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T. Dianne Langford, PhD

Assistant Professor, Neuroscience

Assistant Professor, Neurovirology

Location: Room 750 MERB

Telephone:  215-707-5487

Fax:  215-707-4888

Email: tdl@temple.edu

Department of Neuroscience

Center for Neurovirology

PhD, Biological Sciences, University of Alabama, Tuscaloosa, AL, 1996

 

Postdoctoral Fellowship, University of California San Diego School of Medicine, La Jolla, CA, 2001

 

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A main goal of my research is to better understand signaling crosstalk strategies of cellular components of the blood-brain interface with HIV and antiretroviral medications used to treat infection.

Research Summary

Blood Brain Interface and HIV

As the first point of contact between blood-borne factors and the brain, cerebral endothelial cells of the blood-brain interface participate in dynamic signaling with other cells of the central nervous system (CNS) such as astrocytes, microglia, neurons and oligodendricytes. Maintaining proper communication among these cells is essential for neurocognitive functioning. As a barrier between the periphery and the CNS, cerebral endothelial cells communicate not only with other cells, but also with infectious pathogens, toxins and medications in the blood stream attempting to gain access into the brain. Because HIV infects the CNS and causes neurological disease ranging from dementia to mild cognitive impairment, treating CNS infection is important to successfully manage HIV infection. Combination antiretroviral therapy successfully treats systemic HIV infection in most infected individuals. However, due to poor penetration across the blood brain barrier, therapy only partially suppresses viral replication in the CNS (Langford et al., Journal of NeuroVirology 12: 100-107, 2006). Thus, while HIV is now a chronic and more manageable disease to treat, the increased prevalence of HIV-associated neurological complications illustrates the need for improved understanding of interactions among cellular components of the blood brain interface, circulating virus and antiretroviral medications.

Host and Viral Interaction
HIV proteins such as gp120 are toxic to cerebral endothelial cells of the blood brain interface. However, recent studies from my lab and others, have shown that host-derived growth factors such as fibroblast growth factor-2 (FGF2) that are produced by astrocytes, protect the cerebral endothelial cells from gp120-toxicity (Langford et al., 2005, BMC Neuroscience; Huang et al., 2000 J AIDS). Not only HIV-derived factors, but also medications used to treat infection can disrupt signaling and decrease cell fitness. For example, we have shown that treatment of cerebral endothelial cells with a commonly used HIV protease inhibitor, Indinavir, blocks the protective effects of FGF2 against gp120. Thus, upon viral rebound, the HIV patient adherent to a protease inhibitor-based antiretroviral treatment regimen may experience increased sensitivity to toxic HIV proteins such as gp120.

Host genetic background and viral genetic background play significant roles in the outcome of disease and response to treatment. For example, our studies have shown that patients with HIV who express high levels of FGF2 show less cerebral endothelial cell damage than those patients who produce lower levels of FGF2 (Langford et al., 2005, BMC Neuroscience). Over the past decade, our increased understanding of interactions among cells of the blood brain interface, HIV-1 and antiretroviral therapy has proven important to more effectively treat and manage NeuroAIDS. However, virtually all studies have focused on the B clade, or subtype, of HIV-1, while clade C is responsible for nearly half of the new HIV infections worldwide. Genetic diversity among clades of HIV-1 suggests that both disease progression and response to treatment may vary from clade to clade. In this regard, my laboratory addresses HIV-1 clade-specific signaling dysregulation of components of the blood brain interface and neurovascular dysfunction through collaborative research with the University of Addis Ababa School of Medicine, in Ethiopia, where HIV-1 clade C is dominant. These studies will describe the natural history of HIV in Ethiopia and will serve to characterize the neuropathogenesis of treatment naïve, HIV-1C+ patients and the frequency of CNS opportunistic infections including Cryptococcus, Toxoplasma and Mycobacterium tuberculosis. Of particular interest, unique immune system characteristics found only in the Ethiopian population may influence significantly their response to treatment.

