The pathogenesis and molecular biology of Down’s syndrome are under intense study and advances ha... more The pathogenesis and molecular biology of Down’s syndrome are under intense study and advances have been made in the care of patients with Down’s syndrome. Patients with Down’s syndrome may exhibit cognitive impairment and developmental cognitive disorder; post-mortem brain tissue from patients who were older than 40 years may show senile plaques and neurofibrillary tangles as found in Alzheimer’s disease. Skeletal and soft tissue abnormalities appear as well. Particular patients may have only mild cognitive disability; however, some patients may exhibit psychiatric disorders including autism and major depression. Most often, Down’s syndrome is a noninherited chromosome disorder caused during meiosis by chromosome 21 nondisjunction. This leads to chromosome 21 trisomy. However, there is also an inherited form of Down’s syndrome that is due to translocation of a
From the start, Kurt Godel observed that computer and brain paradigms were considered on a par by... more From the start, Kurt Godel observed that computer and brain paradigms were considered on a par by researchers and that researchers had misunderstood his theorems. He hailed with displeasure that the brain transcends computers. In this brief article, we point out that Artificial Intelligence (AI) comprises multitudes of human-made methodologies, systems, and languages, and implemented with computer technology. These advances enhance development in the electron and quantum realms. In the biological realm, animal neurons function, also utilizing electron flow, and are products of evolution. Mirror neurons are an important paradigm in neuroscience research. Moreover, the paradigm shift proposed here-'hall of mirror neurons'-is a potentially further productive research tactic. These concepts further expand AI and brain research.
Great strides are being made in our understanding of the large sea of non-coding RNAs that are fo... more Great strides are being made in our understanding of the large sea of non-coding RNAs that are found within eukaryotic cells. Regulation of gene expression in cells is subject to microRNA (miRNA) in normal and neuropsychiatric diseases [1, 2]. Here we discuss the involvement of miRNAs in the neurological disease, Multiple Sclerosis (MS). Many physicians and scientists have worked on the problem of MS with a goal to find a cure since Jean-Martin Charcot discovered and characterized MS. We briefly mention a few researchers here who contributed to this field.
Journal of acquired immune deficiency syndromes, 1991
A major question in the pathogenesis of AIDS encephalopathy and dementia is whether HIV-1 directl... more A major question in the pathogenesis of AIDS encephalopathy and dementia is whether HIV-1 directly infects cells of the central nervous system (CNS). The propagation of HIV was attempted in six cell lines: three related and three unrelated to the nervous system. HIV was able to propagate in two human neuroblastoma cell lines and a lymphocytic cell line control but did not result in infections of African green monkey kidney cells, human cervix carcinoma cells, and one human brain astrocytoma cell line. Neuroblastoma cell lines infected with HIV showed peaks of reverse transcriptase activity at 10-14 days postinfection. After prolonged growth in cell cultures, one of the neuroblastoma cell lines showed multiphasic virus production, additional high peaks of reverse transcriptase activity, 20-fold greater than the first, lasting from 36 to 74 days and 110 to 140 days postinfection. The presence of HIV was confirmed by p24 antigen capture. The neuroblastoma cell lines had weak but detect...
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 1992
It is frequently important to identify the types of cells that are infected with human immunodefi... more It is frequently important to identify the types of cells that are infected with human immunodeficiency virus type-1 (HIV-1) in sections of formalin-fixed paraffin-embedded (FFPE) brain tissue. Currently, both immunocytochemical and in situ hybridization methods are used for this purpose. Combined in situ hybridization and immunocytochemistry results in simultaneous detection of HIV-1 nucleic acids and proteins and allow comparison of transcriptional and translational events of cells infected with HIV-1 in the same section. In addition, this technique allows morphologic and immunologic identification of the cells within which in situ hybridization occurs and confirmation of the identity of the cells that are not hybridized. Procedures are described for use with FFPE brain tissue.
