IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

HIV INFECTION: IMMUNOPATHOGENESIS, IMMUNODIAGNOSTICS, IMMUNOTHERAPY

HIV infection. Immunopathogenesis

HIV infection is a disease caused by a retrovirus that affects the Cells of the human immune, nervous, and other systems and Organs. It is characterized by a prolonged, chronic, progressive course culminating in The Development of AIDS and associated opportunistic infections.

Etiology. HIV belongs to the lentivirus subfamily of the Retroviridae family. Two Types of the virus are known: HIV-1 and HIV-2. Both types have a similar Structure; however, they differ in the Molecular Weight of their Proteins and certain accessory genes.

Epidemiology. Since the initial Description of the first cases of HIV and AIDS and the identification of the virus in the early 1980s, the disease has assumed pandemic proportions. According to UNAIDS estimates, there were more than 40 million people living with HIV worldwide in 2008. HIV infection was first registered in Ukraine in 1987. Until 1994, the epidemic progressed at a low rate in the country, with the heterosexual route being the dominant mode of transmission. Between 1987 and 1994, 183 Ukrainian citizens were diagnosed with HIV. From 1995 to 1997, an explosive spread of HIV infection occurred among people who inject drugs across all regions of Ukraine.

Morphology of the Pathogen. A distinctive feature of Retroviruses is the presence of Reverse Transcriptase (RNA-dependent DNA polymerase or revertase) within their genome. The family derives its name from this enzyme (from the English retro - backward).

The mature viral particle is spherical, with a diameter of 100-120 nm. The virion consists of a core (nucleocapsid), surrounded by an outer membrane (supercapsid) and a matrix (the internal content). The core contains The Genome, internal proteins p7 and p9, and the Enzymes reverse transcriptase and endonuclease.

The nucleocapsid is cylindrical or conical in shape and is formed by proteins p18 and p24. The genome consists of two RNA strands bound to proteins p6 and p7. Protein p17 forms a layer (matrix) between the core and the outer envelope.

The outer membrane, or supercapsid, consists of a lipid bilayer studded with 72 glycoprotein spikes. Each spike contains a pair of gp41 and gp120 Glycoproteins (in a trimeric structure). The gp120 glycoproteins are located on the protruding part of the spike and interact with CD4 molecules on The Cell membrane.

MAIN MECHANISMS OF interaction between HIV and target cells. The life cycle of HIV (the period from the infection of a target cell to The production of infectious progeny virus) can be divided into the following stages:

✵ attachment of the virus to cell receptors: the HIV gp120 protein interacts with the CD4 receptor and CCR5/CXCR4 coreceptors;

✵ Conformational Changes in HIV surface proteins and membrane fusion;

✵ "uncoating": the viral RNA is released from the capsid and nucleocapsid proteins;

✵ reverse METABOLISM/31.html">Transcription of the viral RNA mediated by the HIV reverse transcriptase enzyme, resulting in a double-stranded DNA copy of the viral genome;

✵ migration (translocation) of the DNA into the Cell Nucleus;

✵ Integration of the DNA into the host cell's chromosomal DNA via the HIV integrase enzyme; the integrated DNA is referred to as the proviral DNA;

✵ transcription of the proviral DNA mediated by the cellular RNA polymerase enzyme;

✵ transport of HIV mRNA from The Nucleus to the Cytoplasm;

✵ synthesis of viral proteins using cellular machinery;

✵ transport of viral proteins to the assembly site, followed by packaging and assembly of new virions;

✵ budding and maturation of Viral Particles facilitated by the HIV protease enzyme.

Target cells. HIV exhibits a tropism for specific cell types, which is determined by the presence of receptors for the virus On the surface of target cells. Various structures (ligands) and carbohydrate components of proteins and Lipids can function as receptors.

Regardless of their biochemical structure, receptors share a common architectural feature: they consist of three domains — extracellular, transmembrane, and cytoplasmic.

In 1984, it was discovered that the CD4 molecule is the primary and essential receptor for both HIV-1 and HIV-2. Structurally, CD4 is a glycoprotein that shares Homology with certain regions of IMMUNOGLOBULINS. The viral protein gp120 exhibits similar homology, which determines its tropism. CD4 receptors are expressed on The surface of the following cells: CD4+ lymphocytes, CD8+ lymphocytes, dendritic cells, monocytes, eosinophils, megakaryocytes, Neurons, microglial cells, and spermatozoa.

