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Acquired Immune Deficiency Syndrome (AIDS)

Acquired immunodeficiency describes a decrease in the immune response to immunogenic (antigenic) challenge as a consequence of numerous diseases or conditions that include acquired immunodeficiency syndrome (AIDS), chemotherapy, immunosuppressive drugs such as corticosteroids, psychological depression, burns, nonsteroidal antiinflammatory drugs, radiation, Alzheimer’s disease, celiac disease, sarcoidosis, lymphoproliferative disease, Waldenström’s macroglobulinemia, multiple myeloma, aplastic anemia, sickle cell disease, malnutrition, aging, neoplasia, diabetes mellitus, and numerous other conditions. AIDS (acquired immune deficiency syndrome) is a disease induced by the human immunodeficiency retrovirus designated HIV-1. Although first observed in homosexual men, the disease affects both males and females equally in central Africa and is beginning to affect an increasing number of heterosexuals with cases in both males and females in the Western countries in North America and Europe. Following exposure to the AIDS virus, the incubation period is variable and may extend to 11 years before clinical AIDS occurs in HIV-positive males in high-risk groups. It is transmitted by blood and body fluids, but is not transmitted through casual contact or through air, food, or other means. Besides homosexual and bisexual males, others at high risk include intravenous drug abusers, hemophiliacs, the offspring of HIV-infected mothers, and sexual partners of any HIV-infected individuals in the above groups. Acquired immune deficiency syndrome (AIDS) is a retroviral disease marked by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations. It is caused by the human immunodeficiency virus HIV-1, the causative agent for most cases worldwide with a few in western Africa attributable to HIV-2. Principal transmission routes include sexual contact, parenteral inoculation, and passage of the virus from infected mothers to their newborns. Although originally recognized in homosexual or bisexual men in the U.S., it is increasingly a heterosexual disease. It appears to have originated in Africa, where it is a heterosexual disease, and has been reported from more than 193 countries. The CD4 molecule on T lymphocytes serves as a high-affinity receptor for HIV. HIVgp120 must also bind to other cell surface molecules termed coreceptors for cell entry. They include CCR5 and CXCR4 receptors

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for β chemokines and α chemokines. Some HIV strains are macrophage-tropic whereas others are T cell-tropic. Early in the disease HIV colonizes the lymphoid organs. The striking decrease in CD4+ T cells is a hallmark of AIDS that accounts for the immunodeficiency late in the course of HIV infection, but qualitative defects in T lymphocytes can be discovered in HIV-infected persons who are asymptomatic. Infection of macrophages and monocytes is very important, and the dendritic cells in lymphoid tissues are the principal sites of HIV infection and persistence. In addition to the lymphoid system, the nervous system is the major target of HIV infection. It is widely accepted that HIV is carried to the brain by infected monocytes. The microglia in the brain are the principal cell type infected in that tissue. The natural history of HIV infection is divided in three phases that include (1) an early acute phase, (2) a middle chronic phase, and (3) a final crisis phase. Viremia, measured as HIV-1 RNA, is the best marker of HIV disease progression and it is valuable clinically in the management of HIV-infected patients. Clinically, HIV infection can range from a mild acute illness to a severe disease. The adult AIDS patient may present with fever, weight loss, diarrhea, generalized lymphadenopathy, multiple infections, neurologic disease, an in some cases secondary neoplasms. Opportunistic infections account for 80% of deaths in AIDS patients. Prominent among these is pneumonia caused by Pneumocystis carnii as well as other common pathogens. AIDS patients also have a high incidence of certain tumors, especially Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer in women. No effective vaccine has yet been developed. Acute AIDS syndrome: Within the first to the sixth week following HIV-1 infection, some subjects develop the flulike symptoms of sore throat, anorexia, nausea and vomiting, lymphadenopathy, maculopapular rash, wasting, and pain in the abdomen, among other symptoms. The total leukocyte count is slightly depressed with possible CD4 to CD8 ratio inversion. Detectable antibodies with specificity for HIV constituents gp120, gp160, p24, and p41 are not detectable until at least 6 months following infection. Approximately 33% of the infected subjects manifest the acute AIDS syndrome. AIDS serology: Three to six weeks after infection with HIV-1 there are high levels of HIV p24 antigen in the