Influenza A virus is a serious public health threat. Most recently the 2009/H1N1 pandemic virus h... more Influenza A virus is a serious public health threat. Most recently the 2009/H1N1 pandemic virus had an inherent ability to evade the host's immune surveillance through genetic drift, shift, and genomic reassortment. Immune characterization of 2009/H1N1 utilized monoclonal antibodies, neutralizing sera, and proteomics. Increased age may have provided some degree of immunity, but vaccines against seasonal influenza viruses seldom yield cross-reactive immunity, exemplified by 2009/H1N1. Nonetheless, about 33% of individuals, over the age of 60, had cross-reactive neutralizing antibodies against 2009/H1N1, whereas only 6-9% young adults had these antibodies. Children characteristically had no detectable immunity against 2009/H1N1. Taken together, these observations suggest some degree of immune transference with at least certain strains of virus that have afflicted the human population in past decades. Because internal influenza proteins may exhibit less antigenic variation, it is possible that prior exposure to diverse strains of influenza virus provide some immunity to novel strains, including the recent pandemic strain (swine-avian A/H1N1). Current trends in immunological studies-specifically the modulation of cellular immune surveillance provided by TH17 and Tregs-also support the need for additional proteomic research for characterizing novel translational evidence-based treatment interventions based on cytokine function to help defeat the virus. Timely and critical research must characterize the impact of genetics and epigenetics of oral and systemic host immune surveillance responses to influenza A virus. The continued development and application of proteomics and gene expression across viral strains and human tissues increases our ability to combat the spread of influenza epidemics and pandemics.
The human immunodeficiency virus type-1 (HIV-1) gp160 (gp120-gp41 complex) trimer envelope (ENV) ... more The human immunodeficiency virus type-1 (HIV-1) gp160 (gp120-gp41 complex) trimer envelope (ENV) protein is a potential vaccine candidate for HIV/AIDS. HIV-1 vaccine development has been problematic and charge polarity as well as sequence variation across clades may relate to the difficulties. Further obstacles are caused by sequence variation between blood and brain-derived sequences, since the brain is a separate compartment for HIV-1 infection. We utilize a threedimensional residue measure of solvent exposure, accessible surface area (ASA), which shows that major segments of gp120 and gp41 known structures are solvent exposed across clades. We demonstrate a large percent sequence polarity for solvent exposed residues in gp120 and gp41. The range of sequence polarity varies across clades, blood, and brain from different geographical locations. Regression analysis shows that blood and brain gp120 and gp41 percent sequence polarity range correlate with mean Shannon entropy. These results point to the use of protein modifications to enhance HIV-1 ENV vaccines across multiple clades, blood, and brain. It should be noted that we do not address the issue of protein glycosylation here; however, this is an important issue for vaccine design and development.
Cholera is a global disease that has persisted for millennia. The cholera toxin (CT) from Vibrio ... more Cholera is a global disease that has persisted for millennia. The cholera toxin (CT) from Vibrio cholerae is responsible for the clinical symptoms of cholera. This toxin is a hetero-hexamer (AB 5) complex consisting of a subunit A (CTA) with a pentamer (B 5) of subunit B (CTB). The importance of the AB 5 complex for pathogenesis is established for the wild type O1 serogroup using known structural and functional data. However, its role is not yet documented in other known serogroups harboring sequence level residue mutations. The sequences for the toxin from different serogroups are available in GenBank (release 177). Sequence analysis reveals mutations at several sequence positions in the toxin across serogroups. Therefore, it is of interest to locate the position of these mutations in the AB 5 structure to infer complex assembly for its functional role in different serogroups. We show that mutations in the CTA are at the solvent exposed regions of the AB 5 complex, whereas those in the CTB are at the CTB/CTB interface of the homo-pentamer complex. Thus, the role of mutations at the CTB/CTB interface for B 5 complex assembly is implied. It is observed that these mutations are often non-synonymous (e.g. polar to non-polar or vice versa). The formation of the AB 5 complex involves inter-subunit residue-residue interactions at the protein-protein interfaces. Hence, these mutations, at the structurally relevant positions, are of importance for the understanding of pathogenesis by several serogroups. This is also of significance in the improvement of recombinant CT protein complex analogs for vaccine design and their use against multiple serogroups.
