Central Nervous System Infection
Introduction
Central nervous system (CNS) infections encompass a diverse group of conditions where pathogens invade and inflame the brain, spinal cord, and their surrounding membranes (meninges). These infections can be caused by viruses, bacteria, fungi, or parasites, leading to conditions such as meningitis, encephalitis, and myelitis. The CNS is a highly protected environment, making any infection within it a serious medical concern due to the vital functions it controls and its limited capacity for repair.
Biological Basis
The biological basis of CNS infections involves the complex interplay between invading pathogens and host defense mechanisms. Pathogens typically gain access to the CNS by breaching the blood-brain barrier, a highly selective semipermeable border that separates the circulating blood from the brain and extracellular fluid in the CNS. Once inside, pathogens can trigger an inflammatory response, leading to swelling, tissue damage, and disruption of normal neurological function. The specific mechanisms of infection and the host's immune response vary depending on the pathogen, influencing the severity and presentation of the disease.
Clinical Relevance
The clinical relevance of CNS infections is profound, as they can lead to a wide spectrum of symptoms ranging from fever, headache, and altered mental status to seizures, paralysis, and coma. Diagnosis often requires specialized procedures, such as lumbar puncture to analyze cerebrospinal fluid, and neuroimaging. Treatment typically involves targeted antimicrobial therapies, but challenges arise due to the difficulty of many drugs crossing the blood-brain barrier and the potential for rapid neurological deterioration. Even with effective treatment, many individuals experience long-term neurological sequelae, including cognitive impairment, motor deficits, and epilepsy.
Social Importance
The social importance of CNS infections is significant due to their potential for high mortality and morbidity, placing a substantial burden on public health systems and affected individuals and their families. They can lead to prolonged hospitalization, rehabilitation needs, and a reduced quality of life, impacting productivity and increasing healthcare costs. Research into host genetic factors influencing susceptibility, disease progression, and response to treatment is crucial for understanding and combating these diseases. Infectious and inflammatory diseases, including those affecting the CNS, have repeatedly shown strong genetic associations. [1] For instance, studies have investigated common genetic variants related to HIV-1 acquisition [2] host determinants of HIV-1 control [3] and loci associated with the rate of HIV-1 disease progression. [4] Additionally, genome-wide studies have explored associations and interactions with infections like maternal cytomegalovirus (CMV), suggesting links to neurological conditions. [5] Such genetic insights are vital for developing improved diagnostic tools, targeted therapies, and preventive strategies.
Population Homogeneity and Generalizability
Genetic association studies, including those relevant to central nervous system infection, frequently focus on populations of specific ancestries, often excluding individuals with significant non-European admixture . Similarly, the rs534913048 variant, located in proximity to HTR1D, which codes for a serotonin receptor involved in vasoconstriction and mood regulation, could influence serotonin signaling pathways critical for neuronal function and neuroinflammation. [5] Additionally, the rs146288131 variant in KIF26B, a kinesin motor protein vital for intracellular transport within neurons, might affect axonal integrity and the movement of essential cellular components, potentially exacerbating neuronal damage during CNS infectious processes. These genetic differences can collectively contribute to variations in cognitive function, mood disturbances, and overall neurological resilience observed in individuals facing CNS infections.
Beyond direct neuronal activity, genetic variants impacting systemic and localized immune responses are pivotal in determining the outcome of CNS infections. The rs78990680 variant within the GHR gene, encoding the Growth Hormone Receptor, could modulate growth hormone signaling, which has known immunomodulatory effects that are relevant to the body's overall defense against pathogens, including those affecting the CNS. [6] Another key player is GUCY1A2, associated with the rs577353618 variant, which is a subunit of soluble guanylate cyclase, an enzyme critical for the nitric oxide-cGMP signaling pathway involved in vascular tone, neurotransmission, and immune cell regulation. Alterations in this pathway could affect blood-brain barrier permeability and the inflammatory response within the CNS. [7] Furthermore, the rs139842311 variant, located near MFHAS1, a gene implicated in immune regulation and inflammatory responses, may influence the host's ability to mount an effective immune defense against invading pathogens in the brain and spinal cord, impacting both susceptibility and disease progression.
