Publications by authors named "Michael S McGrath"

51 Publications

Peripheral Innate Immune Activation Correlates With Disease Severity in Haploinsufficiency.

Front Neurol 2019 18;10:1004. Epub 2019 Sep 18.

Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States.

To investigate associations between peripheral innate immune activation and frontotemporal lobar degeneration (FTLD) in progranulin gene () haploinsufficiency. In this cross-sectional study, ELISA was used to measure six markers of innate immunity (sCD163, CCL18, LBP, sCD14, IL-18, and CRP) in plasma from 30 mutation carriers (17 asymptomatic, 13 symptomatic) and 29 controls. Voxel based morphometry was used to model associations between marker levels and brain atrophy in mutation carriers relative to controls. Linear regression was used to model relationships between plasma marker levels with mean frontal white matter integrity [fractional anisotropy (FA)] and the FTLD modified Clinical Dementia Rating Scale sum of boxes score (FTLD-CDR SB). Plasma sCD163 was higher in symptomatic carriers [mean 321 ng/ml (SD 125)] compared to controls [mean 248 ng/ml (SD 58); < 0.05]. Plasma CCL18 was higher in symptomatic carriers [mean 56.9 pg/ml (SD 19)] compared to controls [mean 40.5 pg/ml (SD 14); < 0.05]. Elevation of plasma LBP was associated with white matter atrophy in the right frontal pole and left inferior frontal gyrus ( FWE corrected <0.05) in all mutation carriers relative to controls. Plasma LBP levels inversely correlated with bilateral frontal white matter FA (R = 0.59, = 0.009) in mutation carriers. Elevation in plasma was positively correlated with CDR-FTLD SB (b = 2.27 CDR units/μg LBP/ml plasma, R = 0.76, = 0.003) in symptomatic carriers. FTLD- is associated with elevations in peripheral biomarkers of macrophage-mediated innate immunity, including sCD163 and CCL18. Clinical disease severity and white matter integrity are correlated with blood LBP, suggesting a role for peripheral immune activation in FTLD-.
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http://dx.doi.org/10.3389/fneur.2019.01004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759464PMC
September 2019

Emerging Patterns in HIV-1 gp120 Variable Domains in Anatomical Tissues in the Absence of a Plasma Viral Load.

AIDS Res Hum Retroviruses 2019 06 10;35(6):588-596. Epub 2019 Apr 10.

6 Departments of Laboratory Medicine, Pathology and Medicine, The University of California at San Francisco, San Francisco, California.

The HIV envelope protein contains five hypervariable domains (V1-V5) that are fundamental for cell entry. We contrasted modifications in the variable domains derived from a panel of 24 tissues from 7 subjects with no measurable plasma viral load (NPVL) to variable domains from 76 tissues from 15 subjects who had a detectable plasma viral load (PVL) at death. NPVL subject's V1 and V2 domains were usually highly length variable, whereas length variation in PVL sequences was more conserved. Longer V1s contained more charged residues, whereas longer V2s were more glycosylated. Structural analysis demonstrated V1/V2 charge, and N-site additions/subtractions were localized to the CD4 binding pocket. Diversified envelopes in tissues during therapy may represent a mechanism for HIV persistence in tissues, as binding pocket complexity is associated with HIV that may escape neutralization, whereas shorter envelopes are associated with increased infectivity. Further analysis of tissue-derived envelope sequences may enable better understanding of potential immunological approaches targeting the persistent HIV reservoir.
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http://dx.doi.org/10.1089/AID.2018.0267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588100PMC
June 2019

Methylglyoxal-bis-guanylhydrazone inhibits osteopontin expression and differentiation in cultured human monocytes.

PLoS One 2018 14;13(3):e0192680. Epub 2018 Mar 14.

Department of Laboratory Medicine, Medicine, and Pathology, University of California San Francisco, San Francisco, CA, United States of America.

Monocyte activation and polarization play essential roles in many chronic inflammatory diseases. An imbalance of M1 and M2 macrophage activation (pro-inflammatory and alternatively activated, respectively) is believed to be a key aspect in the etiology of these diseases, thus a therapeutic approach that regulates macrophage activation could be of broad clinical relevance. Methylglyoxal-bis-guanylhydrazone (MGBG), a regulator of polyamine metabolism, has recently been shown to be concentrated in monocytes and macrophages, and interfere with HIV integration into the DNA of these cells in vitro. RNA expression analysis of monocytes from HIV+ and control donors with or without MGBG treatment revealed the only gene to be consistently down regulated by MGBG to be osteopontin (OPN). The elevated expression of this pro-inflammatory cytokine and monocyte chemoattractant is associated with various chronic inflammatory diseases. We demonstrate that MGBG is a potent inhibitor of secreted OPN (sOPN) in cultured monocytes with 50% inhibition achieved at 0.1 μM of the drug. Furthermore, inhibition of OPN RNA transcription in monocyte cultures occurs at similar concentrations of the drug. During differentiation of monocytes into macrophages in vitro, monocytes express cell surface CD16 and the cells undergo limited DNA synthesis as measured by uptake of BrdU. MGBG inhibited both activities at similar doses to those regulating OPN expression. In addition, monocyte treatment with MGBG inhibited differentiation into both M1 and M2 classes of macrophages at non-toxic doses. The inhibition of differentiation and anti-OPN effects of MGBG were specific for monocytes in that differentiated macrophages were nearly resistant to MGBG activities. Thus MGBG may have potential therapeutic utility in reducing or normalizing OPN levels and regulating monocyte activation in diseases that involve chronic inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851547PMC
June 2018

The Spleen Is an HIV-1 Sanctuary During Combined Antiretroviral Therapy.

AIDS Res Hum Retroviruses 2018 01 30;34(1):123-125. Epub 2017 Nov 30.

