A degenerative retinal process in HIV-associated non-infectious retinopathy

HIV retinopathy is the most common non-infectious complication in the eyes of HIV-positive individuals. Oncotic lesions in the retinal nerve fiber layer, referred to as cotton wool spots (CWS), and intraretinal (IR) hemorrhages are frequently observed but are not unique to this pathology. HIV-positive patients have impaired color vision and contrast sensitivity, which worsens with age. Evidence of inner-retinal lesions and damage have been documented ophthalmoscopically, however their long term structural effect has not been investigated. It has been hypothesized that they may be partially responsible for loss of visual function and visual field. In this study we utilized clinical data, retinal imaging and transcriptomics approaches to comprehensively interrogate non-infectious HIV retinopathy. The methods employed encompassed clinical examinations, fundus photography, indirect ophthalmoscopy, Farmsworth-Munsell 100 hue discrimination testing and Illumina BeadChip analyses. Here we show that changes in the outer retina, specifically in the retinal pigment epithelium (RPE) and photoreceptor outer segments (POS) contribute to vision changes in non-infectious HIV retinopathy. We find that in HIV-positive retinae there is an induction of rhodopsin and other transcripts (including PDE6A, PDE6B, PDE6G, CNGA1, CNGB1, CRX, NRL) involved in visual transduction, as well as structural components of the rod photoreceptors (ABCA4 and ROM1). This is consistent with an increased rate of renewal of rod outer segments induced via increased phagocytosis by HIV-infected RPE previously reported in culture. Cone-specific transcripts (OPN1SW, OPN1LW, PDE6C, PDE6H and GRK7) are uniformly downregulated in HIV positive retina, likely due to a partial loss of cone photoreceptors. Active cotton wool spots and intraretinal hemorrhages (IRH) may not affect photoreceptors directly and the interaction of photoreceptors with the aging RPE may be the key to the progressive vision changes in HIV-positive patients

Accuracy of the Heidelberg Spectralis in the alignment between near-infrared image and tomographic scan in a model eye: a multicenter study.

PurposeTo evaluate temporal changes and predictors of accuracy in the alignment between simultaneous near-infrared image and optical coherence tomography (OCT) scan on the Heidelberg Spectralis using a model eye.DesignLaboratory investigation.MethodsAfter calibrating the device, 6 sites performed weekly testing of the alignment for 12 weeks using a model eye. The maximum error was compared with multiple variables to evaluate predictors of inaccurate alignment. Variables included the number of weekly scanned patients, total number of OCT scans and B-scans performed, room temperature and its variation, and working time of the scanning laser. A 4-week extension study was subsequently performed to analyze short-term changes in the alignment.ResultsThe average maximum error in the alignment was 15 ± 6 μm; the greatest error was 35 μm. The error increased significantly at week 1 (P = .01), specifically after the second imaging study (P < .05); reached a maximum after the eighth patient (P < .001); and then varied randomly over time. Predictors for inaccurate alignment were temperature variation and scans per patient (P < .001). For each 1 unit of increase in temperature variation, the estimated increase in maximum error was 1.26 μm. For the average number of scans per patient, each increase of 1 unit increased the error by 0.34 μm.ConclusionOverall, the accuracy of the Heidelberg Spectralis was excellent. The greatest error happened in the first week after calibration, and specifically after the second imaging study. To improve the accuracy, room temperature should be kept stable and unnecessary scans should be avoided. The alignment of the device does not need to be checked on a regular basis in the clinical setting, but it should be checked after every other patient for more precise research purposes