Finally, genetic variations affecting neural development, tissue repair, and barrier integrity are crucial for protecting the CNS from infection and mediating recovery. The rs540280981 variant, situated near SEMA3A, a gene that guides neuronal and axonal development and also regulates immune cell migration, could impact the brain's structural organization and its capacity for repair or immune cell trafficking in response to infection. [8] The rs539918358 variant near PTCH1, a receptor in the Hedgehog signaling pathway fundamental for neural stem cell maintenance and neurogenesis, might influence the brain's regenerative capacity following infectious damage. Moreover, elements of the extracellular matrix and tight junctions, such as TINAG (associated with rs187690747) and CLDN23 (part of the rs139842311 locus), are vital for maintaining the blood-brain barrier, which prevents pathogen entry. Variants in these genes, including the rs186305933 variant near the non-coding RNA LINC01945 which can regulate gene expression, could compromise this critical barrier, increasing vulnerability to CNS infections and influencing tissue integrity and repair mechanisms. [9]
Genetic Predisposition and Immune Regulation
Genetic factors play a significant role in an individual's susceptibility to central nervous system (CNS) infections by influencing host immune responses and pathogen control. Inherited variants in genes, particularly those involved in the immune system, can determine the efficacy of the body's defense mechanisms against invading pathogens . [1], [9] For instance, the major genetic determinants of HIV-1 control primarily affect HLA class I peptide presentation, highlighting the critical role of these genes in mounting an effective antiviral response. [1] Specific polymorphisms, such as those in the HLA region on chromosome 6, are significant determinants of immune response to pathogens like Epstein-Barr virus (EBV), affecting antibody titers and overall serostatus. [9]
Furthermore, polygenic risk, where multiple genetic variants collectively contribute to susceptibility, is evident in various infectious and inflammatory diseases, including those that can affect the CNS. [1] Common genetic variants have been associated with HIV-1 acquisition and control, indicating a broad genetic landscape influencing how individuals contract and manage infections. [2] Beyond infectious agents, genetic predispositions are also noted for conditions like glioma, a type of brain tumor, with specific susceptibility loci identified in regions like CDKN2B and RTEL1 [10] and a _ Pro→Ala_ change in TNIP1 along with HLA-B*08 for myasthenia gravis, an autoimmune disease that can affect neurological function. [11] These genetic underpinnings modulate the host's ability to recognize, clear, or tolerate pathogens, thereby impacting the risk and severity of CNS infections.
Environmental Pathogen Exposure
Environmental factors are direct and critical contributors to central nervous system infections, primarily through exposure to various pathogens. The presence and prevalence of infectious agents in a given environment dictate the likelihood of transmission and subsequent infection. [9] For instance, maternal cytomegalovirus (CMV) infection is an environmental exposure that has been investigated for its potential role in influencing the risk of neurological conditions in offspring, such as schizophrenia, suggesting a link between early life pathogen exposure and CNS health. [5]
The seroprevalence of viruses like Epstein-Barr virus (EBV) varies significantly by age and sex, reflecting differing patterns of environmental exposure over a lifetime. [9] While shared household environments might intuitively seem to be a major factor for pathogen transmission, studies have indicated that for highly prevalent pathogens like EBV, individuals can be infected from sources outside their immediate residence. [9] These environmental exposures, whether through direct contact, vectors, or vertical transmission, introduce the infectious agents that can ultimately invade and compromise the central nervous system.
Gene-Environment Interplay and Early Life Influences
The interaction between an individual's genetic makeup and environmental exposures represents a complex causal pathway for central nervous system infections. Genetic predispositions can significantly modify the impact of environmental triggers, leading to varied outcomes in disease susceptibility and progression. [5] For example, genome-wide studies have explored interactions between single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection, suggesting that specific genetic variants can influence the risk of conditions like schizophrenia in offspring when combined with this prenatal environmental exposure. [5]
These gene-environment interactions highlight how inherited genetic variants can either confer resilience or increase vulnerability to environmental insults, including early life pathogen exposures. Maternal infections, such as CMV, represent critical early life influences that can interact with the developing fetus's genetic background, potentially setting the stage for altered neurological development or increased susceptibility to future CNS challenges. The specific mechanisms often involve genetic modulation of immune responses or inflammatory pathways that are activated or altered by environmental pathogens, thereby shaping the long-term neurological health of an individual.