plasma. One week to three months following infection there is an HIV-specific immune response resulting in the formation of antibodies against HIV envelope protein gp-120 and HIV core protein p24. HIV-specific cytotoxic T lymphocytes are also formed. The result of this adaptive immune response is a dramatic decline in viremia and a clinically asymptomatic phase lasting from 2 to 12 years. As CD4+ T cell numbers decrease, the patient becomes clinically symptomatic. HIV-specific antibodies and cytotoxic T lymphocytes decline, and p24 antigen increases. AIDS belt (Figure 19.1) refers to the geographic area across central Africa that describes a region where multiple cases of heterosexual AIDS, related to sexual promiscuity, was reported. Nations in this belt include Burundi, Central African Republic, Kenya, the Congo, Malawi, Rwanda, Tanzania, Uganda, and Zambia. Retrovirus (Figure 19.2 and Figure 19.3) is a reverse transcriptase-containing virus such as the human immunodeficiency virus and human T cell leukemia virus. An RNA virus that can insert and efficiently express its own genetic information in the host cell genome through transcription of its RNA into DNA, which is then integrated into the genome of host cells. Retroviruses are employed in research to deliberately insert foreign DNA into a cell.

FIGURE 19.1 AIDS belt.

FIGURE 19.3 Retroviral genome.

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Thus, they have the potential for use in gene therapy when a host cell gene is either missing or defective. Retroviruses have been used to tag tumor-infiltrating lymphocytes in experimental cancer treatment. Human immunodeficiency virus (HIV) (Figure 19.4) is the retrovirus that induces acquired immune deficiency syndrome (AIDS) and associated disorders. It was previously designated as HTLV-III, LAV, or ARV. It infects CD4+ T lymphocytes, mononuclear phagocytes carrying CD4 molecules on their surface, follicular dendritic cells, and Langerhans cells. It produces profound immunodeficiency affecting both humoral and cell-mediated immunity. There is a progressive decrease in CD4+ helper/inducer T lymphocytes until they are finally depleted in many patients. There may be polyclonal activation of B lymphocytes with elevated synthesis of immunoglobulins. The immune response to the virus is not protective and does not

FIGURE 19.2 Retrovirus.

receptors may predetermine susceptibility of hematopoietic subsets to HIV-1 infection. Certain cytokines can influence the dynamics of HIV-1 infection by altering chemokine receptor expression levels on hematopoietic cells. During chronic HIV-1 infection, proinflammatory cytokines such as TNF-α and IFN-γ are secreted in excess. IFN-γ increases cell surface expression of CCR-5 by human mononuclear phagocytes and of CXCR-4 by primary hematopoietic cells. In addition, GN-CSF can decrease and IL-10 can increase expression of CCR-5. Further research into cytokine-mediated regulation of chemokine receptors may lead to increased understanding of how these receptors affect the pathogenesis of AIDS. Fusin is a receptor present on CD4+ T lymphocytes and selected other human cells that is linked to a G protein and is believed to be requisite for HIV fusion with target cells. HTLV-IV is a human retrovirus isolated from western Africa that is related to HIV-1 and HIV-2, but appears nonpathogenic.

FIGURE 19.4 HIV. Electron micrograph. (Courtesy of Dr. Tom Folks, CDC, Atlanta, GA).

improve the patient’s condition. The virus is comprised of an envelope glycoprotein (gp160) which is its principal antigen. It has a gp120 external segment and a gp41 transmembrane segment. CD4 molecules on CD4+ lymphocytes and macrophages serve as receptors for gp120 of HIV. It has an inner core that contains RNA and is encircled by a lipid envelope. HIV contains structural genes designated env, gag, and pol that encode the envelope protein, core protein, and reverse transcriptase, respectively. HIV also possesses at least six additional genes: Gene tat, that regulate HIV replication. It can increase production of viral protein several thousand fold. Gene rev encodes proteins that block transcription of regulatory genes. Gene vif (sor) is the virus infectivity gene whose product increases viral infectivity and may promote cellto-cell transmission. Gene nef is a negative regulatory factor that encodes a product that blocks replication of the virus. Genes vpr (viral protein R) and vpu (viral protein U) have also been described. No successful vaccine has yet been developed, although several types are under investigation.

