Impact of HIV-1 and drugs of abuse on the blood brain barrier: The first line of investigation the laboratory focuses on is the impact of drugs of abuse, especially opioids, in combination with HIV-1, on blood brain barrier (BBB) structure and function. HIV-1 has demonstrated the ability to cause adverse neurological complications within a subpopulation of those infected with the virus. With the introduction of highly active antiretroviral therapy (HAART), survival rates associated with HIV-1 infection have improved. Although HAART therapy has increased survival, reduced viral loads, increased CD4 cell counts, and reduced opportunistic infections, one fact has not changed: HAND (HIV-associated neurocognitive disorder) is still a serious concern. Although the incidence of the most severe form of HAND, HIV-associated dementia (HAD), has decreased, the overall prevalence of HAND has not declined, potentially because patients with the more mild forms of HAND, including asymptomatic neurocognitive impairment and mild neurocognitive disorder are living longer with persistent impairment. Because of the more chronic nature of HIV/AIDS in the HAART era, the disease state is becoming more the result of a chronic inflammatory state induced by the production of both HIV-1 virions and viral proteins in the periphery and in the central nervous system (CNS). The development of HAND is dependent on passage of virus and virus-infected cells across the blood-brain barrier (BBB).
The integrity of the BBB is compromised by the actions of the HIV-1 virions, viral proteins, and host cytokines and chemokines from both sides of this barrier alone and in combination with drugs of abuse. This compromise results in disruption and dysregulation of the normal function of the BBB. Changes in BBB permeability following HIV-1 infection are likely the result of multiple intracellular and intercellular events involving several cell types in addition to both viral and host proteins. Cells actively infected with HIV-1 exhibit changes in cytokine expression, produce virions, and secrete viral proteins. Damage to the BBB allows increased cell migration from peripheral circulation, increasing the access of virus-infected cells, viral proteins, and free virus to the CNS. The laboratory currently is using in vitro BBB models to assess these alterations in structure and function to understand the full impact of HIV-1 and drugs of abuse on the BBB.
Figure 1 – Tipping point: A model of BBB dysregulation and loss of homeostasis.
A) During acute infection, an initial viral entry event into the CNS occurs. This is believed to be through entry of an infected cell of the monocyte-macrophage lineage. Throughout chronic infection, increased generation of or differentiation to a specific monocyte subset, CD14low/CD16+ that traffics preferentially to the BBB and constitutively secretes IL-1 and TNF-alpha is observed in patients with HIV. Once at the BBB, infected cells secrete IL-1, TNF-alpha, Tat, gp120 and other viral proteins causing altered TJ protein expression and localization and BMEC activation leading to increased passage across the BBB. Crosstalk between monocytes and BMECs in this inflammatory state leads to reciprocal activation of the two cell types, allowing for diapedesis of likely infected monocytes. Tat and gp120 are able to enter BMECs through adsorptive endocytosis, altering TJ regulation and delaying TJ closure, creating an opportunity for free virus and viral proteins to enter the CNS through non-specific passage mechanisms. In addition, gap formation has been observed under these conditions, however, the endothelium is able to repair. In the CNS, other cells including astrocytes, pericytes, and perivascular macrophages can be infected and will further secrete Tat, gp120, and proinflammatory cytokines leading to further BMEC activation. Additionally, astrocytes will express high levels of Nef, and secrete MCP-1/CCL2, IL-2, 6, and 8. This process greatly facilitates viral entry into the CNS. Additionally, Tat has been shown to be chemotactic for monocytes, bringing more monocytes to the site of infection. While homeostasis is strained, as long as the barrier is able to recover and repair balance can be restored. This state of enhanced passage may correlate with early HAND development.
B) After prolonged exposure to viral proteins, proinflammatory cytokines, and infectious virus, BBB dysregulation exceeds the threshold of what can be restored. Constant BMEC activation leads to greatly increased monocyte firm adhesion and diapedesis, further spreading infection throughout the CNS. High levels of Tat and gp120 entering BMECs, and altering TJ protein expression and stability, cause further delays in TJ closing, and there is more leakiness in passage. Gap formation is also enhanced, pushing repair mechanisms to a limit. Astrocyte death is also observed, often in cells neighboring those that are infected. Disturbance of the homeostasis between the periphery and the CNS, along with peaks in inflammatory cytokines, neurotoxic viral proteins, and infectious virions suggest a correlation with the onset of more severe neurocognitive symptoms.
