The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Melissa J Churchill - One of the best experts on this subject based on the ideXlab platform.
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Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-Associated Dementia
Journal of neurovirology, 2010Co-Authors: Daniel Cowley, Paul R Gorry, Steven Lodewyk Wesselingh, Lachlan Robert Gray, Melissa J ChurchillAbstract:Human immunodeficiency virus type 1 (HIV-1) demonstrates a high degree of viral diversity which has an impact on viral fitness. Genetic compartmentalization of HIV-1 proteins between central nervous system (CNS) and lymphoid tissues is well established and reflects altered requirements for HIV-1 replication in macrophages/microglia, brain-specific immune selection pressures and possibly the timing of virus invasion of the CNS. Tat-encoding mRNA has been detected in the CNS of HIV-1 infected individuals and its neurotoxic effects in the CNS are well documented. However, while CNS-derived tat sequences have demonstrated significant diversity, the effect of this molecular diversity on transcriptional regulation and its impact on the pathogenesis of HIV-Associated Dementia (HAD) remains unclear. In this study, we cloned and characterised 44 unique tat alleles from brain, cerebral spinal fluid, spinal cord and blood/lymphoid tissue-derived HIV-1 isolates from five subjects with HAD. While phylogenetic analyses revealed tissue-specific compartmentalization of Tat variants for two patients, broad compartmentalization across the panel of tissue-derived viruses was not observed. Despite the lack of consistent tissue-specific compartmentalization, sequence variations within patients segregated CNS and non-CNS tat alleles. These amino acid alterations predominated within the transactivation domain of Tat and could account for alterations in the ability of particular Tat proteins to transactivate the LTR. Although a subset of patients demonstrated reduced transactivation capacity among CNS-derived Tat proteins compared to those from matched lymphoid tissues, overall Tat proteins from the CNS to lymphoid compartments maintained similar levels of transactivation function. Together, these data suggest that despite the observed heterogeneity in tat alleles isolated from matched lymphoid to CNS compartments, Tat function is maintained, highlighting the importance of Tat function in HIV-1 neuropathogenesis.
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extensive astrocyte infection is prominent in human immunodeficiency virus Associated Dementia
Annals of Neurology, 2009Co-Authors: Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Carlos A Pardo, Justin C Mcarthur, Bruce J Brew, Paul R GorryAbstract:Astrocyte infection with human immunodeficiency virus (HIV) is considered rare, so astrocytes are thought to play a secondary role in HIV neuropathogenesis. By combining double immunohistochemistry, laser capture microdissection, and highly sensitive multiplexed polymerase chain reaction to detect HIV DNA in single astrocytes in vivo, we showed that astrocyte infection is extensive in subjects with HIV-Associated Dementia, occurring in up to 19% of GFAP+ cells. In addition, astrocyte infection frequency correlated with the severity of neuropathological changes and proximity to perivascular macrophages. Our data indicate that astrocytes can be extensively infected with HIV, and suggest an important role for HIV-infected astrocytes in HIV neuropathogenesis.
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transcriptional activity of blood and cerebrospinal fluid derived nef long terminal repeat sequences isolated from a slow progressor infected with nef deleted human immunodeficiency virus type 1 HIV 1 who developed HIV Associated Dementia
Journal of NeuroVirology, 2006Co-Authors: Lachlan Robert Gray, Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Bruce J Brew, Damian F. J. Purcell, John S Sullivan, Anna Figueiredo, Dale A. Mcphee, Paul R GorryAbstract:The authors studied the transcriptional activity of blood- and cerebrospinal fluid (CSF)-derived nef/long-terminal repeat (LTR) sequences isolated from a slow progressor infected with nef-deleted human immunodeficiency virus type 1 (HIV-1) who developed HIV-Associated Dementia (HIVD). The transcriptional activity of CSF-derived nef/LTR clones isolated during HIVD was up to 4.5-fold higher than blood-derived clones isolated before and during HIVD when tested under basal, phorbol 12-myristate 13-acetate-(PMA−), and Tat-activated conditions, and was Associated with the presence of duplicated nuclear factor (NF)-κB and specificity factor-1 (Sp-1) binding sites coupled with a truncated nef sequence, increased replication capacity, and high CSF viral load. Thus, nef and LTR mutations that augment transcription may contribute to neuropathogenesis of nef-deleted HIV-1.