HALV (human AIDS-lymphotropic virus) (historical): Human AIDS-lymphotrophic virus. A designation proposed to replace Montagnier’s LAV designation and Gallo’s HTLV-III designation for the AIDS virus. However, the designation HIV for human immunodeficiency virus was subsequently chosen instead. HIV infection: (Figure 19.5) The recognition of infection by the human immunodeficiency virus (HIV) is through seroconversion. Following conversion to positive reactivity in an antibody screening test, a Western blot analysis is performed to confirm the result of positive testing for HIV. HIV mainly affects the immune system and the brain. It affects primarily the CD4+ lymphocytes which are necessary to initiate an immune response by interaction with

AIDS virus: See human immunodeficiency virus (HIV). Cytokine upregulation of HIV coreceptors: HIV-1 virus strains use the chemokine receptors CCR-5, CXCR-4, or both, to enter cells. Expression of these chemokine

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FIGURE 19.5 HIV infection.

antigen-presenting cells. This also deprives other cells of the immune system from receiving a supply of interleukin2 through CD4+ lymphocyte stimulation, leading to a progressive decline in immune system function. HIV transmission is by either sexual contact, through blood products, or horizontally from mother to young. Although first observed in male homosexuals, it later became a major problem of intravenous drug abusers and ultimately has become more serious in the heterosexual population, affecting an increasing number of women as well as men. Clinically, individuals may develop acute HIV mononucleosis that usually occurs 2 to 6 weeks following infection, although it may occur later. The main symptoms include headache, fever, malaise, sore throat, and rash. Patients may develop pharyngitis; generalized lymphadenopathy; a macular or urticarial rash on the face, trunk, and limbs; and hepatosplenomegaly. The severity of the symptoms may vary from one individual to another. Acute HIV infection may also induce neurologic diseases, including meningitis, encephalitis, and other neurologic manifestations. Some individuals may not develop symptoms or illness for years. Other individuals develop AIDS-related complex (ARC), which represents progressive immune dysfunction. Symptoms include fever, night sweats, weight loss, chronic diarrhea, generalized lymphadenopathy, herpes zoster, and oral lesions. Individuals with ARC may progress to AIDS or death may occur in the ARC stage. ARC patients do not revert to an asymptomatic condition. Other individuals may develop persistent generalized lymphadenopathy (PGL) characterized by enlarged lymph nodes in the neck, axilla, and groin. The Centers for Disease Control (CDC) has set up criteria for the diagnosis of AIDS. These include the individuals who develop certain opportunistic infections and neoplasms, HIV-related encephalopathy, and HIV-induced wasting syndrome. The most frequent opportunistic infections in AIDS patients include Pneumocystis carnii , which produces pneumonia, and Mycobacterium avium-intracellulare , among other microorganisms. The most frequent tumor in AIDS patients is Kaposi’s sarcoma. The definition of AIDS by the CDC now includes HIV-related encephalopathy and HIV wasting syndrome. At the present time, AIDS is 100% fatal. Window refers to: (1) The period between exposure to a microorganism and the appearance of serologically detectable antibody. It is observed in hepatitis B as well as in HIV-1 infections. In hepatitis B, there is a “core window” that occurs in active but unidentified hepatitis B infection. The hepatitis B surface antigen (HBsAg) can no longer be detected, and the antibody against hepatitis B surface antigen (anti-HBs) has not reached sufficiently high levels to be detected. (2) The period between the first infection with HIV-1 and synthesis of anti-p24 and anti-p41 antibodies in amounts measurable by the ELISA assay. Use