5 The AIDS and Cancer Specimen Resource, University of California San Francisco , San Francisco, California.

Combined antiretroviral therapy (cART) does not eradicate HIV, which persists for years and can re-establish replication if treatment is stopped. The current challenge is identifying those tissues harboring virus through cART. Here, we used HIV env-nef single genome sequencing and HIV gag droplet digital PCR (ddPCR) to survey 50 tissues from five subjects on cART with no detectable plasma viral load at death. The spleen most consistently contained multiple proviral and expressed sequences (4/5 participants). Spleen-derived HIV demonstrated two distinct phylogenetic patterns: multiple identical sequences, often from different tissues, as well as diverse viral sequences on long terminal branches. Our results suggested that ddPCR may overestimate the size of the tissue-based viral reservoir. The spleen, a lymphatic organ at the intersection of the immune and circulatory systems, may play a key role in viral persistence.
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http://dx.doi.org/10.1089/AID.2017.0254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771542PMC
January 2018

Brain-specific HIV Nef identified in multiple patients with neurological disease.

J Neurovirol 2018 02 23;24(1):1-15. Epub 2017 Oct 23.

The University of California, San Francisco, CA, USA.

HIV-1 Nef is a flexible, multifunctional protein with several cellular targets that is required for pathogenicity of the virus. This protein maintains a high degree of genetic variation among intra- and inter-host isolates. HIV Nef is relevant to HIV-associated neurological diseases (HAND) in patients treated with combined antiretroviral therapy because of the protein's role in promoting survival and migration of infected brain macrophages. In this study, we analyzed 2020 HIV Nef sequences derived from 22 different tissues and 31 subjects using a novel computational approach. This approach combines statistical regression and evolved neural networks (ENNs) to classify brain sequences based on the physical and chemical characteristics of functional Nef domains. Based on training, testing, and validation data, the method successfully classified brain Nef sequences at 84.5% and provided informative features for further examination. These included physicochemical features associated with the Src-homology-3 binding domain, the Nef loop (including the AP-2 Binding region), and a cytokine-binding domain. Non-brain sequences from patients with HIV-associated neurological disease were frequently classified as brain, suggesting that the approach could indicate neurological risk using blood-derived virus or for the development of biomarkers for use in assay systems aimed at drug efficacy studies for the treatment of HIV-associated neurological diseases.
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http://dx.doi.org/10.1007/s13365-017-0586-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792318PMC
February 2018

Eradication of HIV from Tissue Reservoirs: Challenges for the Cure.

AIDS Res Hum Retroviruses 2018 01 7;34(1):3-8. Epub 2017 Aug 7.

5 The AIDS and Cancer Specimen Resource , San Francisco, California.

The persistence of HIV infection, even after lengthy and successful combined antiretroviral therapy (cART), has precluded an effective cure. The anatomical locations and biological mechanisms through which the viral population is maintained remain unknown. Much research has focused nearly exclusively on circulating resting T cells as the predominant source of persistent HIV, a strategy with limited success in developing an effective cure strategy. In this study, we review research supporting the importance of anatomical tissues and other immune cells for HIV maintenance and expansion, including the central nervous system, lymph nodes, and macrophages. We present accumulated research that clearly demonstrates the limitations of using blood-derived cells as a proxy for tissue reservoirs and sanctuaries throughout the body. We cite recent studies that have successfully used deep-sequencing strategies to uncover the complexity of HIV infection and the ability of the virus to evolve despite undetectable plasma viral loads. Finally, we suggest new strategies and highlight the importance of tissue banks for future research.
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http://dx.doi.org/10.1089/AID.2017.0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771544PMC
January 2018

An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy.

J Neurovirol 2017 08 1;23(4):568-576. Epub 2017 May 1.

Department of Neuroscience, Temple University School of Medicine, 3500 North Broad Street, MERB 755, Philadelphia, PA, 19140, USA.

Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.
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http://dx.doi.org/10.1007/s13365-017-0529-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623097PMC
August 2017

Direct Targeting of Macrophages With Methylglyoxal-Bis-Guanylhydrazone Decreases SIV-Associated Cardiovascular Inflammation and Pathology.

J Acquir Immune Defic Syndr 2017 04;74(5):583-592

*Department of Biology, Boston College, Chestnut Hill, MA; †Cornell University College of Veterinary Medicine, Ithaca, NY; and ‡Department of Pathology and Laboratory Medicine, UCSF, San Francisco, CA.

Background: Despite effective combination antiretroviral therapy, HIV-infected individuals develop comorbidities, including cardiovascular disease, where activated macrophages play a key role. To date, few therapies target activated monocytes and macrophages.

Methods: We evaluated a novel oral form of the polyamine biosynthesis inhibitor methylglyoxal-bis-guanylhydrazone (MGBG) on cardiovascular inflammation, carotid artery intima-media thickness (cIMT), and fibrosis in a simian immunodeficiency virus infection model of AIDS. Eleven simian immunodeficiency virus-infected animals received MGBG (30 mg/kg) once daily and 8 received a placebo control both beginning at 21 days postinfection (dpi). Animals were time sacrificed at 49 days post infection (dpi), when their matched placebo controls developed AIDS (63, 70, 77, 80), or at the study end-point (84 dpi). Aorta, carotid artery, and cardiac tissues were analyzed. Quantitative analyses of macrophage populations and T lymphocytes were done and correlated with cIMT and fibrosis.

Results: MGBG treatment resulted in 2.19-fold (CD163), 1.86-fold (CD68), 2.31-fold (CD206), and 2.12-fold (MAC387) decreases in macrophages in carotid arteries and significant 2.07-fold (CD163), 1.61-fold (CD68), 1.95-fold (MAC387), and 1.62-fold (CD206) decreases in macrophages in cardiac tissues. cIMT (1.49-fold) and fibrosis (2.05-fold) also were significantly decreased with MGBG treatment. Numbers of macrophage and the degree of fibrosis in treated animals were similar to uninfected animals. A positive correlation between decreased macrophage in the carotid artery and cIMT, and cardiac macrophages and fibrosis was found.

