In the current era of potent antiretroviral therapy, patients with HIV are well known to develop both infectious (typically Cytomegalovirus Retinitis) as well as non-infectious (retinal microvascular occlusions most often seen as cotton wool spots) forms of retinopathy. There are over one million HIV positive individuals in the US and the disease disproportionately affects minorities. At the present time, non-infectious retinopathy is common and we have shown it is a cause of vision loss even in eyes without overt infectious retinitis. There is structural damage to the inner retina in HIV patients and that this correlates with vision loss and dysfunction. Infectious CMV retinitis is still a cause of severe vision loss due to resistant CMV retinitis in patients who are not responding well or who cannot reliably take HAART therapy. We will use novel methods to analyze retinal structure and function in HIV patients. We will use molecular genetic methods to determine the molecular pathogenesis of retinopathy and plan to use a novel drug delivery system to develop intravitreal therapies for or difficult to treat CMV retinitis. First, we will determine the prevalence and severity of visual dysfunction in HIV patients. We hypothesize that the cumulative effect of these lesions and other areas of retinal vessel damage seen in HIV patients cause widespread retinal damage accounting for the vision loss. We will determine the correlates between retinal structure and function and real world vision performance such as quality of life and driving simulation. Retinal damage will be assessed using novel eye tracking spectral domain OCT technology and microperimetric techniques. Multifocal electrophysiology will determine the level of the retina most involved. For our second aim, autopsy eye mRNA will be analyzed to determine which pathogenic pathways are active in damaged areas. In addition, histologic and morphometric methods will be used to determine the amount of retinal ganglion cell and nerve fiber layer damage and it's correlation with activated pathogenic pathways. Optic nerve degeneration and apoptosis in tissue will also be evaluated.
The third aim i s to develop an ultra long acting drug delivery system for treatment of resistant CMV retinitis. We have determined that certain derivatives of cidofovir and antiviral acyclic nucleoside phosphonates are highly active against HCMV in vitro even in cases of virus resistant to the usually used anti-CMV compounds. We will be using a novel lipid derivitization method to crystallize these drugs to allow prolonged release and dissolution in the eye. Toxicity and pharmacokinetics will be optimized and be tested in models of retinitis as a precursor to future clinical trials.

Public Health Relevance

Patients with HIV disease, even in the era of highly active antiretroviral therapy, develop vision loss from retinal disease. This grant seeks to determine the nature of vision loss and its relationship to systemic and neurological HIV disease and to determine the molecular basis of non infectious HIV retinopathy. In addition, we will be developing a new drug delivery system to treat resistant CMV retinitis which is the most common cause of infectious retinitis and vision loss in HIV patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007366-26
Application #
8448736
Study Section
Special Emphasis Panel (ZRG1-AARR-D (05))
Program Officer
Mckie, George Ann
Project Start
1987-12-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
26
Fiscal Year
2013
Total Cost
$638,882
Indirect Cost
$217,647
Name
University of California San Diego
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Barteselli, Giulio; Amini, Payam; Ezon, Isaac C et al. (2015) Impact on intraocular pressure after 20-mg decanted triamcinolone acetonide (kenalog) injection when using prophylactic antiglaucoma therapy. Retina 35:75-81
Arcinue, Cheryl A; Ma, Feiyan; Barteselli, Giulio et al. (2015) One-year outcomes of aflibercept in recurrent or persistent neovascular age-related macular degeneration. Am J Ophthalmol 159:426-36.e2
Barteselli, Giulio; Chhablani, Jay; Gomez, Maria Laura et al. (2014) Visual function assessment in simulated real-life situations in HIV-infected subjects. PLoS One 9:e97023
Barteselli, Giulio; Kozak, Igor; El-Emam, Sharif et al. (2014) 12-month results of the standardised combination therapy for diabetic macular oedema: intravitreal bevacizumab and navigated retinal photocoagulation. Br J Ophthalmol 98:1036-41
Barteselli, G; Gomez, M L; Doede, A L et al. (2014) Visual function assessment in simulated real-life situations in patients with age-related macular degeneration compared to normal subjects. Eye (Lond) 28:1231-8
Ma, Feiyan; Arcinue, Cheryl A; Barteselli, Giulio et al. (2014) Optical coherence tomography findings of the vitreoretinal interface in asymptomatic fellow eyes of patients with acute posterior vitreous detachment. Retina 34:447-54
Hartmann, Kathrin I; Schuster, Alexander K; Bartsch, Dirk-Uwe et al. (2014) Restoration of retinal layers after epiretinal membrane peeling. Retina 34:647-54
Ezon, Isaac C; Barteselli, Giulio; Rosenberg, Jay et al. (2014) Concurrent primary vitreoretinal and spinal cord lymphoma: a unique entity. JAMA Ophthalmol 132:902-4
Barteselli, Giulio; Bartsch, Dirk-Uwe; Freeman, William R (2013) Combined depth imaging using optical coherence tomography as a novel imaging technique to visualize vitreoretinal choroidal structures. Retina 33:247-8
Chhablani, Jay; Barteselli, Giulio; Bartsch, Dirk-Uwe et al. (2013) Influence of scanning density on macular choroidal volume measurement using spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 251:1303-9

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