Chemokines and their role in the Pathogenesis of HIV infection. The outer cell membrane may possess several receptors for various types of the virus, but a specific virus interacts strictly with a designated receptor.

Experimental studies have established that CD4 receptors alone are insufficient for viral entry into the cell. This led to the Conclusion that additional receptors, known as coreceptors, must exist.

Data published in 1996 demonstrated that individuals lacking the CCR5 receptor on their monocytes may be resistant to HIV infection. This particular receptor, acting in concert with CD4, determines the ability of HIV to attach to human cells and subsequently penetrate them, leading to cellular destruction and the development of immunodeficiency syndrome. The CCR5 receptor serves as a natural chemokine Ligand.

Chemokines are low-molecular-weight proteins produced primarily by inflammatory cells (such as lymphocytes, macrophages, granulocytes, and eosinophils) in response to stimulation by Antigens, mitogens, and other activators. They direct the targeted migration of cells bearing chemokine receptors, a phenomenon known as chemoattraction.

From a biological perspective, chemokines are proteins consisting of 68–120 Amino Acids. Based on the arrangement of their Cysteine residues, chemokines are classified into C-X-C (α-chemokines), C-C (β-chemokines), and C-chemokines. Chemokines share structural homology and are capable of binding to the same receptors.

Table 78 lists the receptors, their ligands, and the cells bearing these receptors (adapted from C.R. Machery).

Class="center">Table 78. Receptors, their ligands, and receptor-bearing cells

Note: MIP — macrophage inflammatory protein; MCP — monocyte chemoattractant protein; Eotaxin — eosinophil chemoattractant; GRO — neutrophil-activating protein, melanoma growth stimulatory activity; NAP — neutrophil-activating peptide; ENA — epithelial neutrophil-activating protein; IP-10 — interferon-γ-inducible protein 10; Mig — monokine induced by IFN-γ; SDF — stromal-derived factor.

The chemokine receptor CXCR4 mediates The entry of T-cell-tropic HIV strains, CCR2 of macrophage-tropic strains, CCR3 of eosinophil-tropic strains, and CCR5 of type 1 T-helper-tropic strains. Eotaxin interrupts the binding of the virus to the CCR3 receptor, highlighting the crucial role of the latter in the pathogenesis of HIV infection. Natural ligands (MIP-1α, β and RANTES) block macrophage-tropic HIV infection but do not affect Infections caused by T-cell-tropic viral strains.

Under physiological conditions, only the CCR5 and CXCR4 receptors are capable of recognizing HIV-1. Consequently, It is important to note that a genetic defect resulting in the absence of CCR5 almost entirely eliminates the possibility of HIV-1 infection.

Immunopathogenesis. Dendritic cells (including Langerhans cells, which are specialized cells of the Skin and mucous membranes) are among the first to encounter HIV in the mucosal Tissues. True to their function, they capture, process, and present the virus on their surface. Subsequently, they migrate to lymphoid tissue, where they present the antigen to T lymphocytes, thereby triggering their activation.

The HIV-1 envelope glycoprotein gp120 binds to CD4 and chemokine receptors, initiating a complex biological process of virus-cell interaction that culminates in the synthesis of a new generation of virions.

The virus and the target cell move into close proximity, after which the virus recognizes its specific receptors. A mandatory prerequisite is the presence of two receptors located in close spatial proximity to each other.

The CD4-binding domain of the gp120 envelope protein attaches to the CD4 receptor of the target cell. This step immediately triggers conformational changes, causing individual protein segments to alter their relative positions. As a result, a second domain of gp120, designed for coreceptor CCR5 binding, becomes exposed and accessible for interaction.

The next stage involves the interaction of CCR5 with the CCR5-binding region of gp120. Upon completion of this process, conformational changes in gp41 are initiated. The extramembrane region of gp41 contains two α-helices, HR 1 and HR 2, which sequentially begin to coil. Consequently, the gp41 molecule shortens significantly, drawing the viral and cellular membranes together. These conformational changes release energy that drives the fusion of the lipid bilayers. The fusion process involves 4–6 CCR5 molecules, numerous CD4 molecules, and 3–6 Env trimers.