Conclusions: These data demonstrate that directly targeting macrophages with MGBG can reduce cardiovascular inflammation, cIMT, and fibrosis. They suggest that therapies targeting macrophages with HIV could be used in conjunction with combination antiretroviral therapy.
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http://dx.doi.org/10.1097/QAI.0000000000001297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370195PMC
April 2017

HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi's Sarcoma during AIDS.

Sarcoma 2016 29;2016:4510483. Epub 2016 Aug 29.

The AIDS and Cancer Specimen Resource, University of California at San Francisco and the Department of Laboratory Medicine, Pathology, and Medicine, University of California at San Francisco, 1001 Poterero Ave, Bldg 3, Rm 207, UCSF Box 1317, San Francisco, CA 94110, USA.

Kaposi's sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (n = 12). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression.
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http://dx.doi.org/10.1155/2016/4510483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019946PMC
September 2016

HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads.

J Virol 2016 10 29;90(20):8968-83. Epub 2016 Sep 29.

National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA David Geffen School of Medicine and Olive View-UCLA Medical Center, Department of Neurology, Los Angeles, California, USA.

Unlabelled: HIV infection treatment strategies have historically defined effectiveness through measuring patient plasma HIV RNA. While combined antiretroviral therapy (cART) can reduce plasma viral load (pVL) to undetectable levels, the degree that HIV is eliminated from other anatomical sites remains unclear. We investigated the HIV DNA levels in 229 varied autopsy tissues from 20 HIV-positive (HIV(+)) cART-treated study participants with low or undetectable plasma VL and cerebrospinal fluid (CSF) VL prior to death who were enrolled in the National Neurological AIDS Bank (NNAB) longitudinal study and autopsy cohort. Extensive medical histories were obtained for each participant. Autopsy specimens, including at least six brain and nonbrain tissues per participant, were reviewed by study pathologists. HIV DNA, measured in tissues by quantitative and droplet digital PCR, was identified in 48/87 brain tissues and 82/142 nonbrain tissues at levels >200 HIV copies/million cell equivalents. No participant was found to be completely free of tissue HIV. Parallel sequencing studies from some tissues recovered intact HIV DNA and RNA. Abnormal histological findings were identified in all participants, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. All brain tissues demonstrated some degree of pathology. Ninety-five percent of participants had some degree of atherosclerosis, and 75% of participants died with cancer. This study assists in characterizing the anatomical locations of HIV, in particular, macrophage-rich tissues, such as the central nervous system (CNS) and testis. Additional studies are needed to determine if the HIV recovered from tissues promotes the pathogenesis of inflammatory diseases, such as HIV-associated neurocognitive disorders, cancer, and atherosclerosis.

Importance: It is well-known that combined antiretroviral therapy (cART) can reduce plasma HIV to undetectable levels; however, cART cannot completely clear HIV infection. An ongoing question is, "Where is HIV hiding?" A well-studied HIV reservoir is "resting" T cells, which can be isolated from blood products and succumb to cART once activated. Less-studied reservoirs are anatomical tissue samples, which have unknown cART penetration, contain a comparably diverse spectrum of potentially HIV-infected immune cells, and are important since <2% of body lymphocytes actually reside in blood. We examined 229 varied autopsy specimens from 20 HIV(+) participants who died while on cART and identified that >50% of tissues were HIV infected. Additionally, we identified considerable pathology in participants' tissues, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. This study substantiates that tissue-associated HIV is present despite cART and can inform future studies into HIV persistence.
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http://dx.doi.org/10.1128/JVI.00674-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5044815PMC
October 2016

HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer.

J Virol 2016 10 29;90(20):8984-93. Epub 2016 Sep 29.

The AIDS and Cancer Specimen Resource, University of California at San Francisco, San Francisco, California, USA Departments of Laboratory Medicine, Pathology, and Medicine, University of California at San Francisco, San Francisco, California, USA

Unlabelled: While combined antiretroviral therapy (cART) can result in undetectable plasma viral loads, it does not eradicate HIV infection. Furthermore, HIV-infected individuals while on cART remain at an increased risk of developing serious comorbidities, such as cancer, neurological disease, and atherosclerosis, suggesting that during cART, tissue-based HIV may contribute to such pathologies. We obtained DNA and RNA env, nef, and pol sequences using single-genome sequencing from postmortem tissues of three HIV(+) cART-treated (cART(+)) individuals with undetectable viral load and metastatic cancer at death and performed time-scaled Bayesian evolutionary analyses. We used a sensitive in situ hybridization technique to visualize HIV gag-pol mRNA transcripts in cerebellum and lymph node tissues from one patient. Tissue-associated virus evolved at similar rates in cART(+) and cART-naive (cART(-)) patients. Phylogenetic trees were characterized by two distinct features: (i) branching patterns consistent with constant viral evolution and dispersal among tissues and (ii) very recently derived clades containing both DNA and RNA sequences from multiple tissues. Rapid expansion of virus near death corresponded to wide-spread metastasis. HIV RNA(+) cells clustered in cerebellum tissue but were dispersed in lymph node tissue, mirroring the evolutionary patterns observed for that patient. Activated, infiltrating macrophages were associated with HIV RNA. Our data provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread.

Importance: Combined antiretroviral therapy (cART) reduces plasma HIV to undetectable levels; however, removal of cART results in plasma HIV rebound, thus highlighting its inability to entirely rid the body of infection. Additionally, HIV-infected individuals on cART remain at high risk of serious diseases, which suggests a contribution from residual HIV. In this study, we isolated and sequenced HIV from postmortem tissues from three HIV(+) cART(+) individuals who died with metastatic cancer and had no detectable plasma viral load. Using high-resolution evolutionary analyses, we found that tissue-based HIV continues to replicate, evolve, and migrate among tissues during cART. Furthermore, cancer onset and metastasis coincided with increased HIV expansion, suggesting a linked mechanism. HIV-expressing cells were associated with tissue macrophages, a target of HIV infection. Our results suggest the importance of tissues, and macrophages in particular, as a target for novel anti-HIV therapies.
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http://dx.doi.org/10.1128/JVI.00684-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5044847PMC
October 2016

On the Physicochemical and Structural Modifications Associated with HIV-1 Subtype B Tropism Transition.

