HIV and the eye

Human immuno-deficiency virus (HIV) is the causal agent of acquired immuno-deficiency syndrome (AIDS), a disease that is characterised by immuno-suppression and atypical infection. The first cases of AIDS were reported in 1981. Five cases of Pneumocystis carinii pneumonia, an infection that is very rare in immuno-competent individuals, was found in HIV positive patients.1
HIV is a bloodborne infection and is transmitted by sexual intercourse, intravenous drug use, needle stick injuries in health professionals and vertically from mother to newborn child. The incidence of HIV is increasing at an alarming rate. It is thought that more than 40 million people are infected, the majority of whom live in sub-Saharan Africa.
HIV is an RNA virus, which replicates through a DNA copy of the viral RNA.2 It is possible to understand current treatment and future directions for new therapies through knowledge of the structure and life-cycle of the HIV virus.

HIV LIFE-CYCLE
The HIV virus is covered in a viral envelope, through which viral proteins are inserted (glycoproteins gp120 and gp41). Inside the envelope the viral core contains components necessary to continue the viral life-cycle. These include the enzymes reverse transcriptase and integrase, and viral RNA.
As with all viruses, HIV can only replicate in a cell. The first step in the life-cycle is to penetrate the cell surface membrane. The virus binds to the host cell through gp120 to the CD4 receptor principally found on T-lymphocytes and dendritic cells.3 The viral contents enter the cell, where viral RNA undergoes reverse transcription using the reverse transcriptase enzyme, creating a DNA copy of the RNA. This viral DNA is integrated into host DNA.4,5 The DNA then produces viral RNA, which is transcribed and cleaved to form functional viral proteins, which assemble into complete virions (virus particles). These complete virions bud through the host cell membrane - taking part of it with them, which forms the viral envelope. The binding proteins are inserted through the envelope, meaning the completed virions can infect other host cells.6
The repeated process of infecting cells displaying the CD4 receptor leads to the destruction of these cells, leading to immuno-suppression.

Diagnosis
HIV is diagnosed through the presence of anti-HIV IgG antibodies or the presence of HIV viral material in the blood.

CLINICAL FEATURES
The clinical features of HIV are due to the effects of the virus and the associated immune dysfunction. The range of symptoms occur due to immuno-suppression, meaning that there is a wide range of infections that can cause illness.
The disease incubates in an infected individual for two to four weeks. Sero-conversion of the infected individual occurs at six to eight weeks. In most this is a silent process; however, in some individuals they develop a sero-conversion illness, symptoms include fever, joint pain, tiredness and lethargy, lymphadenopathy (enlarged lymph nodes) and a sore throat.
There is a period of latency, where no evidence of infection is seen before HIV progresses to AIDS. Progression from HIV to AIDS can take 15 years. According to a European definition, a patient's condition transforms from HIV to AIDS when they suffer from an AIDS-defining condition. These include cytomegalovirus (outside the liver and spleen), CMV retinitis leading to blindness, Kaposi's sarcoma, (Figure 1) pneumocystis carinii pneumonia, recurrent pneumonia, tuberculosis, toxoplasmosis of the brain and lymphoma.
Another way of defining AIDS is a CD4 cell count of less than 200 cells/l. At levels below 200 cells/l the body is open to atypical infection.
As the patient becomes increasingly immunosuppressed and their CD4 count decreases they become susceptible to infection by less virulent organisms, for example, cryptosporidium. These infections are very difficult to treat successfully as the patient has such a limited immune response.
HIV/AIDS infection leads to a wide range of symptoms, signs and clinical conditions. The disease can affect the skin, brain, gut, kidneys, lungs and heart and eyes.
This review looks at the major ophthalmic complications.

HIV TREATMENT
The basis of current HIV treatment is a combination of drugs that inhibit the virus at different stages of the virus life-cycle. The drugs are combined to form HAART (highly active anti-retroviral therapy). A minimum of three drugs are given at different times of the day to prevent viral replication.
Two classes of drugs commonly used prevent reverse transcriptase from working. Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine, are structural analogues of nucleotides. These molecules are incorporated into the viral DNA and prevent its completion. The second class of drug is the non-nucleoside reverse transcriptase inhibitors (NNRTIs). These drugs prevent reverse transcriptase activity by binding to the enzyme, but are not structural nucleoside analogues. Recent in vitro research using styrylquinoline derivatives has shown that their action is twofold.7 They prevent the binding of viral DNA and the binding of target DNA.
Resistance to NRTIs and NNRTIs is a problem in HIV because reverse transcriptase has a high frequency of mistakes and variability, meaning that there is a high probability of generating a resistant virus, which is selected for by the suppression of virions susceptible to the therapy. This leaves the resistant virions untouched.
Another key class of drugs used are the protease inhibitors. These drugs prevent the viral proteins from being cleaved (cut) into pieces that form the mature virion. The virions remain immature and are not able to infect other cells in the human host. The HIV virus can develop resistance to protease inhibitors.
New drug treatments are focusing on two areas, the first is in simplifying drug regimes; and the second is looking at new drug targets. At the moment, drug regimes are complex and the drugs required have to be taken at specific times. New research is looking at the possibility of taking medication once a day. To achieve this more research is necessary to understand the interactions between the human body and the drugs.8
There are a number of new targets that have been identified. New drugs prevent the virus fusing to the host cell. The first fusion inhibitor (called Enfuvirtide) has been licensed.9 Initial trials of an anti-gp120 vaccine proved unsuccessful; the binding of the host cell to the virus is more complex than originally thought as the gp120 viral protein changes shape when it binds to the human host.10, 11
As new anti-viral targets are identified they allow a multi-targeted approach in treating the virus, reducing the likelihood of developing resistance.