Following membrane fusion, the viral envelope sheds its gp41 and gp120 proteins. The viral RNA, surrounded by nucleocapsid and capsid proteins, enters the cell, and the virion undergoes "uncoating." Weakened intermolecular bonds cause the viral shell to disintegrate. Under the action of MAP kinase, the matrix protein is phosphorylated.

Following uncoating, the Contents of the capsid—most importantly the RNA—are released into the Cell Cytoplasm, initiating reverse transcription of the viral RNA mediated by the enzyme reverse transcriptase.

In the cytoplasm, Genetic information from the viral RNA is transcribed into DNA with the help of reverse transcriptase (revertase).

The proviral DNA formed in the cytoplasm is transported into the cell nucleus as part of a nucleoprotein complex. The nuclear DNA is protected by a double-layered membrane, which acts as a barrier to most retroviruses. During mitosis, this membrane dissolves, making the nucleus accessible to viral genetic material.

A distinctive feature of HIV-1 is its ability to transport its DNA across an intact nuclear membrane, enabling the virus to infect non-dividing cells such as macrophages and microglial cells.

In the subsequent step, the proviral DNA integrates into the chromosomal apparatus of the host cell. The enzyme integrase removes two NUCLEOTIDES from each 3' end of the proviral molecule and cleaves the chromosomal DNA. Host DNA Repair enzymes remove the excess nucleotides at the 5' ends of the provirus, fill in the gaps, and, with the assistance of integrase, ligate the ends of the proviral and chromosomal DNA. Following integration, the proviral DNA serves as a template for transcription.

Transcription. The enzyme RNA polymerase uses the proviral DNA AS A template to synthesize messenger viral RNA (mRNA). The newly formed HIV-1 mRNA is transported from the nucleus to the cytoplasm. Prior to this, it must undergo a maturation or Processing phase within the nucleus. Final mRNA assembly occurs following The addition of an adenosine triphosphate sequence.

The mature mRNA is exported into the cell cytoplasm, where it performs two Functions: it serves as a template for Translation (Protein Synthesis) and is incorporated into new viral particles as the genomic RNA.

During translation, viral proteins are synthesized in exactly the same manner as cellular proteins.

The assembly of new viral particles occurs near The Plasma Membrane, after which they bud off from the cell surface.

B AND T lymphocytes are the primary effector cells of the antigen-specific Immune Response. Their function depends on dendritic cells. Antigen recognition by T lymphocytes is possible only after the preliminary processing and presentation of peptide antigen fragments by dendritic cells. From this moment, a cascade of immunopathological reactions is triggered, characterized by immune system dysfunction accompanied by the development of clinical symptoms.

Viral infection exerts a chronic inflammatory and stimulating effect on The Immune System. Damage to the immune system is both quantitative and qualitative: quantitative changes involve alterations in cell numbers, whereas qualitative changes involve impaired function of cellular subpopulations.

Mechanisms of T-lymphocyte depletion. A key factor in the pathogenesis of HIV infection is the reduction of the CD4+ lymphocyte population. The disappearance of CD4 lymphocytes from the bloodstream has a complex mechanism involving cell death, insufficient production of new lymphocytes, and redistribution of existing ones into lymphoid tissues. Destruction mechanisms associated with infected CD4+ T cells are termed direct, while the destruction of uninfected T-helper cells is grouped under THE CONCEPT OF "indirect mechanisms."

Only 1% of T cells die as a direct result of HIV-1 infection, while the remaining 99% perish due to other causes. One such cause is cell membrane damage occurring during the budding of viral particles.

As the virus replicates within the cytoplasm, viral proteins and Nucleic Acids accumulate. The newly formed virus relies entirely on the host cell, utilizing all its resources for its own development. The ultimate consequence of this is the accelerated depletion of the cell's nutrient reserves and energy supplies.

The interaction of HIV-1 gp120 with the membrane of CD4+ lymphocytes induces programmed cell death—apoptosis—in mature CD4+ lymphocytes or CD34+ hematopoietic progenitor cells, even without direct infection by the virus.

T-suppressor and NK cells lyse infected CD4+ lymphocytes along with the virus itself; this direct pathway is also referred to as cytotoxic.