AIDS Res Hum Retroviruses 2016 08 1;32(8):829-40. Epub 2016 Jun 1.

4 Department of Laboratory Medicine, Pathology, and Medicine, and the AIDS and Cancer Specimen Resource, University of California , San Francisco, California.

HIV-1 enters immune cells via binding the viral envelope to a host cell CD4 receptor, and then a secondary co-receptor, usually CCR5 (R5) or CXCR4 (X4), and some HIV can utilize both co-receptors (R5X4). Although a small set of amino-acid properties such as charge and sequence length applied to HIV-1 envelope V3 loop sequence data can be used to predict co-receptor usage, we sought to expand the fundamental understanding of the physiochemical basis of tropism by analyzing many, perhaps less obvious, amino-acid properties over a diverse array of HIV sequences. We examined 74 amino-acid physicochemical scales over 1,559 V3 loop sequences with biologically tested tropisms downloaded from the Los Alamos HIV sequence database. Linear regressions were then calculated for each feature relative to three tropism transitions (R5→X4; R5→R5X4; R5X4→X4). Independent correlations were rank ordered to determine informative features. A structural analysis of the V3 loop was performed to better interpret these findings relative to HIV tropism states. Similar structural changes are required for R5 and R5X4 to transition to X4, thus suggesting that R5 and R5X4 types are more similar than either phenotype is to X4. Overall, the analysis suggests a continuum of viral tropism that is only partially related to charge; in fact, the analysis suggests that charge modification may be primarily attributed to decreased R5 usage, and further structural changes, particularly those associated with β-sheet structure, are likely required for full X4 usage.
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http://dx.doi.org/10.1089/AID.2015.0373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971420PMC
August 2016

The meningeal lymphatic system: a route for HIV brain migration?

J Neurovirol 2016 06 16;22(3):275-81. Epub 2015 Nov 16.

University of California and the AIDS and Cancer Specimen Resource, San Francisco, CA, USA.

Two innovative studies recently identified functional lymphatic structures in the meninges that may influence the development of HIV-associated neurological disorders (HAND). Until now, blood vessels were assumed to be the sole transport system by which HIV-infected monocytes entered the brain by bypassing a potentially hostile blood-brain barrier through inflammatory-mediated semi-permeability. A cascade of specific chemokine signals promote monocyte migration from blood vessels to surrounding brain tissues via a well-supported endothelium, where the cells differentiate into tissue macrophages capable of productive HIV infection. Lymphatic vessels on the other hand are more loosely organized than blood vessels. They absorb interstitial fluid from bodily tissues where HIV may persist and exchange a variety of immune cells (CD4(+) T cells, monocytes, macrophages, and dendritic cells) with surrounding tissues through discontinuous endothelial junctions. We propose that the newly discovered meningeal lymphatics are key to HIV migration among viral reservoirs and brain tissue during periods of undetectable plasma viral loads due to suppressive combinational antiretroviral therapy, thus redefining the migration process in terms of a blood-lymphatic transport system.
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http://dx.doi.org/10.1007/s13365-015-0399-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868798PMC
June 2016

Identification of dual-tropic HIV-1 using evolved neural networks.

Biosystems 2015 Nov 28;137:12-9. Epub 2015 Sep 28.

University of California at San Francisco, Department of Laboratory Medicine and The AIDS and Cancer Specimen Resource, San Francisco, CA 94143, United States.

Blocking the binding of the envelope HIV-1 protein to immune cells is a popular concept for development of anti-HIV therapeutics. R5 HIV-1 binds CCR5, X4 HIV-1 binds CXCR4, and dual-tropic HIV-1 can bind either coreceptor for cellular entry. R5 viruses are associated with early infection and over time can evolve to X4 viruses that are associated with immune failure. Dual-tropic HIV-1 is less studied; however, it represents functional antigenic intermediates during the transition of R5 to X4 viruses. Viral tropism is linked partly to the HIV-1 envelope V3 domain, where the amino acid sequence helps dictate the receptor a particular virus will target; however, using V3 sequence information to identify dual-tropic HIV-1 isolates has remained difficult. Our goal in this study was to elucidate features of dual-tropic HIV-1 isolates that assist in the biological understanding of dual-tropism and develop an approach for their detection. Over 1559 HIV-1 subtype B sequences with known tropisms were analyzed. Each sequence was represented by 73 structural, biochemical and regional features. These features were provided to an evolved neural network classifier and evaluated using balanced and unbalanced data sets. The study resolved R5X4 viruses from R5 with an accuracy of 81.8% and from X4 with an accuracy of 78.8%. The approach also identified a set of V3 features (hydrophobicity, structural and polarity) that are associated with tropism transitions. The ability to distinguish R5X4 isolates will improve computational tropism decisions for R5 vs. X4 and assist in HIV-1 research and drug development efforts.
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http://dx.doi.org/10.1016/j.biosystems.2015.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921197PMC
November 2015

Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone.

J Virol 2015 Nov 29;89(22):11176-89. Epub 2015 Jul 29.

Pathologica LLC, Burlingame, California, USA

Unlabelled: Macrophages are a target for infection with HIV and represent one of the viral reservoirs that are relatively resistant to current antiretroviral drugs. Here we demonstrate that methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine analog and potent S-adenosylmethionine decarboxylase inhibitor, decreases HIV expression in monocytes and macrophages. MGBG is selectively concentrated by these cells through a mechanism consistent with active transport by the polyamine transporter. Using a macrophage-tropic reporter virus tagged with the enhanced green fluorescent protein, we demonstrate that MGBG decreases the frequency of HIV-infected cells. The effect is dose dependent and correlates with the production of HIV p24 in culture supernatants. This anti-HIV effect was further confirmed using three macrophage-tropic primary HIV isolates. Viral life cycle mapping studies show that MGBG inhibits HIV DNA integration into the cellular DNA in both monocytes and macrophages.