The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-asso... more The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-associated dementia (HAD; also known as AIDS dementia and HIV encephalopathy). HAD is the most significant and devastating central nervous system (CNS) complications associated with HIV infection. Despite recent advances in our knowledge of the clinical features, pathogenesis, and neurobiological aspects of HAD, it remains a formidable scientific and therapeutic challenge. An understanding of the mechanisms of HIV neuroinvasion, CNS proliferation, and HAD pathogenesis provide a basis for the interpretation of the diagnostic features of HAD and its milder form, HIV-associated minor cognitive/motor disorder (MCMD). Current diagnostic strategies are associated with significant limitations, but it is hoped that the use of biomarkers may assist researchers and clinicians in predicting the onset of the disease process and in evaluating the effects of new therapies.
Background: Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive i... more Background: Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive impairment. While the cause remains unclear, recent gene expression studies have identified genes whose transcription is dysregulated in individuals with HIV-association neurocognitive disorder (HAND). However, the methods for interpretation of such data have lagged behind the technical advances allowing the decoding genetic material. Here, we employ systems biology methods novel to the field of NeuroAIDS to further interrogate extant transcriptome data derived from brains of HIV + patients in order to further elucidate the neuropathogenesis of HAND. Additionally, we compare these data to those derived from brains of individuals with Alzheimer's disease (AD) in order to identify common pathways of neuropathogenesis. Methods: In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV + cases, we first employed weighted gene co-expression network analysis (WGCNA) to further explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND without HIVE. We then used a symptomatic approach, employing standard expression analysis and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2, we identified common gene networks associated with NCI in both HIV and AD by correlating gene expression with pre-mortem neurocognitive functioning. Results: Study 1: WGCNA largely corroborated findings from standard differential gene expression analyses, but also identified possible meta-networks composed of multiple gene ontology categories and oligodendrocyte dysfunction. Differential expression analysis identified hub genes highly correlated with NCI, including genes implicated in gliosis, inflammation, and dopaminergic tone. Enrichment analysis identified gene ontology categories that varied across the three brain regions, the most notable being downregulation of genes involved in mitochondrial functioning. Finally, WGCNA identified dysregulated networks associated with NCI, including oligodendrocyte and mitochondrial functioning. Study 2: Common gene networks dysregulated in relation to NCI in AD and HIV included mitochondrial genes, whereas upregulation of various cancer-related genes was found.
The presence of HIV-1 in postmortem brain tissue from 31 patients with AIDS and 12 HIV-1-negative... more The presence of HIV-1 in postmortem brain tissue from 31 patients with AIDS and 12 HIV-1-negative controls was investigated. Most laboratories have access to the methods used. We readily applied in situ hybridization and immunohistochemistry to archival formalin-fixed paraffin-embedded (FFPE) brain specimens. The techniques used to detect HIV-1 were explant culture, in situ hybridization with 35S-labeled polymerase (pol) gene riboprobes and immunohistochemistry with monoclonal antibody to gp41. HIV-1 was isolated from explant cultures in 13 out of 20 (65%) patients, whereas HIV-1-infected cells were detected in FFPE brain tissue from nine out of 26 (35%) patients examined by in situ hybridization and in seven out of 26 (27%) patients examined by immunohistochemistry. Although the isolation technique was the most sensitive of the three techniques tested, infected cells may be identified with in situ hybridization in conjunction with immunohistochemistry.