Host-Specific Modulators
Beyond primary genetic and environmental factors, several host-specific modulators can influence an individual's susceptibility to central nervous system infections. Age-related changes, for instance, are significant determinants of disease patterns, with seroprevalence of certain infections like Epstein-Barr virus (EBV) varying across different age groups. [9] These age-dependent variations can reflect cumulative exposure over time, changes in immune system effectiveness, or differences in lifestyle and environmental interactions at various life stages.
While the provided context does not explicitly detail comorbidities or medication effects directly pertaining to CNS infection, these factors are generally recognized to impact overall host health and immune competence. A weakened immune system due to existing medical conditions or immunosuppressive medications could theoretically increase vulnerability to CNS pathogens. Therefore, the physiological state of the host, influenced by intrinsic factors like age, alongside extrinsic medical conditions and treatments, can collectively alter the risk and trajectory of central nervous system infections.
The Central Nervous System as an Immunologically Distinct Environment
The central nervous system (CNS), encompassing the brain and spinal cord, presents a unique and challenging environment for infectious agents and the host's immune response. Despite its protective barriers, pathogens can breach these defenses, leading to severe and often long-lasting neurological consequences. For example, the human immunodeficiency virus type 1 (HIV-1) is known to infect macrophages within brain tissue, directly contributing to the development of conditions such as encephalopathy and dementia. [12] Even with the advent of highly active antiretroviral therapy (HAART), replication-competent HIV can persist within the CNS, highlighting its role as a sanctuary site that complicates pathogen eradication. [12] This persistence often results in chronic HIV-related CNS disease and neuroinflammation, which profoundly disrupts the delicate homeostatic balance essential for optimal neurological function. [12]
Molecular and Cellular Mechanisms of Pathogen-Host Interaction
At the molecular and cellular level, CNS infections involve intricate and often damaging interactions between pathogens and host cells. In the context of HIV-1, specific cellular responses are triggered, including the programmed cell death, or apoptosis, of both CD4+ and CD8+ T lymphocytes. [12] Macrophages, critical immune cells, mediate the apoptosis of CD4+ T cells through interactions involving biomolecules such as FasL and tumor necrosis factor, and they also facilitate CD8+ T cell apoptosis via the interaction of the viral protein HIV gp120 with the host's chemokine receptor CXCR4. [12] Moreover, the efficiency of HIV-1 replication within monocyte-derived macrophages can be influenced by specific genetic variations, such as a single nucleotide polymorphism found within the DYRK1A gene. [12] These molecular pathways illustrate how viral components and host receptors dictate the progression of infection and the resulting cellular damage within the CNS.
Genetic Determinants of Susceptibility and Disease Progression
An individual's genetic makeup significantly influences their susceptibility to CNS infections and the subsequent progression of the disease. A major genetic factor in controlling HIV-1, for instance, involves the human leukocyte antigen (HLA) class I genes, which are fundamental for presenting viral peptides to T cells, thereby initiating an effective immune response. [1] Specific HLA alleles, notably HLA-B*57 and HLA-B*27, have been consistently associated with a slower progression of HIV-1 infection, suggesting a protective role. [1] Beyond the HLA complex, other genetic variants, such as the CCR5 delta 32 allele, are linked to a natural resistance against HIV-1 acquisition, showcasing the diverse genetic landscape that modulates host defenses. [6] Genome-wide association studies have also identified specific genetic loci, such as one at 1q41, associated with the rate of HIV-1 disease progression to clinical AIDS, and have illuminated common genetic variations that influence overall HIV-1 acquisition and its control in human populations. [13] These genetic insights are crucial for understanding the varied outcomes observed in individuals exposed to CNS pathogens.
Pathophysiological Outcomes and Neurological Manifestations
Infections affecting the central nervous system can lead to a broad spectrum of severe pathophysiological outcomes and distinct neurological manifestations. The quantitative presence of HIV in the brain, for instance, directly correlates with the severity of dementia, indicating significant neurological damage. [12] This can manifest as HIV-related encephalopathy, a condition characterized by cognitive, motor, and behavioral impairments, primarily driven by the infection of brain macrophages. [12] The disruption of normal brain function is often compounded by chronic neuroinflammation, a persistent immune response that can continue even when systemic viral loads are effectively suppressed by antiretroviral therapy. [12] A comprehensive understanding of these disease mechanisms, from the initial stages of infection to the long-term neurological damage, is essential for developing effective therapeutic and preventive strategies against CNS infections.