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of the polymerase chain reaction to demonstrate the p24 antigen can be useful to indicate infection during the window. The window period in HIV-1 infection may be between 3 and 9 months, or it may reach 36 months. Blood donated for transfusion in the U.S. is assayed for antiHIV-1 p24 antibody. Thus, these units of blood could be in the HIV-1 infection window. Anti-p24 antibodies against the viral core protein p24 appear within weeks of acute HIV infection and may have a role in the decrease in plasma viremia associated with primary infection. The decline in anti-p24 antibodies is linked to HIV disease progression. Gay bowel syndrome describes a constellation of gastrointestinal symptoms in homosexual males related to both infectious and noninfectious etiologies before the AIDS epidemic. Clinical features include alterations in bowel habits, condyloma accuminata, bloating, flatulence, diarrhea, nausea, vomiting, adenomatous polyps, fistulas, fissures, hemorrhoids, and perirectal abscesses, among many other features. Associated sexually transmitted infections include syphilis, herpes simplex, gonorrhea, and Chlamydia trachomatis. Numerous other microbial species identified include human papilloma virus, Campylobacter organisms, hepatitis A and B, cytomegalovirus, and parasites such as Entamoeba histolytica. Treatment varies with the etiology of various gay bowel syndrome manifestations. Kaposi’s sarcoma is a malignant neoplasm that may consist of a discreet intradermal nodule with vascular channels lined by atypical endothelial cells and extravasated erthrocytes with deposits of hemosiderin. This vascular tumor, seen previously largely in elderly patients of Mediterranean and Jewish stock, is now recognized in a more aggressive form as one of the presentations of AIDS. Whereas classical Kaposi’s sarcoma is on the lower limbs and is only very slowly progressive, the more aggressive form seen in AIDS of discreet vascular tumors is scattered widely over the body. This tumor is associated with infection by Kaposi’s sarcoma–associated herpes virus (human herpesvirus 8). Progressive multifocal leukoencephalopathy is a central nervous system disease characterized by demyelination, very little inflammation associated with patches of cortical degeneration, oligodendrogliocytes, intranuclear viral inclusions, aberrant large astrocytes, and reactive fibrillary astrocytes. This condition occurs in immunosuppressed individuals such as those with AIDS or latent virus infections such as measles. Papova (DNA type), often JC virus, usually causes it. HUT 78 is the original designation for a cell line derived from a patient with mycosis fungoides, now termed H-9, that was susceptible to infection with HIV-1 virus and has greatly aided in HIV-1 culture in vitro.

Intracellular immunization is a recent term used to describe interference with wild-type virus replication by a dominant negative mutant viral gene. This has been suggested to be of possible use in protecting cells against HIV-1 infection because of the easy accessibility of CD4+ cells. By using tat, gag, and rev mutant genes and a mutant CD4 cell which bears the KDEL sequence, HIV envelope protein transport to the cell surfaces is inhibited. VLIA (virus-like infectious agent) is a mycoplasma, possibly synergistic with HIV-1, leading to profound immunodeficiency. It has been named Mycoplasma incognitos. Retrovirus immunity: See human immunodeficiency virus; AIDS. Persistent generalized lymphadenopathy (PGL) is a clinical stage of HIV infection. PCP is an abbreviation for Pneumocystis carnii pneumonia. Neopterin is a guanosine triphosphate metabolite which macrophages synthesize following their stimulation by γ interferon from activated T lymphocytes. Neopterin levels in both serum and urine of HIV-1 infected patients rise as the infection progresses. This, together with diminishing CD4+ lymphocyte levels, reflects progression of HIV-1 infection to clinical AIDS. Quaternary syphilis is the stage of syphilis that follows tertiary syphilis. It is characterized by a necrotizing encephalitis with tissues rich in spirochetes. End-stage HIV patients who have completely lost cell-mediated immunity against treponemal antigens may show this form of syphilis. Although it has been rare in the past, quaternary syphilis is being seen more and more in AIDS patients also infected with Treponema pallidum who show increased susceptibility to neurosyphilis. AIDS embryopathy is a condition in children born to HIV-infected mothers who are intravenous drug abusers. Affected children have craniofacial region defects that include microcephaly, hypertelorism, a cube-shaped head, a saddle nose, widened palpebral fissures with bluish sclera, triangular philtrum, and widely spreading lips. HIV-1 virus structure (Figure 19.6) is comprised of two identical RNA strands which constitute the viral genome. These are associated with reverse transcriptase and p17 and p24, which are core polypeptides. These components are all enclosed in a phospholipid membrane envelope that is derived from the host cell. Proteins gp120 and gp41 encoded by the virus are anchored to the envelope. Lentiviruses are a group of slow retroviruses that have a long incubation period and may take years to become manifest. Human immunodeficiency virus (HIV) is included in this group.

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FIGURE 19.6 HIV-1 virus structure.