Diagnosis, neurology, and neuroimaging HIV-1 invades the central nervous system (CNS) early and c... more Diagnosis, neurology, and neuroimaging HIV-1 invades the central nervous system (CNS) early and can cause persistent infection and inflammation. Although early infection is typically asymptomatic, cerebrospinal fluid (CSF) analysis and magnetic resonance spectroscopy (MRS) imaging can detect CNS abnormalities during this period [8-11]. Chronic HIV-1 infection can result in neurodegenerative disease, overall termed NeuroAIDS. The clinical expression of this process includes neurocognitive impairments such as decreased attention/concentration, psychomotor speed, memory, learning, information processing, and executive function. There is also motor slowing, incoordination, and tremor, that may progress to disabling weakness, spasticity, extrapyramidal movement disorders, and paraparesis [12,13]. In addition, there may be behavioral effects such as apathy and irritability. Psychomotor retardation (associated with damage to the frontal-striatal systems) also may occur [14,15]. The clinical severity of this process ranges from asymptomatic neurocognitive impairment (ANI), to a mild neurocognitive disorder (MND), to full-blown HIV-associated
Global Virology III: Virology in the 21st Century, 2019
This chapter attempts to encompass and tackle a large problem in Astrovirology and Astrobiology. ... more This chapter attempts to encompass and tackle a large problem in Astrovirology and Astrobiology. There is a huge anthropomorphic prejudice that although life is unlikely, the just-right Goldilocks terrestrial conditions mean that the just-right balance of minerals and basic small molecules inevitably result in life as we know it throughout our solar system, galaxy, and the rest of the universe. Moreover, when such conditions on planets such as ours may not be quite right for the origin of life, it is popularly opined that asteroids and comets magically produce life or at the very least, the important, if not crucial components of terrestrial life so that life then blooms, when their fragments cruise the solar system, stars, and galaxies, and plummet onto appropriately bedecked planets and moons. It is no longer extraordinary to detect extraterrestrial solar systems. Moreover, since extra-solar system space exploration has commenced, this provides the problem of detecting life with e...
Cholera, an acute diarrheal infection has become a major global threat. Vibrio cholerae the causa... more Cholera, an acute diarrheal infection has become a major global threat. Vibrio cholerae the causative agent of cholera has been responsible for six previous pandemics since 1817 that spanned four continents and Australia with the seventh pandemic ongoing since 1961. Two serogroups of V. cholerae O1 and O139 have the ability to secrete the enterotoxin with potential to cause epidemics. The prior six pandemics were caused by the classical biotype of the O1 serogroup. However, the emergence of the El Tor biotype and subsequent variants of El Tor with classical traits are the main isolates in the seventh pandemic. Cholera outbreaks have increased among vulnerable communities affected by war, earthquakes, conflicts and famines. Annually, 2.9 million cases of cholera occur globally in 69 endemic countries with 95,000 deaths. Early detection followed by prompt fluid and electrolyte replacement can reduce the case fatality ratio significantly. Improvements in water systems, sanitation and hygiene have effectively eliminated the transmission of cholera in high-income countries and reduced transmission in some developing nations. However, an estimated 1.8 billion are still at risk for cholera due to lack of potable water, inadequate sanitation and hygiene. Interventions focusing on hygiene in conjunction with proper disposal and treatment of sewage and provision of safe drinking water are likely to be effective in preventing the recurrence of cholera. Lastly, the use of current oral vaccines in endemic settings in combination with WASH interventions may be an effective approach to prevent and reduce the spread of cholera infection.
Events leading to and propagating neurocognitive impairment (NCI) in HIV-1-infected (HIV+) person... more Events leading to and propagating neurocognitive impairment (NCI) in HIV-1-infected (HIV+) persons are largely mediated by peripheral blood monocytes. We previously identified expression levels of individual genes and gene networks in peripheral blood monocytes that correlated with neurocognitive functioning in HIV+ adults. Here, we expand upon those findings by examining if gene expression data at baseline is predictive of change in neurocognitive functioning 2 years later. We also attempt to validate the original findings in a new sample of HIV+ patients and determine if the findings are HIV specific by including HIV-uninfected (HIV-) participants as a comparison group. At two time points, messenger RNA (mRNA) was isolated from the monocytes of 123 HIV+ and 60 HIV- adults enrolled in the Multicenter AIDS Cohort Study and analyzed with the Illumina HT-12 v4 Expression BeadChip. All participants received baseline and follow-up neurocognitive testing 2 years after mRNA analysis. Data...
Gene network analysis was performed based on published literature describing genes that are possi... more Gene network analysis was performed based on published literature describing genes that are possibly interconnected with cholera vaccine responses in vitro in cell culture and in vivo in human patient punch biopsies as well as DNA extracted from blood. These studies produced divergent results. The differences should be replicated and studied further. Included in such studies, patient ethnicities, states of stress, nutrition, and health, as well as the precise characteristics of the various cholera vaccines and modes of delivery need to be considered as well.