Importance: Our work demonstrates for the first time the selective concentration of MGBG by monocytes/macrophages, leading to the inhibition of HIV-1 expression and a reduction in proviral load within macrophage cultures. These results suggest that MGBG may be useful in adjunctive macrophage-targeted therapy for HIV infection.
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http://dx.doi.org/10.1128/JVI.01692-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4645666PMC
November 2015

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques.

J Virol 2015 Aug 3;89(16):8484-96. Epub 2015 Jun 3.

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA

Unlabelled: While a clear understanding of the events leading to successful establishment of host-specific viral populations and productive infection in the central nervous system (CNS) has not yet been reached, the simian immunodeficiency virus (SIV)-infected rhesus macaque provides a powerful model for the study of human immunodeficiency virus (HIV) intrahost evolution and neuropathogenesis. The evolution of the gp120 and nef genes, which encode two key proteins required for the establishment and maintenance of infection, was assessed in macaques that were intravenously inoculated with the same viral swarm and allowed to naturally progress to simian AIDS and potential SIV-associated encephalitis (SIVE). Longitudinal plasma samples and immune markers were monitored until terminal illness. Single-genome sequencing was employed to amplify full-length env through nef transcripts from plasma over time and from brain tissues at necropsy. nef sequences diverged from the founder virus faster than gp120 diverged. Host-specific sequence populations were detected in nef (~92 days) before they were detected in gp120 (~182 days). At necropsy, similar brain nef sequences were found in different macaques, indicating convergent evolution, while gp120 brain sequences remained largely host specific. Molecular clock and selection analyses showed weaker clock-like behavior and stronger selection pressure in nef than in gp120, with the strongest nef selection in the macaque with SIVE. Rapid nef diversification, occurring prior to gp120 diversification, indicates that early adaptation of nef in the new host is essential for successful infection. Moreover, the convergent evolution of nef sequences in the CNS suggests a significant role for nef in establishing neurotropic strains.

Importance: The SIV-infected rhesus macaque model closely resembles HIV-1 immunopathogenesis, neuropathogenesis, and disease progression in humans. Macaques were intravenously infected with identical viral swarms to investigate evolutionary patterns in the gp120 and nef genes leading to the emergence of host-specific viral populations and potentially linked to disease progression. Although each macaque exhibited unique immune profiles, macaque-specific nef sequences evolving under selection were consistently detected in plasma samples at 3 months postinfection, significantly earlier than in gp120 macaque-specific sequences. On the other hand, nef sequences in brain tissues, collected at necropsy of two animals with detectable infection in the central nervous system (CNS), revealed convergent evolution. The results not only indicate that early adaptation of nef in the new host may be essential for successful infection, but also suggest that specific nef variants may be required for SIV to efficiently invade CNS macrophages and/or enhance macrophage migration, resulting in HIV neuropathology.
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http://dx.doi.org/10.1128/JVI.01010-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524235PMC
August 2015

Randomized phase 2 trial of NP001-a novel immune regulator: Safety and early efficacy in ALS.

Neurol Neuroimmunol Neuroinflamm 2015 Jun 9;2(3):e100. Epub 2015 Apr 9.

California Pacific Medical Center (R.G.M., J.S.K.), San Francisco, CA; Neuraltus Pharmaceuticals, Inc. (G.B., V.G., M.S.M., A.A.), Palo Alto, CA; University of Kansas (R.J.B.), Kansas City; Massachusetts General Hospital (M.C.), Boston; University of California, San Francisco (R.Z., M.S.M.); Agility Clinical, Inc. (E.L.), Carlsbad, CA; and The Methodist Hospital (S.H.A.), Houston, TX.

Objective: To assess the safety, tolerability, and preliminary efficacy of NP001, a novel immune regulator of inflammatory monocytes/macrophages, for slowing progression of amyotrophic lateral sclerosis (ALS).

Methods: This was a phase 2 randomized, double-blind, placebo-controlled trial of NP001 in 136 patients with ALS of <3 years' duration and forced vital capacity ≥70%. Participants received NP001 2 mg/kg, NP001 1 mg/kg, or placebo for 6 months. Safety, tolerability, and inflammatory biomarkers were assessed throughout the study. Preliminary efficacy was evaluated using the ALS Functional Rating Scale-Revised (ALSFRS-R) slope and change from baseline, with and without matched historical placebo controls, after 6 months of treatment. A post hoc analysis of the percentage of patients ("responders") whose ALSFRS-R did not change from baseline was also conducted.

Results: NP001 was generally safe and well-tolerated, except for infusion site pain and dizziness. No significant slowing of decline in the primary or secondary measures was observed. However, slowing of progression was observed in the high-dose group in patients with greater inflammation (wide range C-reactive protein). Moreover, NP001 may have dose dependently halted symptom progression in a subset of patients. More than 2 times as many patients on high-dose NP001 (25%) did not progress during 6 months of treatment compared with those on placebo (11%). Most "responders" had an elevated biomarker of inflammation, interleukin-18, and were positive for lipopolysaccharide at baseline, which decreased after treatment with NP001.

Conclusion: The arresting of progression of ALS symptoms by NP001 in a subset of patients with marked neuroinflammation, as observed here, will represent a novel therapeutic approach for patients with ALS, if confirmed.

