 7

Abstract

Microglia are a population of macrophage-like cells in the central nervous system (CNS) which, upon infection by the human immunodeficiency virus (HIV), secrete a plethora of inflammatory factors, including the virus-specified trans-activating protein Tat. Tat has been implicated in HIV neuropathogenesis since it elicits chemokines, cytokines, and a chemotactic response from microglia. It also harbors a β-chemokine receptor binding motif, articulating a mode by which it acts as a migration stimulus. Since select cannabinoids have anti-inflammatory properties, cross the blood-brain barrier, and target specific receptors, they have potential to serve as agents for dampening untoward neuroimmune responses. The aim of this study was to investigate the effect of select cannabinoids on the migration of microglial-like cells toward Tat. Using a mouse BV-2 microglial-like cell model, it was demonstrated that the exogenous cannabinoids Delta-9-tetrahydrocannabinol (THC) and CP55940 exerted a concentration-related reduction in the migration of BV-2 cells towards Tat. A similar inhibitory response was obtained when the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) was used. The CB(2) receptor (CB2R) antagonist SR144528, but not the CB(1) receptor (CB1R) antagonist SR141716A, blocked this inhibition of migration. Similarly, CB2R knockdown with small interfering RNA reversed the cannabinoid-mediated inhibition. In addition, the level of the β-chemokine receptor CCR-3 was reduced and its intracellular compartmentation was altered. These results indicate that cannabinoid-mediated inhibition of BV-2 microglial-like cell migration to Tat is linked functionally to the CB2R. Furthermore, the results indicate that activation of the CB2R leads to altered expression and compartmentation of the β-chemokine receptor CCR-3.

Letendre SL, Zheng JC, Kaul M, Yiannoutsos CT, Ellis RJ, Taylor MJ, Marquie-Beck J, Navia B; HIV Neuroimaging Consortium. Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals. 2011 Feb;17(1):63-9. Epub 2011 Jan 19.

Abstract

Chemokines influence HIV neuropathogenesis by affecting the HIV life cycle, trafficking of macrophages into the nervous system, glial activation, and neuronal signaling and repair processes; however, knowledge of their relationship to in vivo measures of cerebral injury is limited. The primary objective of this study was to determine the relationship between a panel of chemokines in cerebrospinal fluid (CSF) and cerebral metabolites measured by proton magnetic resonance spectroscopy (MRS) in a cohort of HIV-infected individuals. One hundred seventy-one stored CSF specimens were assayed from HIV-infected individuals who were enrolled in two ACTG studies that evaluated the relationship between neuropsychological performance and cerebral metabolites. Concentrations of six chemokines (fractalkine, IL-8, IP-10, MCP-1, MIP-1β, and SDF-1) were measured and compared with cerebral metabolites individually and as composite neuronal, basal ganglia, and inflammatory patterns. IP-10 and MCP-1 were the chemokines most strongly associated with individual cerebral metabolites. Specifically, (1) higher IP-10 levels correlated with lower N-acetyl aspartate (NAA)/creatine (Cr) ratios in the frontal white matter and higher MI/Cr ratios in all three brain regions considered and (2) higher MCP-1 levels correlated with lower NAA/Cr ratios in frontal white matter and the parietal cortex. IP-10, MCP-1, and IL-8 had the strongest associations with patterns of cerebral metabolites. In particular, higher levels of IP-10 correlated with lower neuronal pattern scores and higher basal ganglia and inflammatory pattern scores, the same pattern which has been associated with HIV-associated neurocognitive disorders (HAND). Subgroup analysis indicated that the effects of IP-10 and IL-8 were influenced by effective antiretroviral therapy and that memantine treatment may mitigate the neuronal effects of IP-10. This study supports the role of chemokines in HAND and the validity of MRS as an assessment tool. In particular, the findings identify relationships between the immune response-particularly an interferon-inducible chemokine, IP-10-and cerebral metabolites and suggest that antiretroviral therapy and memantine modify the impact of the immune response on neurons

Vani J, Sharma M, Shaila MS, Kaveri SV, Bayry J. Effect of gp120 on dendritic cell-derived chemokines: relevance for the efficacy of gp120-based vaccines for HIV-1.Clin Vaccine Immunol. 2012 Jun 27

Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor.Auerbach DJ, Lin Y, Miao H, Cimbro R, Difiore MJ, Gianolini ME, Furci L, Biswas P, Fauci AS, Lusso P.Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9569-74. Epub 2012 May 29

Mol Pain. 2009 Aug 12;5:48. Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA.

Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more ikely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using  immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14-48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.

HIV-1 encephalopathy among perinatally infected children: Neuropathogenesis and response to highly active antiretroviral therapy. Mitchell CD.

HIV-1 encephalopathy among perinatally infected children in the United States was initially defined by a classic triad of findings that included: (1) developmental delay, (2) secondary or acquired microcephaly, and (3) pyramidal tract neuromotor deficits. The most severe form of this disorder typically occurred among young children who developed rapidly progressive disease in concert with profound immunosuppression, and Pneumocystis jiroveci pneumonitis (PCP). The neuropathogenesis of this disorder appears to involve a cascade of viral products, various cytokines and chemokines, and neurotransmitters which promote ongoing inflammation, excitation, and overstimualtion of the N-methyl-D-aspartate type receptor (NMDAR) system. These subsequently lead to neuronal injury and death secondary to apoptosis or necrosis, astrocytosis, as well as dentritic and synaptic damage. The frequency of the most severe forms of encephalopathy among children has dropped dramatically since the introduction of highly active antiretroviral therapy (HAART). Of concern, however, is the possibility that a more insidious form of this disorder may be occurring presently among older vertically infected children as a result of inadequate penetration of HAART agents into the cerebrospinal fluid (CSF). This paper will review what published data there is as yet that bears on this question.





Neural progenitors and HIV-1-associated central nervous system disease in adults and children. Curr HIV Res. 2006 Jul;4(3):319-27. Schwartz L, Major EO.

The human immunodeficiency virus type 1 (HIV-1) is a neurotrophic lentivirus that enters and infects the central nervous system (CNS) of adults and children, giving rise to the clinical syndromes of AIDS-dementia complex (ADC) in adults and HIV-1-associated progressive encephalopathy (PE) in pediatric patients. The clinical presentation and progression of neuroAIDS  n the developing brain of children is distinct from that seen in adult patients. Neuroimaging, and upon autopsy, neuropathological findings corresponding to clinical disease in pediatric patients include impaired brain growth, reactive gliosis, myelin pallor, calcifications of the basal ganglia, cortical and cerebral atrophy with neuronal loss and ventricular enlargement, and abnormalities of cerebral vasculature. Although there is som overlap with neuropathologic findings in adult patients, ADC in adults is more typically a late development, often complicated by opportunistic infections of
the CNS. The neuropathogenesis of ADC and PE is incompletely understood. One population of CNS cells critical for brain development and response to injury and inflammation are neural progenitors cells, and it has therefore been suggested that these cells may be involved in theneuropathogenesis of ADC, and especially PE. This review examines the neurobiology of neural progenitor cells and the possibility that HIV-1 infection of neural progenitors, exposure of neural progenitors to virus, viral products, or progenitor exposure to HIV-1associated neuroinflammatory substances and neurotoxins might contribute to the neuropathogenesis of AIDS in adults and children. That some of the clinical differences between ADC and PE might, in part, be explained by differences in neural progenitor involvement will also be considered.

Cognitive functioning in school-aged children with vertically acquired HIV infection being treated with highly active antiretroviral therapy (HAART). Dev Neuropsychol. 2006;30(2):633-57. Martin SC, Wolters PL, Toledo-Tamula MA, Zeichner SL, Hazra R, Civitello L.