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longitudinal analysis of nef long terminal repeat deleted HIV 1 in blood and cerebrospinal fluid of a long term survivor who developed HIV Associated Dementia
The Journal of Infectious Diseases, 2004Co-Authors: Melissa J Churchill, Daniel Cowley, John S Sullivan, Lachlan Robert Gray, Jasminka Sterjovski, Catherine Chatfield, Jennifer Learmont, Suzanne M. CroweAbstract:We studied the evolution and compartmentalization of nef/long terminal repeat (nef/LTR)-deleted human immunodeficiency virus type 1 (HIV-1) from a long-term survivor who developed HIV-Associated Dementia (HIVD). Analysis of sequential blood-derived HIV-1 isolated before and during HIVD revealed a persistent R5X4 phenotype and a progressive loss of nef/LTR sequence; in contrast, HIV-1 present in cerebrospinal fluid during HIVD had an R5 phenotype, distinct nef/LTR sequence of unique deletions and additional nuclear factor- kappa B sites and specificity factor-1 sites, and enhanced transcriptional activity, compared with the blood-derived isolates. Thus, nef/LTR-deleted HIV-1 strains may undergo compartmentalized evolution in long-term survivors and cause neurologic disease.
Justin C Mcarthur - One of the best experts on this subject based on the ideXlab platform.
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extensive astrocyte infection is prominent in human immunodeficiency virus Associated Dementia
Annals of Neurology, 2009Co-Authors: Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Carlos A Pardo, Justin C Mcarthur, Bruce J Brew, Paul R GorryAbstract:Astrocyte infection with human immunodeficiency virus (HIV) is considered rare, so astrocytes are thought to play a secondary role in HIV neuropathogenesis. By combining double immunohistochemistry, laser capture microdissection, and highly sensitive multiplexed polymerase chain reaction to detect HIV DNA in single astrocytes in vivo, we showed that astrocyte infection is extensive in subjects with HIV-Associated Dementia, occurring in up to 19% of GFAP+ cells. In addition, astrocyte infection frequency correlated with the severity of neuropathological changes and proximity to perivascular macrophages. Our data indicate that astrocytes can be extensively infected with HIV, and suggest an important role for HIV-infected astrocytes in HIV neuropathogenesis.
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Evaluation of HIV RNA and markers of immune activation as predictors of HIV-Associated Dementia.
Neurology, 2004Co-Authors: Jeffrey J. Sevigny, Justin C Mcarthur, Ola A Selnes, Steven M. Albert, Michael P. Mcdermott, Ned Sacktor, Katherine Conant, Giovanni Schifitto, Yaakov Stern, Daniel McclernonAbstract:Objective: To evaluate whether baseline levels of plasma and CSF HIV RNA, tumor necrosis factor alpha (TNFα), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2), or macrophage colony stimulating factor (M-CSF) are predictors of incident HIV-Associated Dementia (HIVD) in a cohort with advanced HIV infection. Methods: A total of 203 nondemented subjects with CD4 lymphocyte counts less than 200/μL, or Results: After a median follow-up time of 20.7 months, 74 (36%) subjects reached the HIVD endpoint. The Dementia was mild in 70% of cases. The cumulative incidence of HIVD was 20% at 1 year and 33% at 2 years. Highly active antiretroviral therapy (HAART) was used by 73% of subjects at baseline. A plasma HIV RNA level was undetectable in 23% of subjects and a CSF HIV RNA level was undetectable in 48% of subjects. In adjusted analyses, neither plasma nor CSF HIV RNA levels (log 10 ) were Associated with time to HIVD; log 10 levels of plasma TNFα (HR 3.07, p = 0.03) and CSF MCP-1 (HR = 3.36, p = 0.06) tended to be Associated with time to HIVD. Conclusion: The lack of association between baseline plasma and CSF HIV RNA levels and incident Dementia suggests highly active antiretroviral therapy may be affecting CNS viral dynamics, leading to lower HIV RNA levels, and therefore weakening the utility of baseline HIV RNA levels as predictors of HIV-Associated Dementia.