Classification Of Evidence: This study provides Class I evidence that for patients with ALS, NP001 is safe and did not significantly slow progression of the disease (difference in slope of the ALSFRS-R/month 0.12 favoring NP001, p = 0.55). The study lacks the precision to exclude an important effect of NP001.
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http://dx.doi.org/10.1212/NXI.0000000000000100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396529PMC
June 2015

Factors related to HIV-associated neurocognitive impairment differ with age.

J Neurovirol 2015 Feb 18;21(1):56-65. Epub 2014 Nov 18.

Natural Selection, Inc., San Diego, CA, 92121, USA.

Over 50% of HIV-infected (HIV+) persons are expected to be over age 50 by 2015. The pathogenic effects of HIV, particularly in cases of long-term infection, may intersect with those of age-related illnesses and prolonged exposure to combined antiretroviral therapy (cART). One potential outcome is an increased prevalence of neurocognitive impairment in older HIV+ individuals, as well as an altered presentation of HIV-associated neurocognitive disorders (HANDs). In this study, we employed stepwise regression to examine 24 features sometimes associated with HAND in 40 older (55-73 years of age) and 30 younger (32-50 years of age) HIV+, cART-treated participants without significant central nervous system confounds. The features most effective in generating a true assessment of the likelihood of HAND diagnosis differed between older and younger cohorts, with the younger cohort containing features associated with drug abuse that were correlated to HAND and the older cohort containing features that were associated with lipid disorders mildly associated with HAND. As the HIV-infected population grows and the demographics of the epidemic change, it is increasingly important to re-evaluate features associated with neurocognitive impairment. Here, we have identified features, routinely collected in primary care settings, that provide more accurate diagnostic value than a neurocognitive screening measure among younger and older HIV individuals.
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http://dx.doi.org/10.1007/s13365-014-0296-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320020PMC
February 2015

NP001 regulation of macrophage activation markers in ALS: a phase I clinical and biomarker study.

Amyotroph Lateral Scler Frontotemporal Degener 2014 Dec 5;15(7-8):601-9. Epub 2014 Sep 5.

California Pacific Medical Center , San Francisco.

This is a phase I, placebo-controlled, single ascending dose safety and tolerability study of NP001 in patients with ALS. NP001 is a novel regulator of inflammatory macrophages and monocytes. As ALS progression is thought to be related to neuroinflammation, an additional objective of the study was to assess the effects of NP001 administration on monocyte activation markers. Thirty-two ALS patients were enrolled and received either placebo (eight) or one of four (six at each dose) ascending single i.v. doses (0.2, 0.8, 1.6 and 3.2 mg/kg NP001). Patients were monitored for safety, and blood monocyte immune activation markers CD16 and HLA-DR were assessed pre- and 24 h post-dosing. Changes from baseline were calculated. Results showed that NP001 was generally safe and well tolerated. Importantly, a single dose of NP001 caused a dose-dependent reduction in expression of monocyte CD16, a marker of monocyte activation/inflammation. Additionally, monocyte HLA-DR expression was also decreased in those patients with elevated values at baseline. In conclusion, these data indicate that NP001 has an acute effect on inflammatory monocytes in ALS patient blood. The potential for modulation of inflammation in the context of ALS disease progression will require further study with long-term follow-up.
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http://dx.doi.org/10.3109/21678421.2014.951940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524125PMC
December 2014

Transcriptional profiles of peripheral blood leukocytes identify patients with cholangiocarcinoma and predict outcome.

Asian Pac J Cancer Prev 2014 ;15(10):4217-24

Department of Biochemistry, and Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Thailand E-mail :

Cholangiocarcinoma (CCA), a slow growing but highly metastatic tumor, is highly prevalent in Northeast Thailand. Specific tests that predict prognosis of CCA remain elusive. The present study was designed to investigate whether peripheral blood leukocyte (PBL) transcriptional profiles might be of use as a prognostic test in CCA patients. Gene expression profiles of PBLs from 9 CCA and 8 healthy subjects were conducted using the Affymetrix HG_U133 Plus 2.0 GeneChip. We indentified informative PBLs gene expression profiles that could reliably distinguish CCA patients from healthy subjects. Of these CCA specific genes, 117 genes were up regulated and 60 were down regulated. The molecular and cellular functions predicted for these CCA specific genes according to the Gene Ontology database indicated differential PBL expression of host immune response and tumor progression genes (EREG, TGF β1, CXCL2, CXCL3, IL-8, and VEGFA). The expression levels of 9 differentially expressed genes were verified in 36 CCA vs 20 healthy subjects. A set of three tumor invasion related genes (PLAU, CTSL and SERPINB2) computed as "prognostic index" was found to be an independent and statistically significant predictor for CCA patient survival. The present study shows that CCA PBLs may serve as disease predictive clinically accessible surrogates for indentifying expressed genes reflective of CCA disease severity.
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http://dx.doi.org/10.7314/apjcp.2014.15.10.4217DOI Listing
May 2015

HIV-associated neuropathogenesis: a systems biology perspective for modeling and therapy.

Biosystems 2014 May 13;119:53-61. Epub 2014 Apr 13.

University of Florida, 2055 Mowry Road, Department of Pathology and Laboratory Medicine, Gainesville, FL 32610, USA. Electronic address:

Despite the development of powerful antiretroviral drugs, HIV-1 associated neurological disorders (HAND) will affect approximately half of those infected with HIV-1. Combined anti-retroviral therapy (cART) targets viral replication and increases T-cell counts, but it does not always control macrophage polarization, brain infection or inflammation. Moreover, it remains difficult to identify those at risk for HAND. New therapies that focus on modulating host immune response by making use of biological pathways could prove to be more effective than cART for the treatment of neuroAIDS. Additionally, while numerous HAND biomarkers have been suggested, they are of little use without methods for appropriate data integration and a systems-level interpretation. Machine learning, could be used to develop multifactorial computational models that provide clinicians and researchers with the ability to identify which factors (in what combination and relative importance) are considered important to outcome.
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http://dx.doi.org/10.1016/j.biosystems.2014.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112533PMC
May 2014

Systemic immune system alterations in early stages of Alzheimer's disease.

