HIV and Antiretrovirals in the Central Nervous System: Molecular Mechanisms of Cognitive Impairment / Anna L Stern.

Format:

Book

Thesis/Dissertation

Author/Creator:

Stern, Anna L., author.

Contributor:

Jordan-Sciutto, Kelly L., degree supervisor.

Lynch, David, degree committee member.

Langford, Dianne, degree committee member.

Kolson, Dennis, degree committee member.

Grinspan, Judith, degree committee member.

University of Pennsylvania. Neuroscience, degree granting institution.

Language:

English

Subjects (All):

Neurosciences.

Virology.

Cellular biology.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Local Subjects:

Neurosciences.

Virology.

Cellular biology.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Genre:

Academic theses.

Physical Description:

1 online resource (182 pages)

Contained In:

Dissertation Abstracts International 79-01B(E).

Place of Publication:

[Philadelphia, Pennsylvania]: University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2017.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

HIV-associated neurocognitive disorder (HAND) describes a wide range of cognitive impairments experienced by up to 55% of HIV+ individuals despite viral suppression by combined antiretroviral therapy. Reasons for the persistence of this disease are unknown, but may be related to both the presence of HIV-infected macrophages in the central nervous system as well as neurotoxicity of antiretroviral drugs. In this thesis, we identified two independent mechanisms of HIV-associated and antiretroviral-associated toxicity that may each contribute distinctly to HAND neuropathogenesis. First, we showed that beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which may play a role in the onset and progression of Alzheimer's Disease, was both increased in HIV+ patient brains and required for HIV-associated neurotoxicity in vitro. The BACE1 cleavage target amyloid precursor protein (APP) also mediated toxicity and was required for neuroprotective effects of BACE1 inhibition. Second, we showed that two frontline treatment antiretroviral drugs have neurotoxic potential in vitro and that neurotoxicity of antiretrovirals is highly variable both across and within drug classes. Neurotoxicity of one drug, lopinavir, was mediated by oxidative stress. Taken together, these data indicate that HIV and antiretrovirals may contribute to HAND persistence and that both BACE1 inhibitors and drugs targeting oxidative stress may be effective as adjunctive therapeutics in HIV+ patients.

Notes:

Source: Dissertation Abstracts International, Volume: 79-01(E), Section: B.

Advisors: Kelly L. Jordan-Sciutto; Committee members: Judith Grinspan; Dennis Kolson; Dianne Langford; David Lynch.

Department: Neuroscience.

Ph.D. University of Pennsylvania 2017.

Local Notes:

School code: 0175

ISBN:

9780355182231

Access Restriction:

Restricted for use by site license.