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csf soluble fas correlates with the severity of HIV Associated Dementia
Neurology, 2004Co-Authors: Amytis Towfighi, Richard L. Skolasky, C St Hillaire, Kathy Conant, Justin C McarthurAbstract:Soluble Fas (sFas) and soluble Fas ligand (sFasL) are Associated with cellular dysfunction and death and are elevated in CSF from patients with HIV Dementia (HIV-D). The authors investigated whether these markers correlated with Dementia severity and course. sFas and sFasL were measured in 15 highly active antiretroviral therapy (HAART)-naive HIV-D subjects, 30 HAART-naive HIV+ controls, and 17 HIV-controls. HIV-D subjects had higher CSF sFas levels than controls. Subjects with moderate/severe Dementia had higher CSF sFas levels than those with mild Dementia. CSF sFas trended lower in those with progressive Dementia.
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Progression of HIV-Associated Dementia treated with HAART.
The AIDS reader, 2002Co-Authors: Ryan H. Dougherty, Justin C McarthurAbstract:A consecutive series of 96 patients with HIV-Associated Dementia treated with HAART were studied to identify specific clinical factors Associated with an improved response to therapy. The Memorial Sloan-Kettering Dementia severity scale and the HIV Dementia Scale were used to assess outcomes. Of 30 patients meeting the inclusion criteria with adequate follow-up, 60% improved neurologically and 40% progressed. There was a trend toward improvement Associated with plasma viral suppression, whereas progression was strongly Associated with injection drug use history (odds ratio, 13.3). Age, ethnicity, gender, adherence, and predicted CNS penetrance of HAART were not Associated with improved outcomes.
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Assessing HIV-Associated Dementia: modified HIV Dementia scale versus the Grooved Pegboard.
The AIDS reader, 2002Co-Authors: Henraya F. Davis, Ola A Selnes, David M. Burgess, Justin C McarthurAbstract:The HIV Dementia scale (HDS) previously has been shown to be sensitive in identifying persons with HIV-Associated Dementia (HAD). We aimed to develop a simpler version of the HDS--the Modified HDS (M-HDS)--which would be appropriate for use by nonneurologists. We sought to determine whether the M-HDS and the widely used Grooved Pegboard (GP) were comparable in identifying and staging the severity of Dementia in HIV-seropositive persons. Data from 455 HIV-seropositive persons were analyzed, and patients were separated into 2 groups: demented (n = 144) and nondemented (n = 311), where the diagnosis was established by a single neurologist. Of the 144 with HAD, 13 had severe Dementia, 55 had moderate Dementia, 51 had mild Dementia, and 25 had minor cognitive/motor disorder. We assessed the relationship between Dementia severity and score on the M-HDS and GP (nondominant hand). Results showed both the M-HDS (z = -4.32; P < .05) and the GP nondominant (z = -4.08; P < .05) differentiated demented from nondemented persons. Furthermore, the M-HDS (z = -2.95; P < .05) and GP nondominant (z = -2.68; P < .05) discriminated equally well the stages of Dementia severity. A cutoff score of 7.5 on the M-HDS maximized its sensitivity (70%) and specificity (71%). The M-HDS and the GP (nondominant) were found to be equally sensitive and specific in categorizing and staging HAD. However, the M-HDS requires no equipment and is simpler to administer; so it may be more useful for screening by nonneurologists.
Paul R Gorry - One of the best experts on this subject based on the ideXlab platform.
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Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-Associated Dementia
Journal of neurovirology, 2010Co-Authors: Daniel Cowley, Paul R Gorry, Steven Lodewyk Wesselingh, Lachlan Robert Gray, Melissa J ChurchillAbstract:Human immunodeficiency virus type 1 (HIV-1) demonstrates a high degree of viral diversity which has an impact on viral fitness. Genetic compartmentalization of HIV-1 proteins between central nervous system (CNS) and lymphoid tissues is well established and reflects altered requirements for HIV-1 replication in macrophages/microglia, brain-specific immune selection pressures and possibly the timing of virus invasion of the CNS. Tat-encoding mRNA has been detected in the CNS of HIV-1 infected individuals and its neurotoxic effects in the CNS are well documented. However, while CNS-derived tat sequences have demonstrated significant diversity, the effect of this molecular diversity on transcriptional regulation and its impact on the pathogenesis of HIV-Associated Dementia (HAD) remains unclear. In this study, we cloned and characterised 44 unique tat alleles from brain, cerebral spinal fluid, spinal cord and blood/lymphoid tissue-derived HIV-1 isolates from five subjects with HAD. While phylogenetic analyses revealed tissue-specific compartmentalization of Tat variants for two patients, broad compartmentalization across the panel of tissue-derived viruses was not observed. Despite the lack of consistent tissue-specific compartmentalization, sequence variations within patients segregated CNS and non-CNS tat alleles. These amino acid alterations predominated within the transactivation domain of Tat and could account for alterations in the ability of particular Tat proteins to transactivate the LTR. Although a subset of patients demonstrated reduced transactivation capacity among CNS-derived Tat proteins compared to those from matched lymphoid tissues, overall Tat proteins from the CNS to lymphoid compartments maintained similar levels of transactivation function. Together, these data suggest that despite the observed heterogeneity in tat alleles isolated from matched lymphoid to CNS compartments, Tat function is maintained, highlighting the importance of Tat function in HIV-1 neuropathogenesis.
