What are the principal opportunistic pathogens which cause infection in AIDS patients? Discuss the disease manifestations they cause. What does this group of pathogens and their manifestations tell us about the host defence mechanisms which are protective in the normal host? (Use 5 or 6 of the most important pathogens for the latter discussion, and compare this group of pathogens with the most common infections in non-compromised patients).

Outline:
•	Respiratory infections: PCP, CMV, tuberculosis
•	Gastrointestinal infections: diarrhea, candidiasis, oral ulcerations.
•	Skin infections: athlete’s foot, shingles.
•	Central nervous system infections: toxoplasmosis, meningitis, encephalopathy, progressive multifocal leukoencephalopathy.
•	Role of CD4 cells in host defense.
•	Pathogenesis of HIV.
•	Pathogenesis of common infections.

Suggested Answer:

	Opportunistic pathogens are incapable of causing disease in a healthy individual, but in AIDS patients whose immune system is depressed by HIV infection, they are able to cause a variety of disseminated severe systemic disorders. These infections are common in advanced stages of AIDS when the low CD4 T cell count impairs the immune system to such an extent that it is unable to mount an effective defense against these pathogens and is one of the contributing causes of the high morbidity and mortality associated with AIDS. 

	AIDS is characterized by an extreme degree of immunodeficiency, with low and decreasing CD4 counts, resulting in serious opportunistic infections in the respiratory, gastrointestinal and central nervous system. A respiratory infection often seen in AIDS patients, but almost unheard of in healthy persons is Pneumocystis carinii pneumonia (PCP). P. carinii is a protozoan parasite. PCP results in a progressive breathlessnessand usually a diffuse bilateral shadowing on chest-wall. There is little or no sputum production. Pneumocystis is detected by silver or immunofluorescent monoclonal antibody stain. Treatment is with co-trimoxazole or aerosolized pentamidine. Cytomegalovirus has been associated with a pneumonitis in HIV-positive patients. It is diagnosed by viral culture. Treatment with ganciclovir or foscarnet is of uncertain benefit. Another group of agents causing pulmonary infection in these patients is mycobacteria. ‘Atypical’ mycobacteria, particularly Mycobacterium avium-intracellulare, can be recovered from the lungs, blood, lymph nodes and faeces of patients with severely depressed CD4+ lymphocytes. These mycobacteria are usually resistant to conventional anti-tuberculous agents and require combinations of conventional and other agents. Mycobacterium tuberculosis infection is also more common in HIV-positive patients, because of reactivation of latent infection, and dose not require such severe depletion of CD4+ lymphocytes. Diagnosis and treatment follows a conventional approach, and a full course of chemotherapy may eradicate infection.

The gastrointestinal tract is another important site of infection in HIV-positive patients. Diarrhea lasting longer than 4 weeks, accompanied by weight loss of 10% body mass is regarded as an AIDS-defining illness. One of the common causes of HIV-related diarrhea is the sporozoan parasite Crytosporidium. The diarrhea is profuse and watery and can resemble that in cholera. Diagnosis is by microscopy of faeces treated with a modified version of the Ziehl-Neelsen stain. There is no effective antimicrobial chemotherapy. Other parasites, e.g. microsporidia and Isospora belli, bacteria such as Salmonella spp. and M. avium-intracellulare, and viruses including cytomegalovirus, may also cause diarrhea. Candidiasis is common in the esophagus and oral cavity, forming a distinct white plaque covering the mucosal surface, known as thrush. The presenting symptoms are dysphagia and retrosternal pain. Diagnosis is by microscopy of a potassium hydroxide or Gram-stained preparation of white plaque scraped from affected mucosa. Treatment is with an oral antifungal agent, e.g. nystain, miconazole. Infection by herpes simplex virus can lead to oral ulceration and esophagitis. 

The skin of HIV patients is prone to infection by dermatophytes and reactivation of viral infection. Therefore, severe athlete’s foot and shingles may be seen in these patients. 

Infections of the central nervous system and eyes occurs at a much higher incidence in HIV patients than in the general population due to invasion by opportunistic pathogens. The most common focal intracranial lesion in patients with HIV is caused by Toxoplasma gondii, a protozoan parasite that causes a mild influenza-like illness with lymphadenopathy in immunocompetent adults. In HIV-positive persons, infection is caused by reactivation and results in multiple abscesses in the brain. These can cause epileptic seizures and focal neurological signs. Diagnosis is supported by CT or MRI scans. Treatment is with sulphadiazine or pyrimethamine. The yeast Crytococcus neoformans causes meningitis in HIV-positive patients that can be diagnosed by examination of CSF. Microscopy of an Indian ink preparation, or latex agglutination can produce a rapid diagnosis. Treatment with amphotericin and flucytosine has been only moderately successful. Cytomegalovirus causes an encephalitis which can progress rapidly and a progressive haemorrhagic retinitis, which can permanently impair vision or cause total blindness. Treatment with both conditions is with ganciclovir or foscarnet. Progressive multifocal leukoencephalopathy is a type of demyelination disease seen in AIDS patients following reactivation with the human JC polymavirus. There is no treatment for this condition and death follows a few months after onset of symptoms. 

