¡¡¡¡Once the immune system of HIVª²infected patients is weakened by either preª²existing or newly infected pathogens, such as bacteria, fungi, viruses, parasites, spirochetes, and mycobacteria, these pathogens can be reactivated and spread to the eye via the bloodstream, causing acute or chronic, serious or indistinctive, ocular diseases. CMV retinitis is still one of the most serious opportunistic infection in HIV/AIDS even in the HAART era. Some opportunistic infections, such as varicella zoster virus, toxoplasmosis, are more prevalent in the developing regions, which may arise from complicated ecological, racial, nutritional and socioeconomic factors which favor the viral transmission and reactivation in HIVª²infected patients. The common ocular opportunistic pathogens and sites of infection in HIV/AIDS patients were summarized in Table 3.
Cytomegalovirus  Coª²infection of cytomegalovirus (CMV), a herpes virus, is a major cause of morbidity and mortality of HIV/AIDS patients. The virus can be in a latent state in infected individuals, presumably for life. With immunodeficiency, dissemination and tissue destructive infection can occur. CMV causes a characteristic necrotizing retinitis with clinical symptoms of visual field defects, decreased visual acuity, retinal detachment, floaters and photophobia. CMV retinitis accounts for 75%ª²85% of cytomegalovirus disease and over 90% of blindness in AIDS patients[5]. It usually develops when the CD4+ cell counts fall below 50 cells/¦ÌL. HIV patients with a low CD4+ cells may have the same incidence of CMV as those in the preª²HAART era. Periodic examinations are recommended for those with CD4+ counts below 100 cells/¦ÌL, especially if CMVª²antibody positive. Some studies suggest that HIV RNA blood level is also an important predictor of CMV retinitis since HIV can transactivate CMV[6]. In the preª²HAART era, CMV retinitis is less common in Africa than in North America and Europe, which may be the cause that HIV patients died before the development of CMV retinitis in the poor regions[7]. AIDS patients often die of tuberculosis which appears at an early stage of HIV infection in developing regions. Nowadays, HAART has most significantly changed the incidence, progression and management of CMVR by decreasing the incidence of CMV retinitis by 75%ª²90%. However, CMV retinitis remains the most important issues in HIVª²patients with over 30% prevalence in some developing regions due to the unavailability of HAART.

¡¡¡¡Varicella Zoster Virus  Varicella zoster virus (VZV) is a common infection in humans. Once exposed to VZV, latency can persist throughout life. Reactivation of VZV in the trigeminal ganglion can result in herpes zoster ophthalmicus (HZO), which may be the initial manifestation of HIV infection. HZO affects 5%ª²15% of HIVª²positive patients[8]. Immunocompromised patients and older people are more prone to VZV reactivation[9]. Incidence of HZO is six times greater in HIV/AIDS patients than in healthy people. In Nigeria, herpetic eye disease constituted half of the ocular cases and there is strong association between HZO and HIV infection[10]. Studies found that over 60% patients with HZO are HIVª²positive in Nigeria[11,12]. The anterior presentations in AIDSª²associated HZO include, for example, conjunctivitis, scleritis, epithelial keratitis, stromal keratitis, uveitis, blepharitis, etc.[9] Treatment of HZO in AIDS patients usualª²ly starts with promptand aggressive intravenous antiviral treatment, followed by an oral maintenance regimen. However, when the infection continues and spreads to the posterior parts, necrotizing herpetic retinopathy (NHR) may occur. It is reported that 4%ª²17% of HIVª²positive individuals develop NHR after HZO. Acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN) are the two distinct forms of NHR. Usually the former occurs in those with only mild immune deficiency and elevated CD4+ counts, while the latter happens in those who are severely immunoª²suppressed. However, both forms have been identified simultaneously in an AIDS patient[13]. PORN has a rapid and progressive course leading to devastating vision loss, which, in most cases, is difficult to treat[14]. Intravitreal injection with combined antiviral drugs may be more effective in treating this aggressive disease and quantitative measurements of VZV DNA from aqueous humor appear helpful in the management of PORN[14]. Table 4  Comparison of three common ocular tumors in HIV/AIDS patients£¨ÂÔ£©Table 5  Ophthalmic findings with pediatric HIV infection in some countries which have conducted surveys in the HAART era£¨ÂÔ£©

¡¡¡¡Molluscum Contagiosum  Molluscum contagiosum (MC) virus is another opportunistic pathogen that can cause MC in HIVª²infected patients. MC is a contagious disorder that can occur in both pediatric and adult HIV/AIDS patients, but it is more prevalent in children in undeveloped areas. A crossª²sectional hospital based study in Uganda showed that over 10% of pediatric HIV patients had MC[15]. MC virus commonly infects the eyelid, and, rarely, the conjunctiva, corneal and limbus[16]. Symptoms include chronic follicular conjunctivitis, corneal micropannus and epithelial keratitis[17]. MC is suggested to be a sign of advanced AIDS and appears in advanced HIV infection when CD4+ counts are less than 80 cells/¦ÌL[18,19]. Eyelid lesion can be treated as the first manifestation of AIDS[20]. The disease is more aggressive in AIDS patients with immunosuppression, and there is usually multiple lesion involvement[17,21]. No drug is effective in treatment of MC. Traditional treatments, such as local excision, laser or cryotherapy, can be applied to MC in AIDS patients. If treatment is not prompt enough, severe complications will ensue. Nevertheless, the high recurrence may make the original treatment a failure[21,22].

¡¡¡¡Ocular Toxoplasmosis  Toxoplasma gondii is a common parasites infection in HIV/AIDS patients[23]. Ocular toxoplasmosis accounts for 1%ª²3% infection in AIDS patients. Single or multiple lesion of retinitis may affect both eyes with massive areas of retinal necrosis. Combination therapy of pyrimethamine with sulfadiazine and/or clindamycin is effective and lifelong maintenance treatment is necessary to prevent recurrence. System evaluation is suggested once the ocular toxoplasmosis is defined due to the high incidence of concomitant CNS toxoplasmosis[24].