The pathogenesis and molecular biology of Down’s syndrome are under intense study and advances ha... more The pathogenesis and molecular biology of Down’s syndrome are under intense study and advances have been made in the care of patients with Down’s syndrome. Patients with Down’s syndrome may exhibit cognitive impairment and developmental cognitive disorder; post-mortem brain tissue from patients who were older than 40 years may show senile plaques and neurofibrillary tangles as found in Alzheimer’s disease. Skeletal and soft tissue abnormalities appear as well. Particular patients may have only mild cognitive disability; however, some patients may exhibit psychiatric disorders including autism and major depression. Most often, Down’s syndrome is a noninherited chromosome disorder caused during meiosis by chromosome 21 nondisjunction. This leads to chromosome 21 trisomy. However, there is also an inherited form of Down’s syndrome that is due to translocation of a
From the start, Kurt Godel observed that computer and brain paradigms were considered on a par by... more From the start, Kurt Godel observed that computer and brain paradigms were considered on a par by researchers and that researchers had misunderstood his theorems. He hailed with displeasure that the brain transcends computers. In this brief article, we point out that Artificial Intelligence (AI) comprises multitudes of human-made methodologies, systems, and languages, and implemented with computer technology. These advances enhance development in the electron and quantum realms. In the biological realm, animal neurons function, also utilizing electron flow, and are products of evolution. Mirror neurons are an important paradigm in neuroscience research. Moreover, the paradigm shift proposed here-'hall of mirror neurons'-is a potentially further productive research tactic. These concepts further expand AI and brain research.
Great strides are being made in our understanding of the large sea of non-coding RNAs that are fo... more Great strides are being made in our understanding of the large sea of non-coding RNAs that are found within eukaryotic cells. Regulation of gene expression in cells is subject to microRNA (miRNA) in normal and neuropsychiatric diseases [1, 2]. Here we discuss the involvement of miRNAs in the neurological disease, Multiple Sclerosis (MS). Many physicians and scientists have worked on the problem of MS with a goal to find a cure since Jean-Martin Charcot discovered and characterized MS. We briefly mention a few researchers here who contributed to this field.
Journal of acquired immune deficiency syndromes, 1991
A major question in the pathogenesis of AIDS encephalopathy and dementia is whether HIV-1 directl... more A major question in the pathogenesis of AIDS encephalopathy and dementia is whether HIV-1 directly infects cells of the central nervous system (CNS). The propagation of HIV was attempted in six cell lines: three related and three unrelated to the nervous system. HIV was able to propagate in two human neuroblastoma cell lines and a lymphocytic cell line control but did not result in infections of African green monkey kidney cells, human cervix carcinoma cells, and one human brain astrocytoma cell line. Neuroblastoma cell lines infected with HIV showed peaks of reverse transcriptase activity at 10-14 days postinfection. After prolonged growth in cell cultures, one of the neuroblastoma cell lines showed multiphasic virus production, additional high peaks of reverse transcriptase activity, 20-fold greater than the first, lasting from 36 to 74 days and 110 to 140 days postinfection. The presence of HIV was confirmed by p24 antigen capture. The neuroblastoma cell lines had weak but detect...
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 1992
It is frequently important to identify the types of cells that are infected with human immunodefi... more It is frequently important to identify the types of cells that are infected with human immunodeficiency virus type-1 (HIV-1) in sections of formalin-fixed paraffin-embedded (FFPE) brain tissue. Currently, both immunocytochemical and in situ hybridization methods are used for this purpose. Combined in situ hybridization and immunocytochemistry results in simultaneous detection of HIV-1 nucleic acids and proteins and allow comparison of transcriptional and translational events of cells infected with HIV-1 in the same section. In addition, this technique allows morphologic and immunologic identification of the cells within which in situ hybridization occurs and confirmation of the identity of the cells that are not hybridized. Procedures are described for use with FFPE brain tissue.