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extensive astrocyte infection is prominent in human immunodeficiency virus Associated Dementia
Annals of Neurology, 2009Co-Authors: Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Carlos A Pardo, Justin C Mcarthur, Bruce J Brew, Paul R GorryAbstract:Astrocyte infection with human immunodeficiency virus (HIV) is considered rare, so astrocytes are thought to play a secondary role in HIV neuropathogenesis. By combining double immunohistochemistry, laser capture microdissection, and highly sensitive multiplexed polymerase chain reaction to detect HIV DNA in single astrocytes in vivo, we showed that astrocyte infection is extensive in subjects with HIV-Associated Dementia, occurring in up to 19% of GFAP+ cells. In addition, astrocyte infection frequency correlated with the severity of neuropathological changes and proximity to perivascular macrophages. Our data indicate that astrocytes can be extensively infected with HIV, and suggest an important role for HIV-infected astrocytes in HIV neuropathogenesis.
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transcriptional activity of blood and cerebrospinal fluid derived nef long terminal repeat sequences isolated from a slow progressor infected with nef deleted human immunodeficiency virus type 1 HIV 1 who developed HIV Associated Dementia
Journal of NeuroVirology, 2006Co-Authors: Lachlan Robert Gray, Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Bruce J Brew, Damian F. J. Purcell, John S Sullivan, Anna Figueiredo, Dale A. Mcphee, Paul R GorryAbstract:The authors studied the transcriptional activity of blood- and cerebrospinal fluid (CSF)-derived nef/long-terminal repeat (LTR) sequences isolated from a slow progressor infected with nef-deleted human immunodeficiency virus type 1 (HIV-1) who developed HIV-Associated Dementia (HIVD). The transcriptional activity of CSF-derived nef/LTR clones isolated during HIVD was up to 4.5-fold higher than blood-derived clones isolated before and during HIVD when tested under basal, phorbol 12-myristate 13-acetate-(PMA−), and Tat-activated conditions, and was Associated with the presence of duplicated nuclear factor (NF)-κB and specificity factor-1 (Sp-1) binding sites coupled with a truncated nef sequence, increased replication capacity, and high CSF viral load. Thus, nef and LTR mutations that augment transcription may contribute to neuropathogenesis of nef-deleted HIV-1.
Daniel Cowley - One of the best experts on this subject based on the ideXlab platform.
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Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-Associated Dementia
Journal of neurovirology, 2010Co-Authors: Daniel Cowley, Paul R Gorry, Steven Lodewyk Wesselingh, Lachlan Robert Gray, Melissa J ChurchillAbstract:Human immunodeficiency virus type 1 (HIV-1) demonstrates a high degree of viral diversity which has an impact on viral fitness. Genetic compartmentalization of HIV-1 proteins between central nervous system (CNS) and lymphoid tissues is well established and reflects altered requirements for HIV-1 replication in macrophages/microglia, brain-specific immune selection pressures and possibly the timing of virus invasion of the CNS. Tat-encoding mRNA has been detected in the CNS of HIV-1 infected individuals and its neurotoxic effects in the CNS are well documented. However, while CNS-derived tat sequences have demonstrated significant diversity, the effect of this molecular diversity on transcriptional regulation and its impact on the pathogenesis of HIV-Associated Dementia (HAD) remains unclear. In this study, we cloned and characterised 44 unique tat alleles from brain, cerebral spinal fluid, spinal cord and blood/lymphoid tissue-derived HIV-1 isolates from five subjects with HAD. While phylogenetic analyses revealed tissue-specific compartmentalization of Tat variants for two patients, broad compartmentalization across the panel of tissue-derived viruses was not observed. Despite the lack of consistent tissue-specific compartmentalization, sequence variations within patients segregated CNS and non-CNS tat alleles. These amino acid alterations predominated within the transactivation domain of Tat and could account for alterations in the ability of particular Tat proteins to transactivate the LTR. Although a subset of patients demonstrated reduced transactivation capacity among CNS-derived Tat proteins compared to those from matched lymphoid tissues, overall Tat proteins from the CNS to lymphoid compartments maintained similar levels of transactivation function. Together, these data suggest that despite the observed heterogeneity in tat alleles isolated from matched lymphoid to CNS compartments, Tat function is maintained, highlighting the importance of Tat function in HIV-1 neuropathogenesis.