A degenerative retinal process in HIV-associated non-infectious retinopathy

HIV retinopathy is the most common non-infectious complication in the eyes of HIV-positive individuals. Oncotic lesions in the retinal nerve fiber layer, referred to as cotton wool spots (CWS), and intraretinal (IR) hemorrhages are frequently observed but are not unique to this pathology. HIV-positive patients have impaired color vision and contrast sensitivity, which worsens with age. Evidence of inner-retinal lesions and damage have been documented ophthalmoscopically, however their long term structural effect has not been investigated. It has been hypothesized that they may be partially responsible for loss of visual function and visual field. In this study we utilized clinical data, retinal imaging and transcriptomics approaches to comprehensively interrogate non-infectious HIV retinopathy. The methods employed encompassed clinical examinations, fundus photography, indirect ophthalmoscopy, Farmsworth-Munsell 100 hue discrimination testing and Illumina BeadChip analyses. Here we show that changes in the outer retina, specifically in the retinal pigment epithelium (RPE) and photoreceptor outer segments (POS) contribute to vision changes in non-infectious HIV retinopathy. We find that in HIV-positive retinae there is an induction of rhodopsin and other transcripts (including PDE6A, PDE6B, PDE6G, CNGA1, CNGB1, CRX, NRL) involved in visual transduction, as well as structural components of the rod photoreceptors (ABCA4 and ROM1). This is consistent with an increased rate of renewal of rod outer segments induced via increased phagocytosis by HIV-infected RPE previously reported in culture. Cone-specific transcripts (OPN1SW, OPN1LW, PDE6C, PDE6H and GRK7) are uniformly downregulated in HIV positive retina, likely due to a partial loss of cone photoreceptors. Active cotton wool spots and intraretinal hemorrhages (IRH) may not affect photoreceptors directly and the interaction of photoreceptors with the aging RPE may be the key to the progressive vision changes in HIV-positive patients

Abundance of transcript measured by qPCR (relative to a reference gene <i>GAPDH</i>) in retinae of HIV-negative and HIV-positive donors as function of time of death.

<p>Abundance of transcript measured by qPCR (relative to a reference gene <i>GAPDH</i>) in retinae of HIV-negative and HIV-positive donors as function of time of death.</p

Oncotic lesions (CWS) in the retinal nerve fiber layer were investigated.

<div><p>After resolution permanent damage remained to the inner retinal layer.</p> <p>A: Color photograph of the retina of an HIV-positive patient with non-infectious retinopathy. Cotton wool spots (arrow) are present along the retinal blood vessels.</p> <p>B: Infrared image of the same retina 18 years after resolution of the cotton wool spot with the arrow pointing to its previous location. The green line represents high-resolution spectral-domain optical coherence tomography (SD-OCT) sectioning through the ischemic spot co-localizing it to an adjacent B-scan.</p> <p>C: Adjacent B-scan showing all retinal layers. The hyper-reflective layer on the top is the nerve fiber layer, original location of the cotton wool spot, which shows thinning. There is a compensatory shift of outer retinal layers including the outer nuclear layer towards the inner retina (arrowhead).</p> <p>D: Farnsworth-Munsell diagram showing averaged data for all three groups of eyes. Each group - the group with high CD4, the group with low CD4, and the control group – was significantly different from every other group (p < 0.0001 in each comparison).</p></div

Example of the CWS microperimetric abnormality demonstrating long term-damage.

<div><p>Left Panel: Microperimetry examination overlaid on color fundus photograph, at the area of the previous cotton wool spot. An intraretinal hemorrhage is present superotemporal to the macula and a CWS is inferior to the optic nerve.</p> <p>Middle Panel: Enlarged image of microperimetry overlay showing sensitivity values in dB over the area of CWS shows decreased sensitivity (lower numbers in violet) over the area of previous cotton wool spot demonstrating long-term damage.</p> <p>Right Panel: Color photograph of the retina of the same eye with a dot hemorrhage superotemporal to the macula and fading cotton wool spot.</p></div

Interaction network of genes involved in visual perception using MetaCore™ knowledge base [48].

<p>The color reflects direction and size of regulation in HIV-positive retinae compared to HIV-negative controls. A link signifies interaction, a bullet is binding of protein products, an arrow means regulation of transcription or activation, and a hammer means inhibition or deactivation.</p