Influenza A virus is a serious public health threat. Most recently the 2009/H1N1 pandemic virus h... more Influenza A virus is a serious public health threat. Most recently the 2009/H1N1 pandemic virus had an inherent ability to evade the host's immune surveillance through genetic drift, shift, and genomic reassortment. Immune characterization of 2009/H1N1 utilized monoclonal antibodies, neutralizing sera, and proteomics. Increased age may have provided some degree of immunity, but vaccines against seasonal influenza viruses seldom yield cross-reactive immunity, exemplified by 2009/H1N1. Nonetheless, about 33% of individuals, over the age of 60, had cross-reactive neutralizing antibodies against 2009/H1N1, whereas only 6-9% young adults had these antibodies. Children characteristically had no detectable immunity against 2009/H1N1. Taken together, these observations suggest some degree of immune transference with at least certain strains of virus that have afflicted the human population in past decades. Because internal influenza proteins may exhibit less antigenic variation, it is possible that prior exposure to diverse strains of influenza virus provide some immunity to novel strains, including the recent pandemic strain (swine-avian A/H1N1). Current trends in immunological studies-specifically the modulation of cellular immune surveillance provided by TH17 and Tregs-also support the need for additional proteomic research for characterizing novel translational evidence-based treatment interventions based on cytokine function to help defeat the virus. Timely and critical research must characterize the impact of genetics and epigenetics of oral and systemic host immune surveillance responses to influenza A virus. The continued development and application of proteomics and gene expression across viral strains and human tissues increases our ability to combat the spread of influenza epidemics and pandemics.
The human immunodeficiency virus type-1 (HIV-1) gp160 (gp120-gp41 complex) trimer envelope (ENV) ... more The human immunodeficiency virus type-1 (HIV-1) gp160 (gp120-gp41 complex) trimer envelope (ENV) protein is a potential vaccine candidate for HIV/AIDS. HIV-1 vaccine development has been problematic and charge polarity as well as sequence variation across clades may relate to the difficulties. Further obstacles are caused by sequence variation between blood and brain-derived sequences, since the brain is a separate compartment for HIV-1 infection. We utilize a threedimensional residue measure of solvent exposure, accessible surface area (ASA), which shows that major segments of gp120 and gp41 known structures are solvent exposed across clades. We demonstrate a large percent sequence polarity for solvent exposed residues in gp120 and gp41. The range of sequence polarity varies across clades, blood, and brain from different geographical locations. Regression analysis shows that blood and brain gp120 and gp41 percent sequence polarity range correlate with mean Shannon entropy. These results point to the use of protein modifications to enhance HIV-1 ENV vaccines across multiple clades, blood, and brain. It should be noted that we do not address the issue of protein glycosylation here; however, this is an important issue for vaccine design and development.
Cholera is a global disease that has persisted for millennia. The cholera toxin (CT) from Vibrio ... more Cholera is a global disease that has persisted for millennia. The cholera toxin (CT) from Vibrio cholerae is responsible for the clinical symptoms of cholera. This toxin is a hetero-hexamer (AB 5) complex consisting of a subunit A (CTA) with a pentamer (B 5) of subunit B (CTB). The importance of the AB 5 complex for pathogenesis is established for the wild type O1 serogroup using known structural and functional data. However, its role is not yet documented in other known serogroups harboring sequence level residue mutations. The sequences for the toxin from different serogroups are available in GenBank (release 177). Sequence analysis reveals mutations at several sequence positions in the toxin across serogroups. Therefore, it is of interest to locate the position of these mutations in the AB 5 structure to infer complex assembly for its functional role in different serogroups. We show that mutations in the CTA are at the solvent exposed regions of the AB 5 complex, whereas those in the CTB are at the CTB/CTB interface of the homo-pentamer complex. Thus, the role of mutations at the CTB/CTB interface for B 5 complex assembly is implied. It is observed that these mutations are often non-synonymous (e.g. polar to non-polar or vice versa). The formation of the AB 5 complex involves inter-subunit residue-residue interactions at the protein-protein interfaces. Hence, these mutations, at the structurally relevant positions, are of importance for the understanding of pathogenesis by several serogroups. This is also of significance in the improvement of recombinant CT protein complex analogs for vaccine design and their use against multiple serogroups.