As a result of membrane fusion, HIV-infected cells form clusters (containing up to 500 cells) known as syncytia. The Env protein, which exhibits an affinity for the CD4 receptor, is expressed on the cell surface and forms "bridges" between neighboring lymphocytes. Cell apposition is followed by their fusion. Cells incorporated into such a network become accessible to the virus, lose their functional activity, and may be destroyed by the Organism.

HIV-1 half-life—the time required for 50% of virions to enter cells, replicate, and infect a new target—is estimated by various researchers to range from half an hour to 1–2 days. This means that between 2,000 and 20,000 million new viral particles are produced daily in the body of an infected person.

More than 99% of viral particles are produced by CD4+ lymphocytes (approximately 2.6x109 cells daily), with macrophages accounting for the remainder. Infected T cells live for no more than 3 days, meaning that billions of new CD4+ lymphocytes must make up for the deficit at approximately the same rate. About 2% of these cells enter the Blood, while the rest populate Lymph Nodes AND other tissues. This process continues for a long time as long as the immune system is able to maintain a relative equilibrium between the destruction and synthesis of infected cells (lasting an average of 11 years). During the natural course of HIV infection, the count of CD4+ lymphocytes gradually decreases, whereas the concentration of HIV in the blood increases. At a certain stage, the immune system is no longer able to independently replenish its cells, leading to viral proliferation and the development of immunodeficiency.

Quantitative alterations in the cellular branch of Immunity are inevitably accompanied by qualitative impairments—specifically, a decline in the functional activity of T lymphocytes.

Cellular immune response. Depending on the secreted cytokines, T helpers are divided into two types. Type 1 T helpers predominantly produce interleukin-2 (IL-2) and interferon-alpha. These cytokines support the EFFECTOR FUNCTIONS OF the immune system (cytotoxic T lymphocytes, NK lymphocytes, and macrophages). Type 2 T helpers primarily produce IL-4, IL-5, IL-6, and IL-10, which activate the humoral response. T lymphocytes lose their ability to produce the T-cell growth factor IL-2; consequently, the differentiation of T cells into various functional subpopulations (CD4 and CD8) as well as NK cell activity is impaired.

IL-6 plays a major role in terminal B-Cell Differentiation into immunoglobulin-secreting cells. The viral envelope protein acts directly on CD4 T-cell clones, inducing the synthesis of IL-6 and enhancing its production. The reduction of the Type 1 T-helper subpopulation is accompanied by a decrease in the production of alpha- and gamma-interferon. In turn, the functional activity of NK lymphocytes is under the direct influence of such cytokines as IL-2 and gamma-interferon.

During the progression of HIV infection, not only are lymphocytes with the CD4+ phenotype affected, but the function of lymphocytes with the CD8+ phenotype (i.e., T suppressors) is also impaired. The viral protein p15 exerts a suppressive effect on the production of IL-2 and gamma-interferon by T cells.

Closely linked to IL-2 and other cytokines is the function of cytotoxic T lymphocytes, which are responsible for the body's antiviral and antitumor defense.

HUMORAL IMMUNE RESPONSE. HIV affects the functional activity of B lymphocytes, increasing immunoglobulin synthesis and especially IgG production. Despite the presence of the virus, the majority of Antibodies are non-specific (only about 5% of all immunoglobulins are specific), and they are produced in quantities vastly exceeding those of normal B cells. This hyperproduction of immunoglobulins intensifies as the infection progresses.

Monocytes and macrophages. Tissue macrophages in HIV-infected individuals frequently harbor the virus, and since they do not die from its effects, they can serve as a viral reservoir in the body. Macrophages exhibit reduced chemotaxis, diminished production of reactive oxygen species, and impaired antibacterial toxicity.

Thus, immune system damage in HIV infection is systemic in nature, manifesting as profound suppression of the T- and B-cell branches of cellular immunity. Along with the depletion of T lymphocytes, HIV-infected patients exhibit polyclonal activation of B lymphocytes with increased synthesis of immunoglobulins of all classes, particularly IgG and IgA, followed by the exhaustion of this compartment of the immune system. Dysregulation of immune processes is also manifested by elevated levels of alpha-interferon and alpha-2-macroglobulin, alongside a decreased level of IL-2.