The host defence mechanisms that are protective in the normal host against this group of pathogens are humoral and cell-mediated immunity. The main immune system defect in AIDS patients is low CD4 T cell count which allows these opportunistic infections to proliferate uncontrollably. CD4 T cells perform the following helper functions: they help B cells develop into antibody-producing plasma cells; they help CD8 T cells to become cytotoxic T cells; and they help macrophages effect delayed hypersensitivity. Production of antibodies enhances opsonization and phagocytosis of infectious agents, such as viruses and bacteria. Phagocytosis of these agents by macrophages kills them intracellularly and prevent their spread throughout the body. Cytotoxic T cells eliminate host cells which have been infested by the pathogen and stems further cellular damage and pathogen growth within the body. With the loss of CD4 helper T cells, these protective immune mechanisms are greatly impaired. As such, opportunistic pathogens such as Pneumocystis carinii, Cytomegalovirus, Crytosporidium, Candida albicans, Mycobacterium avium-intracellulare, and the human JC polymavirus are able to grow and infect body tissues. For example, human JC polymavirus infection is a asymptomatic childhood infection prevalent in more than 90% of the population. In AIDS patients, the normal immune mechanisms that limits the activity of this virus are absent, which allows it to reactivates and cause a CNS disease never occurred in immunocompetent hosts. 

The high-affinity binding of the HIV envelope glycoprotein to the CD4 receptor is a crucial step in the pathogenesis of HIV, since the major cell expressing CD4 is the T4 lymphocyte (often a helper cell). The T4 cell plays a central role in all aspects of immune system function, so that death or impairment of this cell results in widespread immune dysfunction. There are several potential ways that HIV can damage T4 cells. HIV replication may kill T4 cells as a result of destruction of the cell membrane by viral proteins. The production of large quantities of viral genetic material and proteins may interfere with normal cell metabolism. HIV may also infect and destroy the progenitor cells that are responsible for the propagation of the lymphoid cell pool. In addition to direct cytopathicity, HIV infection may indirectly cause T4-cell death. One mechanism of indirect cell killing may involve autoimmune phenomena in which anti-HIV immune responses are targeted to uninfected T4 cells that either have free envelope protein bound to their membrane or present processed envelope antigens. In addition, since both the HIV envelope protein and the class II major histocompatibility complex antigens bind to the CD4 receptor, their common binding sites may represent cross-reacting antigens. Therefore, anti-HIV antibodies may react with uninfected T4 cells that express class II major histocompatibility complex molecules. Also, it is very likely that anti-HIV immune effectors kill many infected cells. HIV-infected individuals usually exhibit immune dysfunction prior to a depletion of their T4 cells. HIV may induce these functional abnormalities by a variety of pathways not necessarily involving a spreading infection of T4 cells. For example, by binding to the CD4 receptor, HIV or its envelope protein can interfere with the CD4-mediated monocyte-T-cell interactions that are necessary for antigen-specific responses. In addition, crosslinking of the CD4 molecules by the envelope protein may render the cell nonresponsive to subsequent antigenic stimulation. 

The common pathogens causing infections in the healthy hosts are able to do so not because of a decreased CD4 T cell count or impaired immune response, but due to subversion of the immune system by various microbial escape mechanisms. In the normal course of an infection, disease is followed by an adaptive immune response that clears the infection and establishes a state of protective immunity. However, some pathogens are able to avoid or subvert the normal immune response thereby enabling them to cause disease. The most common respiratory infections in a non-compromised patient are due to viruses such as influenza, respiratory syncytial virus, paramyxoviruses and adenoviruses, and certain bacteria like Haemophilius influenzae and Streptococcus pneumoniae. Many of these infectious agents exist in a wide variety of antigenic types so that a permanent lifelong immunity to the agent do not develop and the same pathogen can cause disease many times in the same individual. For example, point mutations in the genes encoding the surface antigens of the influenza virus enables it to re-infect the same individual again and again as antibodies cannot recognize the new mutant antigen. There are 84 antigenic types of Streptococcus pneumoniae, each type differs from the others in the structure of its polysaccharide capsule. 

Common gastrointestinal infections present in the non-compromised patient are often due to faecal-oral transmission under overcrowded and poor sanitary conditions or food poisoning. Rotaviruses and the enteroviruses are the main culprits of viral diarrheas while the enterobacteria E. coli, Proteus, Salmonella, Shigella and V. cholerae are responsible for bacterial-caused diarrheas. In these infections, the offending organisms exist within the body lumens or on its epithelial surfaces, free from protective antibodies, cytotoxic T cells and macrophages which are more widely found in the blood and tissues. Therefore, they are able to cause gastrointestinal infections by production of toxins or direct invasion of the epithelial lining. 

CNS infections in immunocompetent patients often arises as a rare complication of a primary infection established elsewhere in the body which spreads to the brain, usually via the bloodstream. Meningitis is the most common clinical manifestation and the main aetiological agents are echoviruses, coxsackieviruses and mumps virus.