The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-asso... more The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-associated dementia (HAD; also known as AIDS dementia and HIV encephalopathy). HAD is the most significant and devastating central nervous system (CNS) complications associated with HIV infection. Despite recent advances in our knowledge of the clinical features, pathogenesis, and neurobiological aspects of HAD, it remains a formidable scientific and therapeutic challenge. An understanding of the mechanisms of HIV neuroinvasion, CNS proliferation, and HAD pathogenesis provide a basis for the interpretation of the diagnostic features of HAD and its milder form, HIV-associated minor cognitive/motor disorder (MCMD). Current diagnostic strategies are associated with significant limitations, but it is hoped that the use of biomarkers may assist researchers and clinicians in predicting the onset of the disease process and in evaluating the effects of new therapies.
Background: Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive i... more Background: Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive impairment. While the cause remains unclear, recent gene expression studies have identified genes whose transcription is dysregulated in individuals with HIV-association neurocognitive disorder (HAND). However, the methods for interpretation of such data have lagged behind the technical advances allowing the decoding genetic material. Here, we employ systems biology methods novel to the field of NeuroAIDS to further interrogate extant transcriptome data derived from brains of HIV + patients in order to further elucidate the neuropathogenesis of HAND. Additionally, we compare these data to those derived from brains of individuals with Alzheimer's disease (AD) in order to identify common pathways of neuropathogenesis. Methods: In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV + cases, we first employed weighted gene co-expression network analysis (WGCNA) to further explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND without HIVE. We then used a symptomatic approach, employing standard expression analysis and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2, we identified common gene networks associated with NCI in both HIV and AD by correlating gene expression with pre-mortem neurocognitive functioning. Results: Study 1: WGCNA largely corroborated findings from standard differential gene expression analyses, but also identified possible meta-networks composed of multiple gene ontology categories and oligodendrocyte dysfunction. Differential expression analysis identified hub genes highly correlated with NCI, including genes implicated in gliosis, inflammation, and dopaminergic tone. Enrichment analysis identified gene ontology categories that varied across the three brain regions, the most notable being downregulation of genes involved in mitochondrial functioning. Finally, WGCNA identified dysregulated networks associated with NCI, including oligodendrocyte and mitochondrial functioning. Study 2: Common gene networks dysregulated in relation to NCI in AD and HIV included mitochondrial genes, whereas upregulation of various cancer-related genes was found.
The presence of HIV-1 in postmortem brain tissue from 31 patients with AIDS and 12 HIV-1-negative... more The presence of HIV-1 in postmortem brain tissue from 31 patients with AIDS and 12 HIV-1-negative controls was investigated. Most laboratories have access to the methods used. We readily applied in situ hybridization and immunohistochemistry to archival formalin-fixed paraffin-embedded (FFPE) brain specimens. The techniques used to detect HIV-1 were explant culture, in situ hybridization with 35S-labeled polymerase (pol) gene riboprobes and immunohistochemistry with monoclonal antibody to gp41. HIV-1 was isolated from explant cultures in 13 out of 20 (65%) patients, whereas HIV-1-infected cells were detected in FFPE brain tissue from nine out of 26 (35%) patients examined by in situ hybridization and in seven out of 26 (27%) patients examined by immunohistochemistry. Although the isolation technique was the most sensitive of the three techniques tested, infected cells may be identified with in situ hybridization in conjunction with immunohistochemistry.