Genetic Determinants of Host Response
Host genetic factors profoundly influence the susceptibility and progression of central nervous system infections. A major genetic determinant governing the host's ability to control HIV-1 infection is the HLA class I peptide presentation system, which is crucial for immune recognition and viral clearance. [1] These genetic variations establish an innate regulatory framework that modulates the host's vulnerability and the trajectory of the infection. Beyond HLA, common genetic variants identified through genome-wide association studies are associated with HIV-1 acquisition and the rate of progression to clinical AIDS, illustrating a systems-level integration of genetic predisposition with disease outcomes. [14]
Intracellular Regulation of Viral Replication
The intricate process of viral replication within host cells of the central nervous system, such as macrophages and monocytes, is governed by specific intracellular signaling pathways and regulatory mechanisms. For example, the NF-ATc (nuclear factor of activated T-cells, cytoplasmic) transcription factor plays a role in positively regulating HIV-1 replication and gene expression in T cells through specific signaling cascades. [12] In primary macrophages, CCAAT/enhancer binding protein (C/EBP) binding sites are essential for HIV-1 replication, as C/EBP proteins regulate proviral transcription by recruiting coactivators to the viral long-terminal repeat (LTR) region. [12] Furthermore, the dual-specificity tyrosine-phosphoryrated and -regulated kinase 1A (DYRK1A), a gene implicated in neurogenesis, has a single nucleotide polymorphism associated with HIV-1 replication in monocyte-derived macrophages, suggesting its involvement in post-translational regulation and modulation of the viral life cycle. [12]
Cellular Permissiveness and Disease Progression
Cellular permissiveness to viral infection is a critical factor determining the progression of central nervous system infections. For HIV-1, the processes of viral entry and subsequent transcription are key determinants influencing the susceptibility of CD4 T-cells to infection, representing a form of hierarchical regulation within the host-pathogen interaction. [12] Macrophages serve as a strategic reservoir for HIV-1, contributing to persistent infection within the CNS and posing a challenge for therapeutic strategies aimed at viral eradication. [12] The complex interplay between sustained viral replication in these cellular reservoirs and the host's immune response can lead to conditions such as HIV-related CNS disease and neuroinflammation, where the dysregulation of homeostatic pathways contributes to emergent pathological properties. [12]
Immune Presentation and Viral Control
Effective control of central nervous system infections relies significantly on the host's adaptive immune response, particularly the presentation of viral antigens. The major genetic determinants influencing HIV-1 control are closely linked to HLA class I peptide presentation, a process where host cells display fragments of viral proteins to cytotoxic T lymphocytes for recognition. [1] This antigen presentation serves as a crucial signaling mechanism, activating immune cells to identify and eliminate infected cells, thereby regulating viral load and influencing the rate of disease progression. [1] Compromised efficiency or dysregulation in HLA class I presentation can allow the virus to evade immune surveillance, representing a critical disease-relevant mechanism that could be targeted to enhance viral control.
Genetic Predisposition and Risk Stratification for HIV-1 Central Nervous System Involvement
Understanding the genetic factors that influence HIV-1 acquisition and control is crucial for identifying individuals at higher risk of developing central nervous system (CNS) complications. Research has identified common genetic variants associated with HIV-1 acquisition, offering insights into host susceptibility. [2] Furthermore, host genetic determinants, including those affecting HLA class I peptide presentation, are major factors in how effectively the body controls HIV-1 replication. [14] These genetic insights can inform risk stratification strategies, allowing for more personalized prevention and early intervention approaches for individuals with specific genetic profiles, particularly within diverse populations such as African Americans, where unique host determinants of HIV-1 control have been observed. [3]
Specific genetic variations, such as a single nucleotide polymorphism in DYRK1A, have been associated with the replication of HIV-1 in monocyte-derived macrophages. [12] Given that macrophages play a critical role in HIV-1 pathogenesis within the CNS, identifying such variants could help predict an individual's propensity for CNS viral reservoir establishment or inflammation. This knowledge enables clinicians to identify high-risk individuals who may benefit from intensified monitoring or tailored prophylactic measures, thereby moving towards personalized medicine approaches in managing potential HIV-1 CNS involvement.