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extensive astrocyte infection is prominent in human immunodeficiency virus Associated Dementia
Annals of Neurology, 2009Co-Authors: Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Carlos A Pardo, Justin C Mcarthur, Bruce J Brew, Paul R GorryAbstract:Astrocyte infection with human immunodeficiency virus (HIV) is considered rare, so astrocytes are thought to play a secondary role in HIV neuropathogenesis. By combining double immunohistochemistry, laser capture microdissection, and highly sensitive multiplexed polymerase chain reaction to detect HIV DNA in single astrocytes in vivo, we showed that astrocyte infection is extensive in subjects with HIV-Associated Dementia, occurring in up to 19% of GFAP+ cells. In addition, astrocyte infection frequency correlated with the severity of neuropathological changes and proximity to perivascular macrophages. Our data indicate that astrocytes can be extensively infected with HIV, and suggest an important role for HIV-infected astrocytes in HIV neuropathogenesis.
-
transcriptional activity of blood and cerebrospinal fluid derived nef long terminal repeat sequences isolated from a slow progressor infected with nef deleted human immunodeficiency virus type 1 HIV 1 who developed HIV Associated Dementia
Journal of NeuroVirology, 2006Co-Authors: Lachlan Robert Gray, Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Bruce J Brew, Damian F. J. Purcell, John S Sullivan, Anna Figueiredo, Dale A. Mcphee, Paul R GorryAbstract:The authors studied the transcriptional activity of blood- and cerebrospinal fluid (CSF)-derived nef/long-terminal repeat (LTR) sequences isolated from a slow progressor infected with nef-deleted human immunodeficiency virus type 1 (HIV-1) who developed HIV-Associated Dementia (HIVD). The transcriptional activity of CSF-derived nef/LTR clones isolated during HIVD was up to 4.5-fold higher than blood-derived clones isolated before and during HIVD when tested under basal, phorbol 12-myristate 13-acetate-(PMA−), and Tat-activated conditions, and was Associated with the presence of duplicated nuclear factor (NF)-κB and specificity factor-1 (Sp-1) binding sites coupled with a truncated nef sequence, increased replication capacity, and high CSF viral load. Thus, nef and LTR mutations that augment transcription may contribute to neuropathogenesis of nef-deleted HIV-1.
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longitudinal analysis of nef long terminal repeat deleted HIV 1 in blood and cerebrospinal fluid of a long term survivor who developed HIV Associated Dementia
The Journal of Infectious Diseases, 2004Co-Authors: Melissa J Churchill, Daniel Cowley, John S Sullivan, Lachlan Robert Gray, Jasminka Sterjovski, Catherine Chatfield, Jennifer Learmont, Suzanne M. CroweAbstract:We studied the evolution and compartmentalization of nef/long terminal repeat (nef/LTR)-deleted human immunodeficiency virus type 1 (HIV-1) from a long-term survivor who developed HIV-Associated Dementia (HIVD). Analysis of sequential blood-derived HIV-1 isolated before and during HIVD revealed a persistent R5X4 phenotype and a progressive loss of nef/LTR sequence; in contrast, HIV-1 present in cerebrospinal fluid during HIVD had an R5 phenotype, distinct nef/LTR sequence of unique deletions and additional nuclear factor- kappa B sites and specificity factor-1 sites, and enhanced transcriptional activity, compared with the blood-derived isolates. Thus, nef/LTR-deleted HIV-1 strains may undergo compartmentalized evolution in long-term survivors and cause neurologic disease.
Lachlan Robert Gray - One of the best experts on this subject based on the ideXlab platform.