In today's era of highly active antiretroviral therapy (HAART), few children with HIV-1 infection experience severe central nervous system (CNS) manifestations indicative of encephalopathy. However, little is known about the neurocognitive strengths and weaknesses of HIV-infected children treated with HAART. This cross-sectional study is the first to systematically investigate the relation between cognitive functioning and medical markers in HIV-infected children and adolescents treated with HAART with varying levels of computed tomography (CT) brain scan abnormalities. The Wechsler Intelligence Scale for Children-Third Edition was administered to 41 vertically infected children (mean age = 11.2 years) treated with HAART for at least 1 year. Other procedures at the time of testing included CT brain scans and collection of CD4 cell counts and plasma HIV1 RNA PCR. Although global cognitive functioning among participants was in the Average range, children with minimal to moderate CT brain scan abnormalities scored significantly lower than children with normal scans on composite measures of cognitive functioning and five specific subtests, especially tasks involving executive functions. Furthermore, children with worse immune status (CD4+ counts < or = 500) scored lower on subtests measuring processing speed. Viral load was unrelated to cognitive test scores. Thus, children with HIV being treated with HAART remain at risk for developing CNS disease. Findings emphasize the importance of conducting neuropsychological assessments in this population, particularly for children with cortical atrophy and absolute CD4+ cell counts < or = 500

Drug Metab Dispos. 2007 Nov;35(11):2076-85. Epub 2007 Aug 20. P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. Shaik N, Giri N, Pan G, Elmquist WF.

P-glycoprotein (P-gp)-mediated efflux at the blood-brain barrier has been implicated in limiting the brain distribution of many anti-HIV1 drugs, primarily protease inhibitors, resulting in suboptimal concentrations in this important sanctuary site. The objective of this study was to characterize the interaction of abacavir with P-gp and determine whether P-gp is an important mechanism in limiting abacavir delivery to the central nervous system (CNS). In vitro and in vivo techniques were employed to characterize this interaction. Abacavir stimulated P-gp ATPase activity at high concentrations. The cellular accumulation of abacavir was significantly decreased by approximately 70% in Madin-Darby canine kidney II (MDCKII)-MDR1 monolayers compared with wild-type cells and was completely restored by the P-gp inhibitors ((R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6-yl)-alpha-((5-quinoloyloxy)methyl)-piperazineethanol, trihydrochloride) (LY335979) and N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918). Directional flux experiments indicated that abacavir had greater permeability in the basolateral-to-apical direction (1.58E-05 cm/s) than in the apical-to-basolateral direction (3.44E-06 cm/s) in MDR1-transfected monolayers. The directionality in net flux was abolished by both LY335979 and GF120918. In vivo brain distribution studies showed that the AUC(plasma) in mdr1a(-/-) CF-1 mutant mice was approximately 2-fold greater than the AUC(plasma) in the wild type, whereas the AUC(brain) in the mutant was 20-fold higher than that in the wild type. Therefore, the CNS drug targeting index, defined as the ratio of AUC brain-to-plasma for mutant over wild type, was greater than 10. These data are the first in vitro and in vivo evidence that a nucleoside reverse transcriptase inhibitor is a P-gp substrate. The remarkable increase in abacavir brain distribution in P-gp-deficient mutant mice over wild-type mice suggests that P-gp may play a significant role in restricting the abacavir distribution to the CNS.

Cytokine. 2001 Jul 21;15(2):96-107. Role of CD23 in astrocytes inflammatory reaction during HIV-1 related encephalitis. Dugas N, Lacroix C, Kilchherr E, Delfraissy JF, Tardieu M.

Soluble factors released by intra-cerebral activated cells are implicated in neuronal alterations during central nervous system inflammatory diseases. In this study, the role of the CD23 pathway in astrocyte activation and its participation in human immunodeficiency virus-1 (HIV-1)-induced neuropathology were evaluated. In human primary astrocytes, CD23 protein membrane expression was dose-dependently upregulated by gp120. It was also upregulated by gamma-interferon (gamma-IFN) and modulated by interleukin-1-beta (IL-1beta) whereas microglial cells in these stimulation conditions did not express CD23. Cell surface stimulation of CD23 expressed by astrocytes induced production of nitric oxide (NO) and IL-1beta which was inhibited by a specific inducible NO-synthase (iNOS) inhibitor (aminoguanidine), indicating the implication of this receptor in the astrocyte inflammatory reaction. On brain tissues from five out of five patients with HIV-1-related encephalitis, CD23 was expressed by astrocytes and by some microglial cells, whereas it was not detectable on brain tissue from five of five HIV-1-infected patients without central nervous system (CNS) disease or from two of two control subjects. In addition, CD23 antigen was co-localized with iNOS and nitrotyrosine on brain tissue from patients with HIV1-related encephalitis, suggesting that CD23 participates in iNOS activation of astrocytes in vivo. In conclusion, CD23 ligation is an alternative pathway in the induction of inflammatory product synthesis by astrocytes and participates in CNS inflammation.