In summary, my research focuses on increased understanding of signaling crosstalk strategies of cellular components of the blood-brain interface with HIV and antiretroviral medications used to treat infection in the setting of diverse host and viral genetic backgrounds.

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Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

17180161. Ellis R, Langford D, Masliah E, HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:1(33-44)2007 Jan

17060582. Chana G, Everall IP, Crews L, Langford D, Adame A, Grant I, Cherner M, Lazzaretto D, Heaton R, Ellis R, Masliah E, Cognitive deficits and degeneration of interneurons in HIV+ methamphetamine users. Neurology 67:8(1486-9)2006 Oct 24

16798671. Langford D, Marquie-Beck J, de Almeida S, Lazzaretto D, Letendre S, Grant I, McCutchan JA, Masliah E, Ellis RJ, Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients. J Neurovirol 12:2(100-7)2006 Apr

15960237. Tadesse T, Langford D, Manji K, Mehari E, Patterns of neuroAIDS in Africa. J Neurovirol 11 Suppl 1:(22-6)2005

15765804. Langford D, Grigorian A, Hurford R, Adame A, Crews L, Masliah E, The role of mitochondrial alterations in the combined toxic effects of human immunodeficiency virus Tat protein and methamphetamine on calbindin positive-neurons. J Neurovirol 10:6(327-37)2004 Dec

15689238. Langford D, Hurford R, Hashimoto M, Digicaylioglu M, Masliah E, Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120. BMC Neurosci 6:(8)2005 Feb 2

15579294. Masliah E, Roberts ES, Langford D, Everall I, Crews L, Adame A, Rockenstein E, Fox HS, Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis. J Neuroimmunol 157:1-2(163-75)2004 Dec

15535131. Langford D, Grigorian A, Hurford R, Adame A, Ellis RJ, Hansen L, Masliah E, Altered P-glycoprotein expression in AIDS patients with HIV encephalitis. J Neuropathol Exp Neurol 63:10(1038-47)2004 Oct

15081264. Carlson KA, Limoges J, Pohlman GD, Poluektova LY, Langford D, Masliah E, Ikezu T, Gendelman HE, OTK18 expression in brain mononuclear phagocytes parallels the severity of HIV-1 encephalitis. J Neuroimmunol 150:1-2(186-98)2004 May

14769347. Langford D, Masliah E, The emerging role of infectious pathogens in neurodegenerative diseases. Exp Neurol 184:2(553-5)2003 Dec

14657756. Langford D, Adame A, Grigorian A, Grant I, McCutchan JA, Ellis RJ, Marcotte TD, Masliah E, Patterns of selective neuronal damage in methamphetamine-user AIDS patients. J Acquir Immune Defic Syndr 34:5(467-74)2003 Dec 15

12498789. Everall IP, Bell C, Mallory M, Langford D, Adame A, Rockestein E, Masliah E, Lithium ameliorates HIV-gp120-mediated neurotoxicity. Mol Cell Neurosci 21:3(493-501)2002 Nov

12476355. Langford D, Masliah E, Role of trophic factors on neuroimmunity in neurodegenerative infectious diseases. J Neurovirol 8:6(625-38)2002 Dec

12238761. Chismar JD, Mondala T, Fox HS, Roberts E, Langford D, Masliah E, Salomon DR, Head SR, Analysis of result variability from high-density oligonucleotide arrays comparing same-species and cross-species hybridizations. Biotechniques 33:3(516-8, 520, 522 passim)2002 Sep

12095987. Hashimoto M, Sagara Y, Langford D, Everall IP, Mallory M, Everson A, Digicaylioglu M, Masliah E, Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway. Implications for neuroprotection. J Biol Chem 277:36(32985-91)2002 Sep 6

12044982. Langford D, Sanders VJ, Mallory M, Kaul M, Masliah E, Expression of stromal cell-derived factor 1alpha protein in HIV encephalitis. J Neuroimmunol 127:1-2(115-26)2002 Jun

11414473. Langford D, Masliah E, Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS. Brain Pathol 11:3(306-12)2001 Jul

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