Prognostic Indicators and Disease Progression in HIV-1 Central Nervous System Infection
Genetic factors serve as significant prognostic indicators for the progression of HIV-1 disease, which directly impacts the likelihood and severity of CNS infection. A specific locus at 1q41 has been identified as being associated with the rate of HIV-1 disease progression to clinical AIDS. [4] This genetic marker can help predict the speed at which the disease might advance, allowing for earlier and more aggressive therapeutic interventions to prevent or mitigate CNS manifestations, such as HIV-associated neurocognitive disorders or opportunistic CNS infections.
A critical prognostic challenge in HIV-1 CNS infection is the persistence of replication-competent HIV in the central nervous system, even in patients receiving long-term, effective highly active antiretroviral therapy. [12] This persistent viral presence highlights the CNS as a sanctuary site, influencing long-term outcomes and necessitating continuous monitoring strategies to detect early signs of neurological deterioration or viral rebound within the CNS. The identification of genetic determinants that influence overall HIV-1 control, such as HLA variants, further contributes to understanding individual variations in viral suppression and the potential for CNS viral persistence, guiding the prognostication of disease course and the need for specialized CNS-penetrating treatments. [14]
Guiding Therapeutic Strategies and Managing Neurological Complications
The understanding of genetic variants influencing HIV-1 control and the virus's presence in the CNS has profound implications for guiding therapeutic strategies and managing associated neurological complications. Genetic insights into how the host controls HIV-1, including HLA class I peptide presentation, can inform the selection and optimization of antiretroviral regimens, aiming to achieve better viral suppression and potentially reduce CNS viral load. [14] This personalized approach to treatment can be crucial, particularly when considering the challenge of eradicating HIV-1 from CNS reservoirs, which necessitates therapies with adequate CNS penetration and efficacy against latent virus. [12]
Beyond direct viral control, genetic factors also play a role in susceptibility to treatment-related neurological complications. For instance, genome-wide association studies have explored genetic links to peripheral neuropathy associated with D-drug-containing antiretroviral regimens. [15] Identifying individuals predisposed to such adverse drug reactions through genetic screening could enable clinicians to select alternative drug combinations, thereby preventing debilitating neurological side effects and improving overall patient quality of life. This integration of pharmacogenomics into HIV-1 management exemplifies a targeted approach to minimizing comorbidities and enhancing patient care.
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs571777981 | RAB3C | central nervous system infection |
| rs78990680 | GHR | central nervous system infection |
| rs534913048 | HTR1D - RPL29P6 | central nervous system infection |
| rs540280981 | RAD23BP2 - SEMA3A | central nervous system infection |
| rs577353618 | GUCY1A2 | central nervous system infection |
| rs187690747 | TINAG | central nervous system infection |
| rs186305933 | CDRT15P3 - LINC01945 | central nervous system infection |
| rs539918358 | PTCH1 - ERCC6L2-AS1 | central nervous system infection |
| rs146288131 | KIF26B | central nervous system infection |
| rs139842311 | CLDN23 - MFHAS1 | central nervous system infection |
Frequently Asked Questions About Central Nervous System Infection
These questions address the most important and specific aspects of central nervous system infection based on current genetic research.
1. Why did my friend get really sick from a bug I barely noticed?
Your genetic makeup can play a big role in how your body responds to infections, including those affecting the brain and spinal cord. Some people have genetic variations that make their immune system react more strongly or less effectively to a pathogen, leading to vastly different outcomes even from the same exposure. This can influence how severe your symptoms are and how quickly you recover.
2. Could my family history mean I'm more prone to serious infections?
Yes, there's evidence that genetic factors inherited from your family can influence your susceptibility to various infectious diseases, including those affecting the central nervous system. These genetic predispositions can affect how well your immune system identifies and fights off pathogens, potentially making you more vulnerable to severe illness. Understanding your family's health history can offer insights into your own potential risks.