J Acquir Immune Defic Syndr. 1999 Aug 15;21(5):371-5. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. Kravcik S, Gallicano K, Roth V, Cassol S, Hawley-Foss N, Badley A, Cameron DW.

Combination antiretroviral therapy with ritonavir and saquinavir has established potent and durable activity on plasma viremia. CNS HIV infection may be sequestered from drug therapy that does not penetrate the blood-brain barrier. Penetration of these protease inhibitors into the cerebrospinal fluid (CSF) and CSF HIV RNA levels on such therapy has not been well described.

In a cross-sectional study, 28 HIV1-infected study subjects were evaluated either before initiation of or before maximal response to ritonavir-saquinavir therapy, during maximal plasma virologic response, and after virologic failure. Simultaneous samples of plasma and cerebrospinal fluid were obtained from 24 study subjects to measure HIV RNA and protease inhibitor levels.

Across the treatment groups, a strong correlation was found between plasma and CSF HIV RNA levels (r = 0.870; p < .001). In each study subject with plasma HIV RNA levels below assay limit (80 copies/ml), the CSF HIV RNA level was also below the limit of quantitation. Low levels of saquinavir (<2 ng/ml) and ritonavir (<25 ng/ml) in the CSF were observed, with a CSF:plasma drug concentration ratio of < or = 0.005 (0.5%) in all study subjects evaluated (n = 11). The plasma:CSF HIV RNA ratio was high before or early in treatment (median, 38; interquartile range [IQR], 13,97), but low (median, 0.29; IQR, 0.17, 7.5) in those failing therapy (group C, p < .001).

CSF ritonavir and saquinavir levels are consistent with the estimated known fraction of unbound drug in plasma (<2%). Across these treatment response groups, suppression of plasma viremia can predict low CSF HIV RNA levels. This correlation may represent HIV RNA transport and equilibrium between CSF and plasma, or it may represent CNS anti-HIV activity of protease inhibitors. The low drug levels and inverted ratio of HIV RNA in the CSF compared with plasma early in plasma virologic breakthrough suggests CSF virologic failure may contribute to failure of plasma virologic response.

J Neuropathol Exp Neurol. 1995 May;54(3):350-7. Differential vulnerability of calbindin-immunoreactive neurons in HIV encephalitis. E Masliah E, Ge N, Achim CL, Wiley CA.

Recent studies have suggested that the neuronal damage during human immunodeficiency virus encephalitis (HIVE) might be mediated by increased intracellular calcium. Since in vitro studies have shown that calcium-binding proteins protect neurons from calcium-mediated toxicity, we hypothesized that calbindin-expressing neurons might be resistant to HIV1-mediated damage. We compared patterns of calbindin immunoreactivity in the cortex and subcortex of autopsied AIDS cases with and without HIVE. Calbindin-immunoreactive neurons in the neocortex were significantly reduced in HIVE (one-way ANOVA, p < 0.001), while these neurons in the basal ganglia and hippocampus were unaffected. The loss of calbindin-immunolabeled neurons in the neocortex was correlated with viral burden (r = -0.45, p < 0.001). Differential loss of calbindin-immunoreactive neurons in HIVE suggests that neuronal damage in different regions of the CNS may be mediated by different pathogenic mechanisms

Res Virol. 1994 May-Aug;145(3-4):147-53. Restricted expression of HIV1 in human astrocytes: molecular basis for viral persistence in the CNS. Kleinschmidt A, Neumann M, Möller C, Erfle V, Brack-Werner R.