J Neuroimmunol 2013 Mar 4;256(1-2):38-42. Epub 2013 Feb 4.

University of California, San Francisco, San Francisco, CA 94110, USA.

Immune activation and inflammation play significant roles in the pathogenesis of Alzheimer's disease (AD). To test whether AD patients showed systemic manifestations of inflammation, blood from 41 patients with early stages of AD and 31 aged-match elderly controls were evaluated. Cellular markers for monocyte/macrophage (MO) activation and CD8 T lymphocyte were increased in early AD patients. Expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), was decreased; however, plasma MCP-1 levels were significantly increased and were related to the degree of MO activation in AD. These findings suggest that AD pathogenesis may be influenced by systemic immunologic dysfunction and provides potential immunologic targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jneuroim.2013.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641776PMC
March 2013

HIV-1 Nef in macrophage-mediated disease pathogenesis.

Int Rev Immunol 2012 Dec;31(6):432-50

BioInfoExperts, Thibodaux, LA, USA.

Combined anti-retroviral therapy (cART) has significantly reduced the number of AIDS-associated illnesses and changed the course of HIV-1 disease in developed countries. Despite the ability of cART to maintain high CD4+ T-cell counts, a number of macrophage-mediated diseases can still occur in HIV-infected subjects. These diseases include lymphoma, metabolic diseases, and HIV-associated neurological disorders. Within macrophages, the HIV-1 regulatory protein "Nef" can modulate surface receptors, interact with signaling pathways, and promote specific environments that contribute to each of these pathologies. Moreover, genetic variation in Nef may also guide the macrophage response. Herein, we review findings relating to the Nef-macrophage interaction and how this relationship contributes to disease pathogenesis.
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http://dx.doi.org/10.3109/08830185.2012.737073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544535PMC
December 2012

Elevated levels of proliferating and recently migrated tumor-associated macrophages confer increased aggressiveness and worse outcomes in breast cancer.

Ann Surg Oncol 2012 Nov 24;19(12):3979-86. Epub 2012 May 24.

Department of Surgery, University of California, San Francisco, CA, USA.

Purpose: Macrophages play a major role in inflammatory processes and have been associated with poor prognosis in a variety of cancers, including breast cancer. Previously, we investigated the relationship of a subset of tumor-associated macrophages (PCNA(+) TAMs) with clinicopathologic characteristics of breast cancer. We reported that high PCNA(+) TAM counts were associated with hormone receptor (HR)-negative, high-grade tumors and early recurrence. To further understand the significance of elevated PCNA(+) TAMs and the functionality of TAMs, we examined the expression of S100A8/S100A9 with the antibody Mac387. The heterodimeric S100A8/S100A9 complex plays a role in inflammation and is increased in several cancer types.

Methods: We performed immunohistochemistry using the Mac387 antibody on 367 invasive human breast cancer cases. Results were compared to previous PCNA(+) TAM counts and were correlated with patient outcomes adjusting for HR status and histologic grade.

Results: Like PCNA(+) TAMs, high Mac387 counts were associated with HR negativity, high tumor grade, younger age, and decreased recurrence-free survival. Mac387, however, appears to identify both a subset of macrophages and a subset of tumor cells. The concordance between Mac387 and PCNA(+) TAM counts was low and cases that had both high Mac387 and high PCNA(+) TAMs counts had a stronger association with early recurrence.

Conclusions: The presence of high numbers of PCNA(+) TAMs and Mac387-positive cells in breast cancers with poor outcomes may implicate a subset of TAMs in breast cancer pathogenesis, and may ultimately serve to develop potential cellular targets for therapeutic interventions.
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http://dx.doi.org/10.1245/s10434-012-2415-2DOI Listing
November 2012

Tissue invasive macrophage density is correlated with prognosis in cholangiocarcinoma.

Mol Med Rep 2010 Jul-Aug;3(4):597-605

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.

Cholangiocarcinoma (CCA) is a high metastatic cancer with no effective treatment. Here, the pro-metastatic action of tissue macrophages in CCA is demonstrated and suggested as a prognostic marker and novel target for the therapeutic intervention of CCA. Fifty CCA tissues were immunohistochemically stained with a marker for reactive/infiltrating monocytes/macrophages (MAC387) and matrix metalloproteinase (MMP)-9. The antigenic densities in positively-stained cells along the leading edge of tumors were scored. Correlations between the densities of MAC387, MMP-9-positive cells, clinicopathological features and patient survival were investigated. High densities of MAC387-positive cells were detected in more than 60% of the CCA tissues. This was significantly associated with poor prognosis parameters (non-papillary and mass-forming type CCA). Overall survival was worst in patients with high-density MAC387-positive cells. Double immunofluorescent staining indicated that MAC387-positive cells co-expressed MMP-9. Immunohistochemical staining of MMP-9 in serial sections of CCA tissues indicated that MMP-9 was rarely expressed in CCA tumor cells, but highly expressed in MAC387-positive cells and polymorphonucleated infiltrating cells. Patients with high tissue expression levels of MAC387 in combination with MMP-9-expressing cells had the worst survival. These factors were found to be independent predictors of the post-resectional survival of CCA patients. Since CCA tumor cells rarely expressed MMP-9, it is likely that tissue macrophages are critical for degrading the extracellular matrix and for facilitating tumor metastasis. They may therefore serve as a prognostic marker for poor clinical outcome, and represent novel targets for the therapeutic intervention of CCA.
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http://dx.doi.org/10.3892/mmr_00000303DOI Listing
October 2012

HIV-1 nef protein structures associated with brain infection and dementia pathogenesis.

PLoS One 2011 Feb 9;6(2):e16659. Epub 2011 Feb 9.

Polytechnic Institute of New York University, New York, New York, United States of America.