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Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-Associated Dementia
Journal of neurovirology, 2010Co-Authors: Daniel Cowley, Paul R Gorry, Steven Lodewyk Wesselingh, Lachlan Robert Gray, Melissa J ChurchillAbstract:Human immunodeficiency virus type 1 (HIV-1) demonstrates a high degree of viral diversity which has an impact on viral fitness. Genetic compartmentalization of HIV-1 proteins between central nervous system (CNS) and lymphoid tissues is well established and reflects altered requirements for HIV-1 replication in macrophages/microglia, brain-specific immune selection pressures and possibly the timing of virus invasion of the CNS. Tat-encoding mRNA has been detected in the CNS of HIV-1 infected individuals and its neurotoxic effects in the CNS are well documented. However, while CNS-derived tat sequences have demonstrated significant diversity, the effect of this molecular diversity on transcriptional regulation and its impact on the pathogenesis of HIV-Associated Dementia (HAD) remains unclear. In this study, we cloned and characterised 44 unique tat alleles from brain, cerebral spinal fluid, spinal cord and blood/lymphoid tissue-derived HIV-1 isolates from five subjects with HAD. While phylogenetic analyses revealed tissue-specific compartmentalization of Tat variants for two patients, broad compartmentalization across the panel of tissue-derived viruses was not observed. Despite the lack of consistent tissue-specific compartmentalization, sequence variations within patients segregated CNS and non-CNS tat alleles. These amino acid alterations predominated within the transactivation domain of Tat and could account for alterations in the ability of particular Tat proteins to transactivate the LTR. Although a subset of patients demonstrated reduced transactivation capacity among CNS-derived Tat proteins compared to those from matched lymphoid tissues, overall Tat proteins from the CNS to lymphoid compartments maintained similar levels of transactivation function. Together, these data suggest that despite the observed heterogeneity in tat alleles isolated from matched lymphoid to CNS compartments, Tat function is maintained, highlighting the importance of Tat function in HIV-1 neuropathogenesis.
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transcriptional activity of blood and cerebrospinal fluid derived nef long terminal repeat sequences isolated from a slow progressor infected with nef deleted human immunodeficiency virus type 1 HIV 1 who developed HIV Associated Dementia
Journal of NeuroVirology, 2006Co-Authors: Lachlan Robert Gray, Melissa J Churchill, Steven Lodewyk Wesselingh, Daniel Cowley, Bruce J Brew, Damian F. J. Purcell, John S Sullivan, Anna Figueiredo, Dale A. Mcphee, Paul R GorryAbstract:The authors studied the transcriptional activity of blood- and cerebrospinal fluid (CSF)-derived nef/long-terminal repeat (LTR) sequences isolated from a slow progressor infected with nef-deleted human immunodeficiency virus type 1 (HIV-1) who developed HIV-Associated Dementia (HIVD). The transcriptional activity of CSF-derived nef/LTR clones isolated during HIVD was up to 4.5-fold higher than blood-derived clones isolated before and during HIVD when tested under basal, phorbol 12-myristate 13-acetate-(PMA−), and Tat-activated conditions, and was Associated with the presence of duplicated nuclear factor (NF)-κB and specificity factor-1 (Sp-1) binding sites coupled with a truncated nef sequence, increased replication capacity, and high CSF viral load. Thus, nef and LTR mutations that augment transcription may contribute to neuropathogenesis of nef-deleted HIV-1.
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longitudinal analysis of nef long terminal repeat deleted HIV 1 in blood and cerebrospinal fluid of a long term survivor who developed HIV Associated Dementia
The Journal of Infectious Diseases, 2004Co-Authors: Melissa J Churchill, Daniel Cowley, John S Sullivan, Lachlan Robert Gray, Jasminka Sterjovski, Catherine Chatfield, Jennifer Learmont, Suzanne M. CroweAbstract:We studied the evolution and compartmentalization of nef/long terminal repeat (nef/LTR)-deleted human immunodeficiency virus type 1 (HIV-1) from a long-term survivor who developed HIV-Associated Dementia (HIVD). Analysis of sequential blood-derived HIV-1 isolated before and during HIVD revealed a persistent R5X4 phenotype and a progressive loss of nef/LTR sequence; in contrast, HIV-1 present in cerebrospinal fluid during HIVD had an R5 phenotype, distinct nef/LTR sequence of unique deletions and additional nuclear factor- kappa B sites and specificity factor-1 sites, and enhanced transcriptional activity, compared with the blood-derived isolates. Thus, nef/LTR-deleted HIV-1 strains may undergo compartmentalized evolution in long-term survivors and cause neurologic disease.