3. Is there a special test to see if I'm at high risk for brain infections?
While general genetic tests for overall "high risk" of all brain infections aren't standard, research is actively exploring how specific genetic markers influence susceptibility. Such tests could potentially identify individuals who might respond differently to certain pathogens or treatments, guiding personalized preventive strategies or earlier interventions. However, widespread clinical application for CNS infections is still developing.
4. Does my ethnic background change my risk for these infections?
Yes, your ethnic background can influence your genetic risk for infectious diseases, including those affecting the central nervous system. Genetic variations that affect immune response can differ across various ancestral groups, meaning some populations might be more or less susceptible to certain pathogens or experience different disease progression. This highlights the need for diverse research to understand these differences.
5. Why do some people recover fully from CNS infections, but others don't?
How well someone recovers from a CNS infection can be influenced by their unique genetic makeup. Genetic factors can impact the severity of the initial inflammatory response, the extent of tissue damage, and even the body's capacity for repair. These differences can explain why some individuals experience long-term neurological problems while others make a full recovery.
6. Can eating healthy or exercising reduce my genetic risk for these?
While genetics play a significant role in susceptibility and disease progression, a healthy lifestyle can absolutely support your overall immune function. Eating well, regular exercise, and managing stress can help optimize your body's defenses, potentially mitigating some genetic predispositions and improving your resilience against infections, including those that might target the CNS.
7. If I get a CNS infection, will treatments work differently for me?
Your genetic profile can indeed influence how effectively your body responds to treatments for CNS infections. Genetic variations can affect how you metabolize drugs or how your immune system reacts to therapies. This is why researchers are studying genetic factors to help tailor treatments for better outcomes and reduced side effects in individuals.
8. Why are some kids more likely to get severe brain infections than others?
Just like adults, children have unique genetic makeups that influence their immune system's strength and response to pathogens. These inherited differences can explain why some children might be more susceptible to serious brain infections or experience more severe symptoms, while others exposed to the same pathogen might only have a mild illness.
9. Does getting enough sleep actually help my body fight these infections better?
Absolutely, adequate sleep is crucial for a robust immune system, which is your primary defense against infections, including those that could affect your central nervous system. While genetics influence your inherent susceptibility, maintaining healthy sleep patterns helps your body's immune cells function optimally, bolstering your ability to fight off pathogens.
10. My sibling and I are so different; does that explain infection risks?
Even siblings share only about half their genes, so it's common to have different genetic predispositions. These subtle genetic differences can lead to variations in immune system function, explaining why you and your sibling might have different susceptibilities to infections or respond differently if exposed to the same pathogen, including those affecting the CNS.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
[1] Pereyra F, et al. "The major genetic determinants of HIV-1 control affect HLA class I peptide presentation." Science, 2010.
[2] McLaren PJ et al. "Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls." PLoS Pathog. 2013.
[3] Pelak K et al. "Host determinants of HIV-1 control in African Americans." J Infect Dis. 2010.
[4] Herbeck JT et al. "Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS." J Infect Dis. 2010.
[5] Borglum, A. D. "Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci." Molecular Psychiatry, vol. 18, no. 5, 2013, pp. 591-600.
[6] Petrovski, S., et al. "Common human genetic variants and HIV-1 susceptibility: a genome-wide survey in a homogeneous African population." AIDS, 2010.
[7] Davila, S. "Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease." Nature Genetics, vol. 42, no. 9, 2010, pp. 772-776.
[8] Yang, T. H., et al. "Combinations of newly confirmed Glioma-Associated loci link regions on chromosomes 1 and 9 to increased disease risk." BMC Medical Genomics, vol. 4, 2011, p. 63.
[9] Rubicz, R et al. "A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1)." PLoS Genetics, 2013, 9.1: e1003211.
[10] Shete S et al. "Genome-wide association study identifies five susceptibility loci for glioma." Nat Genet. 2009.
[11] Gregersen PK. "Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08." Ann Neurol. 2012.
[12] Bol SM, et al. "Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages." PLoS One, 2011.
[13] Fellay, J et al. "Common genetic variation and the control of HIV-1 in humans." PLoS Genet, 2009.
[14] Fellay J, et al. "Common genetic variation and the control of HIV-1 in humans." PLoS Genet, 2010.
[15] Leger PD, et al. "Genome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS Clinical Trials Group protocol 384." J Neurovirol, 2014.