Abstract

Besides macrophages and microglial cells, cells of astroglial origin are thought to be targets of HIV1 in the brain. HIV1 infection of astroglial cells results in restricted production of the virus. To analyse the molecular basis of this restricted infection phenotype, we established a chronically HIV1-infected low-producer astrocytoma cell line. These cells show only low levels of mRNA encoding structural proteins, due to a cell-determined blockage in the Rev/RRE regulatory axis. The low-producer state could not be overcome by treatment with known stimulators of virus expression such as phorbol ester, (12-O-tetradecanoylphorbol-13-acetate), tumour necrosis factor alpha or sodium butyrate. This indicates that the molecular mechanisms involved in restricting virus production in astroglial cells differ from those in latently infected T cells and monocytes.



Res Virol. 1991 Mar-Jun;142(2-3):145-9. HIV receptors within the brain: a study of CD4 and MHC-II on human neurons, astrocytes and microglial cells.Peudenier S, Héry C, Ng KH, Tardieu M.

We have investigated the level of expression of CD4 and MHC-II antigens on CNS cells and compared it to that on monocytes. MHC-II antigens were expressed spontaneously on cultured astrocytes and monocytes, whereas they were detected only after IFN gamma stimulation of microglial cells. In vitro, CD4 receptor was present on monocytes but not on neurons, astrocytes or microglial cells. In normal brain, CD4 antigen was expressed on perivascular microglial cells, a specialized microglia expressing monocytic markers, whereas in HIV1-infected brain, CD4+ cells were numerous and scattered throughout the whole parenchyma. These CD4+ macrophages may be HIV1-infected monocytes which have crossed the blood-brain barrier after infection, or perivascular
microglial cells infected by HIV1-infected blood lymphocytes or five virions.



Acta Neurol (Napoli). 1990 Feb;12(1):53-7. HIV1-Ag in cerebrospinal fluid during AIDS. Scalzini A, Scura G, Stellini R, Cristini G.

HIV infection may display neurological symptoms at any stage; the virus can be isolated from the cerebrospinal fluid (CSF) of both symptomatic and asymptomatic patients and of two third of patients with AIDS. This study sought to determine the sensitivity of HIV1-Ag in the CSF of an HIV-Ab positive population to evaluate its diagnostic and/or prognostic significance. CSF HIV1-Ag was dosed in 48 patients: 9 patients belonged to the III CDC group, 2 to group IVA, 1 to IVB and 36 to IVC1. In the last group, 14 patients had not opportunistic infections of the CNS. The tests proved positive in: 1 IVB patient and 16 IVC patients with focal lesions of the CNS or cerebral atrophy; HIV1-Ag was present in the CSF of 63% of patients displaying neurologic symptoms and it reached 84% in patients with diffuse CNS pathology.

Accumulation of nuclear and mitochondrial DNA damage in the frontal cortex cells of patients with HIV-associated neurocognitive disorders. Zhang Y, Wang M, Li H, Zhang H, Shi Y, Wei F, Liu D, Liu K, Chen D. Brain Res. 2012 Jun 6;1458:1-11. Epub 2012 Apr 11.

Oxidative stress has been suggested to play a key role in the neuropathogenesis of HIV infection. HIV proteins (gp120, Tat) and proinflammatory cytokines can trigger the production of reactive oxygen species (ROS), resulting in DNA and RNA lesions. Among all the lesions induced by ROS, one of the most abundant lesions in DNA and RNA is 8-hydroxydeoxyguanosine (8-oxoG). Here, we studied accumulated DNA oxidative damage induced by ROS in the central nervous system (CNS) in tissue from neuro-AIDS patients. The frontal cortex of autopsy tissue from HIV-1 infected patients was adopted for analysis for HIV-1 subtype, nuclear and mitochondrial DNA lesions by immunofluorescence staining, qPCR and sequencing of PCR cloning. This study provides evidence that HIV infection in the CNS leads to nuclear and mitochondrial genomic DNA damage in the brain. High level of nuclear and mtDNA 8-oxoG damage were identified in the cortex autopsy tissue of HAND patients. Increased accumulation of mtDNA mutations and depletion occurs in brain tissue
in a subset of HAND cases, and is significantly different from that observed in control cases. These findings suggest that higher level of ROS in the CNS of HAND patients would contribute to the HIV induced neuro-inflammation and apoptosis of neuronal and glial cells.