The difference between regional rates of HIV-associated dementia (HAD) in patients infected with different subtypes of HIV suggests that genetic determinants exist within HIV that influence the ability of the virus to replicate in the central nervous system (in Uganda, Africa, subtype D HAD rate is 89%, while subtype A HAD rate is 24%). HIV-1 nef is a multifunctional protein with known toxic effects in the brain compartment. The goal of the current study was to identify if specific three-dimensional nef structures may be linked to patients who developed HAD. HIV-1 nef structures were computationally derived for consensus brain and non-brain sequences from a panel of patients infected with subtype B who died due to varied disease pathologies and consensus subtype A and subtype D sequences from Uganda. Site directed mutation analysis identified signatures in brain structures that appear to change binding potentials and could affect folding conformations of brain-associated structures. Despite the large sequence variation between HIV subtypes, structural alignments confirmed that viral structures derived from patients with HAD were more similar to subtype D structures than to structures derived from patient sequences without HAD. Furthermore, structures derived from brain sequences of patients with HAD were more similar to subtype D structures than they were to their own non-brain structures. The potential finding of a brain-specific nef structure indicates that HAD may result from genetic alterations that alter the folding or binding potential of the protein.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016659PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036659PMC
February 2011

HIV-1 nef protein visits B-cells via macrophage nanotubes: a mechanism for AIDS-related lymphoma pathogenesis?

Curr HIV Res 2010 Dec;8(8):638-40

Polytechnic Institute of New York University, Brooklyn, NY, USA.

This letter refers to the recent demonstration that HIV-1 infected macrophages form specialized conduits that connect to B-cells (1). The conduit selectively transports the HIV-1 nef protein, providing nef with numerous means to interfere with cellular processes. Currently, no consideration of the connection between the conduit and the development of AIDS-related lymphoma (ARL) has been offered. ARL is one of the primary causes of death in the HIV-infected population and is related to B-cell proliferation and activation. In this letter we discuss several studies that link HIV-infected macrophages and specific forms of the nef protein to the development of ARL. The conduits discovered by Xu et al. may lead to a better understanding of how HIV infection results in lymphomagenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471533PMC
http://dx.doi.org/10.2174/157016210794088209DOI Listing
December 2010

HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues.

Infect Genet Evol 2011 Jan 3;11(1):31-7. Epub 2010 Nov 3.

Polytechnic Institute of New York University, Brooklyn, NY, USA.

Brain infection by the human immunodeficiency virus type 1 (HIV-1) has been investigated in many reports with a variety of conclusions concerning the time of entry and degree of viral compartmentalization. To address these diverse findings, we sequenced HIV-1 gp120 clones from a wide range of brain, peripheral and meningeal tissues from five patients who died from several HIV-1 associated disease pathologies. High-resolution phylogenetic analysis confirmed previous studies that showed a significant degree of compartmentalization in brain and peripheral tissue subpopulations. Some intermixing between the HIV-1 subpopulations was evident, especially in patients that died from pathologies other than HIV-associated dementia. Interestingly, the major tissue harboring virus from both the brain and peripheral tissues was the meninges. These results show that (1) HIV-1 is clearly capable of migrating out of the brain, (2) the meninges are the most likely primary transport tissues, and (3) infected brain macrophages comprise an important HIV reservoir during highly active antiretroviral therapy.
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http://dx.doi.org/10.1016/j.meegid.2010.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005076PMC
January 2011

The AIDS and Cancer Specimen Resource.

Methods Mol Biol 2011 ;675:193-203

Department of Pathology, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.

The AIDS and Cancer Specimen Resource (ACSR) is a cooperative agreement among the United States National Cancer Institute (NCI) (Office of the Director, Office of HIV and AIDS Malignancy (OHAM)) and regional US consortia, University of California, San Francisco (West Coast), George Washington University (East Coast), and The Ohio State University (Mid-Region). The ACSR's main objective is to collect, preserve, and disperse HIV-related tissues and biologic fluids along with clinical data to qualified investigators with a focus on HIV/AIDS-related malignancies. The ACSR biorepository has more than 265,000 human HIV-positive and control samples available from 39 processing types, 16 specimen types, and 52 anatomical site types. These HIV-infected biological fluids and tissues are made available to funded approved investigators at no fee. Technical support such as HIV DNA identification in tissues and tissue microarray (TMA) blocks are available to assist approved investigators. Research needs may be filled through ACSR cooperative arrangements when not met by currently banked material. Those participating with the ACSR are expected to share their research findings with the scientific community. Some 117 abstract/poster and podium reports at national and international scientific meetings and 94 publications have been contributed to the scientific literature (as of 2010). Investigators can browse the ACSR Internet site at http://acsr.ucsf.edu for biospecimens to support their scientific initiatives, including basic, translational, biomarker discovery, and molecular epidemiology studies.
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http://dx.doi.org/10.1007/978-1-59745-423-0_8DOI Listing
January 2011

Gene expression profiling in peripheral blood mononuclear cells from patients with sporadic amyotrophic lateral sclerosis (sALS).

J Neuroimmunol 2011 Jan 29;230(1-2):114-23. Epub 2010 Sep 29.

University of California, San Francisco, San Francisco, CA 94110, USA.

The aim of this study was to identify gene expression profiles in peripheral blood mononuclear cells (PBMCs) from sporadic amyotrophic lateral sclerosis (sALS) patients to gain insights into the pathogenesis of ALS. We found that upregulation of LPS/TLR4-signaling associated genes was observed in the PMBCs from sALS patients after short-term cultivation, and that elevated levels of gene expression correlated with degree of peripheral blood monocyte activation and plasma LPS levels in sALS. Similar patterns of gene expression were reproduced in LPS stimulated PBMCs from healthy controls. These data suggest that chronic monocyte/macrophage activation may be through LPS/TLR4-signaling pathways in ALS.
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http://dx.doi.org/10.1016/j.jneuroim.2010.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448551PMC
January 2011