HIV-1 genetic variation in clinical disease progression: The second line of investigation within the laboratory is focused on studying the impact of genetic variation and drugs of abuse on HIV-1 and SIV replication and pathogenesis. Studies in this line of investigation are focused on understanding if genetic variation that occurs throughout a patient’s course of disease can be utilized as a diagnostic or predictive marker of peripheral or neurologic disease progression. This study is being performed utilizing patients enrolled in a longitudinal study in the DrexelMed HIV/AIDS Genetic Analysis Cohort. These patients are recruited to this cohort from the HIV/AIDS clinic in the Division of Infectious Diseases and HIV Medicine and the Internal Medicine Clinic in the Department of Medicine at the College of Medicine. As these markers are identified, the laboratory then focuses on understanding the functional implications these variations may have on HIV-1 replication and pathogenesis. These studies have classically focused on the HIV-1 promoter or LTR but have expanded to the whole viral genome.
Selected Publications:
"Deployment of the HIV-1 protein arsenal: Combating the host to enhance viral transcription and providing targets for therapeutic development"
Dahiya S, Nonnemacher MR, and B Wigdahl
Journal of General Virology, 93(Pt 6): 1151-1172, 2012.
"Extracellular human immunodeficiency virus type 1 viral protein R causes a reduction in ATP and glutathione levels in an astrocytic cell line resulting in a compromised antioxidant reservoir"
Ferrucci A, Nonnemacher MR, Cohen EA, and B Wigdahl
Virus Research, 167(2): 358-369, 2012
PMCID: PMC3398186
"Impact of Tat genetic variation on HIV-1 disease"
Li L, Dahiya S, Kortagere S, Cunningham D, Pirrone V, Nonnemacher MR, and B Wigdahl
Advances in Virology, Volume 2012, Article ID 123605, 2012
PMCID: PMC3414192
"Impact of Substance Abuse and Hepatitis Virus Coinfection on HIV-1 Disease"
Parikh N, Nonnemacher MR, Pirrone V, Block T, Mehta A, and B Wigdahl
Current HIV Research, 10(7): 557-571, 2012
"Human immunodeficiency virus viral protein R as an extracellular protein in neuropathogenesis"
Ferrucci A, Nonnemacher MR, and B Wigdahl
Advances in Virus Research, 81: 165-199, 2011
"Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment"
Li L, Aiamkitsumrit B, Pirrone V, Nonnemacher MR, Wojno A, Passic S, Flaig K, Kilareski E, Blakey B, Ku J, Parikh N, Shah R, Martin-Garcia J, Moldover B, Servance L, Downie D, Lewis S, Jacobson JM, Kolson D, and B Wigdahl
Journal of Neurovirology, 17(1): 92-109, 2011
PMCID: PMC3057211
"Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway"
Banerjee A, Pirrone V, Wigdahl B, and MR Nonnemacher
Biomedicine and Pharmacotherapy, 65(4): 293-297, 2011
PMCID: PMC3150495
"Breaking Down the Barrier: The effects of HIV-1 on the Blood-Brain Barrier"
Strazza M, Pirrone V, Wigdahl B, and MR Nonnemacher
Brain Research, 1399: 96-115, 2011
PMCID: PMC3139430
"Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis"
Banerjee A, Strazza M, Wigdahl B, Pirrone V, Meucci O, and MR Nonnemacher
Journal of Neurovirology, 17(4): 291-302, 2011
"Cellular phenotype impacts human immunodeficiency virus type 1 viral protein R subcellular localization"
Ferrucci A, Nonnemacher MR, and B Wigdahl
Virology Journal, 8(1): 397, 2011
PMCID: PMC3168423
"Innate and Adaptive Factors Regulating Human Immunodeficiency Virus Type 1 Genomic Activation"
Shah S, Nonnemacher MR, Pirrone V, and B Wigdahl
J Neuroimmune Pharmacol, 5(3): 278-293, 2010
PMCID: PMC3057210
"Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency type 1 subtype C LTR"
Liu Y, Nonnemacher MR, Stauff DL, Li L, Banerjee A, Irish B, Kilareski E, Rajagopalan N, Suchitra JB, Khan ZK, Ranga U, and B Wigdahl
Biomedicine and Pharmacotherapy, 64(10): 672-680, 2010
PMCID: PMC2998390
"Mortality Among HIV-infected Patients in Resource Limited Settings: A Case Controlled Analysis of Inpatients at a Community Care Center"
Rajagopalan N, Suchitra JB, Shet A, Khan ZK, Martin-Garcia J, Nonnemacher MR, Jacobson JM, and B Wigdahl
American J. Infect. Disease, 5: 226-231, 2009
PMCID: PMC2831752
"Molecular Mechanisms of Neurodegenerative Diseases Induced by Human Retroviruses"
Irish BP, Khan ZK, Jain P, Nonnemacher MR, Pirrone V, Rahman S, Rajagopalan N, Suchitra JB, and B Wigdahl
American J. Infect. Disease, 5:238-265, 2009
PMCID: PMC2845477
"Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage"
Kilareski EM, Shah S, Nonnemacher MR, and B Wigdahl
Retrovirology, 6: 118-140, 2009
PMCID: PMC2805609 |