Diagnosis, neurology, and neuroimaging HIV-1 invades the central nervous system (CNS) early and c... more Diagnosis, neurology, and neuroimaging HIV-1 invades the central nervous system (CNS) early and can cause persistent infection and inflammation. Although early infection is typically asymptomatic, cerebrospinal fluid (CSF) analysis and magnetic resonance spectroscopy (MRS) imaging can detect CNS abnormalities during this period [8-11]. Chronic HIV-1 infection can result in neurodegenerative disease, overall termed NeuroAIDS. The clinical expression of this process includes neurocognitive impairments such as decreased attention/concentration, psychomotor speed, memory, learning, information processing, and executive function. There is also motor slowing, incoordination, and tremor, that may progress to disabling weakness, spasticity, extrapyramidal movement disorders, and paraparesis [12,13]. In addition, there may be behavioral effects such as apathy and irritability. Psychomotor retardation (associated with damage to the frontal-striatal systems) also may occur [14,15]. The clinical severity of this process ranges from asymptomatic neurocognitive impairment (ANI), to a mild neurocognitive disorder (MND), to full-blown HIV-associated
Global Virology III: Virology in the 21st Century, 2019
This chapter attempts to encompass and tackle a large problem in Astrovirology and Astrobiology. ... more This chapter attempts to encompass and tackle a large problem in Astrovirology and Astrobiology. There is a huge anthropomorphic prejudice that although life is unlikely, the just-right Goldilocks terrestrial conditions mean that the just-right balance of minerals and basic small molecules inevitably result in life as we know it throughout our solar system, galaxy, and the rest of the universe. Moreover, when such conditions on planets such as ours may not be quite right for the origin of life, it is popularly opined that asteroids and comets magically produce life or at the very least, the important, if not crucial components of terrestrial life so that life then blooms, when their fragments cruise the solar system, stars, and galaxies, and plummet onto appropriately bedecked planets and moons. It is no longer extraordinary to detect extraterrestrial solar systems. Moreover, since extra-solar system space exploration has commenced, this provides the problem of detecting life with e...
Cholera, an acute diarrheal infection has become a major global threat. Vibrio cholerae the causa... more Cholera, an acute diarrheal infection has become a major global threat. Vibrio cholerae the causative agent of cholera has been responsible for six previous pandemics since 1817 that spanned four continents and Australia with the seventh pandemic ongoing since 1961. Two serogroups of V. cholerae O1 and O139 have the ability to secrete the enterotoxin with potential to cause epidemics. The prior six pandemics were caused by the classical biotype of the O1 serogroup. However, the emergence of the El Tor biotype and subsequent variants of El Tor with classical traits are the main isolates in the seventh pandemic. Cholera outbreaks have increased among vulnerable communities affected by war, earthquakes, conflicts and famines. Annually, 2.9 million cases of cholera occur globally in 69 endemic countries with 95,000 deaths. Early detection followed by prompt fluid and electrolyte replacement can reduce the case fatality ratio significantly. Improvements in water systems, sanitation and hygiene have effectively eliminated the transmission of cholera in high-income countries and reduced transmission in some developing nations. However, an estimated 1.8 billion are still at risk for cholera due to lack of potable water, inadequate sanitation and hygiene. Interventions focusing on hygiene in conjunction with proper disposal and treatment of sewage and provision of safe drinking water are likely to be effective in preventing the recurrence of cholera. Lastly, the use of current oral vaccines in endemic settings in combination with WASH interventions may be an effective approach to prevent and reduce the spread of cholera infection.
Events leading to and propagating neurocognitive impairment (NCI) in HIV-1-infected (HIV+) person... more Events leading to and propagating neurocognitive impairment (NCI) in HIV-1-infected (HIV+) persons are largely mediated by peripheral blood monocytes. We previously identified expression levels of individual genes and gene networks in peripheral blood monocytes that correlated with neurocognitive functioning in HIV+ adults. Here, we expand upon those findings by examining if gene expression data at baseline is predictive of change in neurocognitive functioning 2 years later. We also attempt to validate the original findings in a new sample of HIV+ patients and determine if the findings are HIV specific by including HIV-uninfected (HIV-) participants as a comparison group. At two time points, messenger RNA (mRNA) was isolated from the monocytes of 123 HIV+ and 60 HIV- adults enrolled in the Multicenter AIDS Cohort Study and analyzed with the Illumina HT-12 v4 Expression BeadChip. All participants received baseline and follow-up neurocognitive testing 2 years after mRNA analysis. Data...
Gene network analysis was performed based on published literature describing genes that are possi... more Gene network analysis was performed based on published literature describing genes that are possibly interconnected with cholera vaccine responses in vitro in cell culture and in vivo in human patient punch biopsies as well as DNA extracted from blood. These studies produced divergent results. The differences should be replicated and studied further. Included in such studies, patient ethnicities, states of stress, nutrition, and health, as well as the precise characteristics of the various cholera vaccines and modes of delivery need to be considered as well.
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Papers by Paul Shapshak