HIV EYE DISEASE
The list of diseases that affect the eye in HIV include cytomegalovirus (CMV) retinitis, HIV-related retinopathy (Figure 2), maculopathy, ocular syphilis, ocular tuberculosis and drug reactions.

CMV retinitis
CMV retinitis occurs in advanced HIV disease (CD4 T cell count <50 cells/l). CMV is a herpes virus. It can be acquired congenitally or in adult life, such as through sexual transmission. The majority of clinical disease occurs through latent infection.
CMV retinitis initially presents as unilateral disease, but can disseminate causing bi-lateral disease. Peripheral retinitis can be asymptomatic; however, it can present with floaters, scotomata or as a peripheral visual field defect. Decreased visual acuity and central visual field defects occur when the lesions are more central or impinge on the macula. CMV lesions have characteristic areas known as focal necrotising retinitis; they appear as peri-vascular fluffy, yellow-white retinal infiltrates. These lesions can be granular in appearance and appear as 'crumbled cheese'. They may or may not have accompanying intra-retinal haemorrhages ('pizza appearance') and the surrounding blood vessels may have a sheathed appearance.12 In the absence of suitable treatment these lesions progress and the characteristic brushfire lesion can be seen, with a white, granular outer edge and an atrophic gliotic scar.13
If on slit-lamp examination vitreous cells are seen then careful examination of the retina should be carried out. To find the extent of the disease the eye should be fully dilated and examined using indirect ophthalmoscopy. If the lesions are seen then examination with a +90 dioptre lens gives information about the extent of the disease compared to fixed landmarks of the eye.14
If there is any suspicion of CMV retinitis there should be an urgent referral and urgent treatment is necessary with gancyclovir or foscarnet. CMV retinitis cannot be cured and any loss of vision cannot be restored. To diagnose the condition, the virus can be cultured from urine or blood or can be detected by polymerase chain reaction (PCR).
Before the development of HAART 30 per cent of HIV positive patients developed CMV retinitis. HAART has led to a 75 per cent reduction in incidence.15

HIV retinopathy
In patients with low numbers of CD4 cells, little micro-infarcts block the retinal capillaries. They are commonly seen in patients with pneumocystis carinii pneumonia, but can also be seen with other chest infections. The patient can have no symptoms or present with symptoms similar to CMV retinitis.
The multiple lesions are small, pale and found around the retinal blood vessels. Small haemorrhages can be seen around the lesions. These lesions appear as 'cotton-wool spots' at high magnification, the appearance is due to the swelling of retinal nerve fibres. These cotton-wool spots differ to those seen in diabetic eye disease, in that they are more 'boomerang shaped'(Figure 2).16
In retinopathy no vitreous cells are seen. This is important as retinopathy can co-exist with CMV retinitis. If asymptomatic signs of retinopathy appear the diagnosis of HIV should be considered.

Other eye infections
CMV retinitis is the most important and most common form of eye disease in HIV sufferers; however, other significant infections should be excluded if an infection is suspected.17
Herpes virus (either zoster or simplex) can cause retinal necrosis. Patients can present with blurred vision, eye pain, and photophobia. Small pale spots combine to form areas of deep necrosis in the retina. The diagnosis of acute retinal necrosis (ATN) or progressive outer retinal necrosis (PORN) needs to be excluded. This is achieved by aspirating vitreous and looking for viral DNA.
Candida endophthalmitis is an infection associated with intravenous drug abuse, particularly heroin. Systemic candida infection leads to eye infection. On examination the retina shows fluffy areas and shadows of fungal spores floating in the vitreous.
There is usually no associated haemorrhage. These lesions are non-specific and can be similar to diabetic or hypertensive lesions of the retina.
Toxoplasmosis in the choroid and retina is rare. It can be confused with viral retinitis.18 Most infections occur after infection of the central nervous system. Symptoms include pain, blurred vision and the onset of new floating spots. To diagnose cerebral infection a CT or MRI scan shows the characteristic ring lesions. The multiple retinal lesions are pale and dense. They enlarge and are associated with the presence of vitreous cells. There is no associated haemorrhage. In the immuno-suppressed patient there may not be a focal scar.
Lymphoma is rare in the eye. The reason it is necessary to exclude it from a differential diagnosis is because the treatment is significantly different. The lesions are deep and there are associated vitreous cells. No haemorrhage is seen. There may be other sites of disease including lymph nodes, liver and spleen.
Other problems associated with HIV and AIDS include tuberculosis (rare and associated with infection elsewhere in the body), allergic conjunctivitis, Kaposi's sarcoma of the conjunctiva or skin around the eye, syphilis, molluscum contagiosum, blepharitis, uveitis and the side-effects of HAART.

CONCLUSION
As HIV therapy and subsequent immune function have improved, conditions such as CMV retinitis are decreasing in incidence. However, other conditions are emerging such as accumulation of fluid at the macula (cystoid macular oedema).
The list of disorders that affect the eye in HIV infection is long because the patient lacks a competent immune system. This means that organisms not usually able to cause disease are now sufficiently virulent.
If signs of HIV infection are suspected the patient should be referred for an immediate ophthalmology opinion. They should also be referred to an HIV physician. It is important to remember that an immuno-suppressed individual may not mount an immune response to a secondary infection such as CMV retinitis, meaning that symptoms are an important part of diagnosis and urgent management is necessary.

Acknowledgement
The author wishes to thank Robert Petrarca for help with this article.
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Dr Iain Phillips is a house officer with a special interest in infectious diseases