As a result of immune dysfunction, when the CD4+ T-lymphocyte count drops to 400 cells per microliter of blood or lower, conditions arise for uncontrolled HIV Replication accompanied by a significant surge in virion numbers in various Body Fluids. Due to the impairment of multiple Components of the immune system, an HIV-infected person becomes defenseless against various infectious pathogens. Immune status deterioration clinically manifests as infectious, allergic, autoimmune, and lymphoproliferative syndromes, as well as immunodeficiency syndrome. All of these characterize the clinical picture of HIV infection.

Clinical presentation. The consequence of viral impact is the progressive suppression of immune function followed by the development of opportunistic infections (of viral, bacterial, fungal, or protozoal etiology). In its course, HIV infection passes through several stages characterized by distinct clinical manifestations and clear laboratory criteria.

Incubation period can range from 3 weeks to 3 months, and in some cases from 2 to 5 years or more from the moment of infection.

Acute infection stage is characterized by the development of a "mononucleosis-like" symptom complex. This is accompanied by a fever up to 38–38.5°C, signs of intoxication, pharyngitis, lymphadenopathy, hepatosplenomegaly, diarrhea (lasting more than 1 week), and a fine, non-pruritic skin rash (persisting from 1–2 weeks to 1–2 months). Meningeal signs may also occur.

Blood tests reveal a transient decrease in CD4+-lymphocyte levels and an increase in the CD8+-lymphocyte count.

The duration of this stage is 2–3 weeks, after which the disease transitions into one of two other stages: asymptomatic infection or persistent generalized lymphadenopathy (PGL). Relapses of the clinical manifestations of the acute stage are possible.

Asymptomatic carrier stage is registered in half of the patients and can last from 3 to 6 years. During this period, the patient has no Complaints, and clinical manifestations of the disease are absent. Antibodies to HIV antigens are detected in the patient's blood. Throughout this entire time, the individual remains a virus carrier and can be a source of infection.

Persistent generalized lymphadenopathy stage. At this stage of the disease, enlargement of the cervical, supraclavicular, axillary, cubital, and inguinal lymph nodes is observed. The glands reach 1-3 cm in diameter (rarer up to 4-5 cm), usually soft, though they can also be firm, tender upon Palpation, mobile, and not fused with surrounding tissues or each other.

This stage corresponds to the stress on the B-cell component of the immune system and is characterized by the accumulation of antibodies to HIV, as well as to all microbial antigens the HIV-infected person has ever encountered. A gradual decrease in the level of CD4+ lymphocytes is observed.

AIDS-related complex, besides lymphadenopathy, is characterized by prolonged Temperature elevations up to 38-39оС, sweating—especially at night, which may occur even without fever—prolonged diarrhea, progressive weight loss, weakness, malaise, and loss of appetite. Splenomegaly is observed, and neurological disorders develop, leading to memory loss and peripheral neuropathy.

Laboratory signs of the AIDS-related complex include: decreased level of CD4+ lymphocytes; lowered T-helper/T-suppressor ratio; anemia, leukopenia, thrombocytopenia, lymphopenia; elevated levels of IgA and IgG; increased circulating immune complexes (CIC); and skin allergy in delayed-type hypersensitivity reactions.

To establish a Diagnosis, two of the listed laboratory signs are sufficient.

AIDS leads to a complete failure of the immune response, resulting in severe opportunistic infections and aggressive blastomatous processes. The clinical picture depends on The Nature and localization of the associated diseases. These conditions are called AIDS-defining (indicator) diseases.

The first group comprises conditions characteristic only of severe immunodeficiency (CD4+ level below 200). A clinical diagnosis is made even in the absence of anti-HIV antibodies or HIV antigens.

The second group includes conditions that can develop both against the Background of severe immunodeficiency and, in A number of cases, without it. Therefore, laboratory confirmation of the diagnosis is necessary in these instances.

First group:

✵ candidiasis of the Esophagus, Trachea, and Bronchi;

✵ extrapulmonary cryptococcosis;

✵ cryptosporidiosis with diarrhea lasting more than 1 month;

✵ cytomegalovirus infections of various organs, excluding the Liver, Spleen, or lymph nodes, in a patient older than 1 month;

✵ Herpes simplex virus infection manifested by ulcers on the skin and mucous membranes persisting for more than 1 month, as well as Bronchitis, Pneumonia, or esophagitis of any duration affecting a patient older than 1 month;

✵ generalized Kaposi's Sarcoma in patients younger than 60 years;

✵ primary Brain lymphoma in patients younger than 60 years;

✵ lymphocytic interstitial pneumonia and/or pulmonary lymphoid Dysplasia in children under 12 years of age;

✵ disseminated infection caused by atypical mycobacteria (Mycobacterium avium-intracellulare complex) with extrapulmonary localization or localization (In addition to the Lungs) in the skin, cervical lymph nodes, or pulmonary hilum lymph nodes;

✵ Pneumocystis pneumonia;

✵ progressive multifocal leukoencephalopathy;

✵ cerebral Toxoplasmosis in a patient older than 1 month.