¡¡¡¡Ocular Tuberculosis  Tuberculosis, a mycobacterial infection caused by Mycobacterium tuberculosis, has a higher incidence in AIDS patients than the general population, especially in developing region[25]. 46% of HIVª²positive patients in the developing world are coª²infected with tuberculosis and as many as 23% HIVª²tuberculosis coª²infection patients had disseminated ocular tuberculosis[25,26]. Ocular tuberculosis can occur even with very high CD4+ cell counts. Regular ocular examination for ocular tuberculosis is necessary in HIV infected cases in the developing regions despite the relative high CD4+ counts and prescription of HAART.

¡¡¡¡Fungi  Cryptococcosis is the most common fungal infection occurring in 5%ª²10% of all AIDS patients[27]. Lungs and CNS are the two most common sites for cryptococcus infection. The fungi causing ocular infection in HIVª²positive patients is believed to be the spread from the infected CNS. Cryptococcal encephalitis is one of the major causes of AIDS mortality. A Subª²Sahara African study show that in Zimbabwe, 45% of meningitis in adults is cryptococcal, and cryptococcal meningitis is the third leading cause of death in HIV patients in rural Uganda. In Rwanda, 9% of patients with cryptococcal meningitis developed visual loss and sixth nerve palsy[28]. In the eyes, cryptococcal encephalitis frequently presents as papilledema, multifocal choroiditis, visual loss, optic nerve irruption and optic atrophy[29]. Not only can HIV invade the nervous system, but HIVª²1 gp41 ectodomain also plays a role in enhancing Cryptococcus neoformans invasion of human brain microvascular endothelial cells[30]. Neverª²theless, patients can regain their visual function follow optimal therapy.

¡¡¡¡Bacteria  The differences in ocular bacterial flora between HIVª²infected subjects and healthy populations have been controversial. Although some studies have suggested no significant differences between the two[31,32]. Comerieª²Smith
et al[33] reported that even asymptomatic HIVª²positive patients had increased colony counts of bacterial flora in the lids. Candida albicans, Candida parapsilosis, Staphylococcus aureus, Pseudomonas aeruginosa, Capnocytophaga, alphaª²hemolytic streptococci, and Acanthamoeba have been isolated from infected corneas in patients with AIDS[34]. An adult AIDS patient with gonococcal infection developed keratoconjunctivitis. Preª²existing keratoconjunctivitis sicca and viral keratitis, microvascular abnormalities, which present epithelial leakage giving rise to bacterial entry, and crack cocaine usage, are the risk factors for bacterial ocular infection in HIV/AIDS patients. Since systemic antibiotics are ineffective to ocular flora in HIVª²infected patients[31], aggressive medication or surgical intervention should be considered once the diagnosis is made.

¡¡¡¡MICROVASULOPATHY

¡¡¡¡Microvasculopathy, also known as AIDS retinopathy, is the most common ocular complication, and it can affect 40%ª²60% of AIDS patients and HAART has greatly decrease its incidence[35]. Its frequency increases according to the stage of HIV progression. Notably, a decreasing CD4+ count correlates with the occurrence of HIVª²related retinopathy, especially in those with CD4+ counts less than 200 cells/mm[3,36]. It is a noninfectious microvascular disorder characterized by cottonª²wool spots, microaneurysms, retinal hemorrhages, telangiectatic vascular changes, and the presence of capillary nonperfusion[1]. Although commonly found in the retina, microvasculopathy may present in conjunctiva and optic disk. Because of the isolation of HIV from human retina and the detection of its antigen in retinal endothelial cells, it is believed that HIV infection of endothelial cells may contribute to this ocular abnormity. Microvascular abnormalities in those with HIVª²associated retinopathy include loss and degeneration of pericytes, swollen endothelial cells, thickened basement membranes, shrunken capillary lumina in retinal vessels and tubuloreticular structures, all of which are found in almost all HIVª²positive patients[36,37].
¡¡¡¡Reduced leukocyte density in macular capillaries, which may lead to retinal hypoxia, and increased polymorphonuclear leukocyte rigidity, which can cause microvascular damage by releasing proteases, toxic oxygen radicals, as well as influence microvascular blood flow, are commonly found in HIVª²positive patients[36,38]. Even without retinopathy or optic nerve disease, obvious thinning of the retinal nerve fiber layer is found in HIVª²positive patients[39,40]. Other factors, such as damage from immune complexes and hemorrhagic abnormalities, can also contribute to the vascular alterations. Both the structural proteins and the regulatory proteins of HIV itself play a role in the viral ocular infection. It has been reported that HIV gp120 can activate apoptosis in endothelial cells and change the function barrier of the microvascular endothelial cell monolayer by increasing vasopermeability[41].
¡¡¡¡Moreover, HIV Tat protein, a transcriptional activator of viral gene expression produced early after infection, exerts both proliferative and apoptotic effects on endothelial cells[41,42]. It has been shown in vitro to induce changes of the tight junction proteins in the retinal pigment epithelium (RPE), which is responsible for altering the bloodª²retinal barrier and subsequent HIV trafficking into the eyes[43,44]. Microvasculopathy is often asymptomatic and no treatment is involved in most cases[36,45]. However, it may be the initial cause of other ocular complications in HIVª²positive patients, such as CMV infection, retinal and optic nerve damage and various vision abnormalities, including abnormal color vision, reduced contrast sensitivity, and visual field abnormalities[46]. The severity of vascular damage correlates well with the multiple opportunistic infections in AIDS patients[47].

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