As an example of T-cell immune deficiency resulting from HIV infection, we present the medical history of patient K., 31 years old, admitted to the therapeutic department with a diagnosis of community-acquired right-sided middle-lobe pneumonia, clinical group 3. Stage I respiratory failure. Anamnesis: over the past 3 months, the patient experienced unmotivated body temperature rises up to 37.4 °C–38.1 °C, loose stools, night sweats, progressive weakness, and a 10 kg weight loss (Table 79).

Immunogram: low Hemoglobin and erythrocyte levels, high ESR, neutrophilic leukocytosis with a left shift in the leukocyte formula, basophilia, pronounced lymphopenia, Stage 3 endotoxicosis. Elevated Complement levels (CH50) and neutrophil phagocytic activity (phagocytic index, phagocytic number) with an insufficient functional reserve of the oxidation-reduction potential (NBT reserve). High levels of circulating immune complexes (CIC) and immunoglobulins of all studied classes.

Conclusion: anemia, profound quantitative and functional T-cell deficiency against the background of lymphopenia, signs of neutrophil activation and pronounced endogenous intoxication, elevated acute-phase protein levels. Rule out AIDS-related complex.

To confirm the patient's diagnosis, an enzyme-linked immunosorbent assay (ELISA) was performed, revealing antibodies to HIV-1, followed by an immunoblot assay, which confirmed HIV-1 infection. Sputum culture revealed Coccidioides immitis.

The patient was referred to the AIDS center for further monitoring and Treatment.

Table 79. Immunogram in AIDS-related complex

Second group:

✵ bacterial infections, concurrent or recurrent in children under 13 years of age (more than 2 episodes within a 2-year observation period): Sepsis, pneumonia, meningitis, bone or joint involvement, abscesses caused by Haemophilus influenzae or streptococci;

✵ disseminated coccidioidomycosis (extrapulmonary localization);

✵ HIV encephalopathy (HIV dementia, AIDS dementia);

✵ histoplasmosis with diarrhea persisting for more than 1 month;

✵ isosporiasis with diarrhea persisting for more than 1 month;

✵ Kaposi's sarcoma at any age;

✵ primary brain lymphoma in individuals of any age;

✵ other B-cell lymphomas (except Hodgkin's disease) or lymphomas of unknown immunophenotype:

- small-cell lymphomas (Burkitt-type lymphomas, etc.);

- immunoblastic sarcomas (immunoblastic, large-cell, diffuse histiocytic, and diffuse undifferentiated lymphomas);

✵ disseminated mycobacteriosis (non-tuberculous) involving sites other than the lungs, such as the skin, cervical, or hilar lymph nodes;

✵ Extrapulmonary tuberculosis (involving Internal Organs other than the lungs);

✵ recurrent salmonella septicemia;

✵ HIV wasting syndrome (emaciation, severe weight loss).

Classification of AIDS. According to the classification (Table 80), the diagnosis of AIDS

is established in individuals with a CD4+ lymphocyte count below 200 cells/μL of blood, even in the absence of AIDS-indicator conditions.

Category A includes asymptomatic HIV-seropositive individuals, persons with persistent generalized lymphadenopathy, and those with acute primary HIV infection.

Table 80. Classification of AIDS

Note: PGL - persistent generalized lymphadenopathy.

Category B includes various syndromes, The most significant of which are bacillary angiomatosis, oropharyngeal candidiasis, refractory recurrent vulvovaginal candidiasis, cervical dysplasia, cervical carcinoma, idiopathic thrombocytopenic purpura, Listeriosis, and peripheral neuropathy.

Secondary infections occurring in HIV-infected patients and blood CD4 T-cell counts are listed in Table 81 (Rich R. R., 2001).

Table 81. Secondary infections observed in HIV-infected patients