RNA-directed DNA polymerase (reverse transcriptase) is a DNA polymerase present in retroviruses such as human immunodeficiency virus (HIV) and Rous sarcoma virus that can use an RNA template to produce DNA. The primer needed must contain a free 3′-hydroxyl group that is base paired with the template. This produces a DNA–RNA hybrid. Reverse transcriptase is critical in recombinant DNA techniques since it is employed for first-strand cDNA synthesis. Reverse transcriptase is an enzyme that is a critical component of retroviruses. It translates the RNA genome into DNA before integration into host cell DNA. It also permits RNA sequences to be converted into complementary DNA (cDNA) and to be cloned. It is encoded by HIV, and the purified form is used to clone complementary DNAs encoding a gene of interest from messenger RNA. Inhibitors of the enzyme have been used as therapy for HIV-1 infection. p24 antigen is a human immunodeficiency virus type 1 (HIV-1), 24-kDa core antigen that is the earliest indicator of infection with HIV-1. It is demonstrable days to weeks prior to seroconversion to antibody synthesis against HIV-1. Testing for the p24 antigen does not reveal anti-HIV-1 seronegative persons or those with inapparent infections who wish to donate blood. rev protein is a product encoded by the rev gene of the human immunodeficiency virus (HIV). Rev protein facilitates the transport of viral RNA from the nucleus to the cytoplasm during replication of HIV. LAV: Lymphadenopathy-associated virus (See HIV-1). gp120 is a surface 120-kDa glycoprotein of human immunodeficiency virus type 1 (HIV-1) that combines with the CD4 receptor on T lymphocytes and macrophages. Synthetic soluble CD4 molecules have been used to block gp120 antigens and spare CD4+ lymphocytes from becoming infected. The env gene, which mutates frequently,

FIGURE 19.7 HIV-1 genes.

FIGURE 19.9 HIV-1 protease. NMR.

FIGURE 19.8 IgG/gp120 complex.

encodes gp120, thereby interfering with host efforts to manufacture effective or protective antibodies. Peptide T is a small HIV-1 envelope polypeptide that was first believed to have potential in treating AIDS but was later withdrawn. Tat is the protein product of the tat gene of HIV. It increases the rate of transcription of viral RNA. The activation of latently infected cells leads to synthesis. Tat protein binds to a transcriptional enhancer in the long terminal repeat of the provirus increasing proviral genome transcription. HIV-1 genes (Figure 19.7 and Figure 19.8) include the gag gene which encodes the structural core proteins p17, p24, p15, and p55 precursor. pol encodes a protease (Figure 19.9) that cleaves gag precursors. It also encodes reverse transcriptase (Figure 19.10) that produces proviral DNA from RNA and encodes an integrase that is necessary for proviral insertion. env encodes gp160 precursor, gp120, and gp41 in mature proteins. gp120 binds CD4 molecules, and gp41 is needed for fusion of the virus with the cell. vpr’s function is unknown. vif encodes a 23-kDa product that is necessary for infection of cells by free virus and is

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FIGURE 19.10 HIV-1 reverse transcriptase.

not needed for infection from cell to cell. tat encodes a p14 product that binds to viral long-terminal repeat (LTR) sequence and activates viral gene transcription. rev encodes a 20-kDa protein product that is needed for posttranscriptional expression of gag and env genes. nef encodes a 27-kDa protein that inhibits HIV transcription and slows viral replication. vpu encodes a 16-kDa protein product that may be required for assembly and packaging of new virus particles.

Envelope glycoprotein (env) is a gene of retroviruses that codes for env envelope glycoprotein. (See HIV-1 genes.) It is present on the plasma membrane of infected cells and on the host cell-derived membrane coat of viral particles. The NV proteins may be required for viral infectivity. HIV env proteins include gp41 and gp120 that bind to CD4 and chemokine receptors, respectively, on human T lymphocytes and facilitate fusion of viral and T cell membrane. Pol is a retrovirus structural gene that codes for reverse transcriptase. The structural genes of HIV-1 also include gag and env. gag is the retroviral HIV-1 gene that encodes the heterogeneous p24 protein of the virus core. HIV-2 is an abbreviation for human immunodeficiency virus-2. Previously referred to as HTLV-IV, LAV-2, and SIV/AGM. This virus was first discovered in West African individuals who showed aberrant reactions to HIV-1 and simian immunodeficiency virus (SIV). It shows greater sequence homology (70%) with SIV/MAC than with HIV-1 (40% sequence homology). HIV-2 has only 50% conservation for gag and pol. The remaining HIV genes are even less conserved than this. It has p24, gp36, and gp140 structural antigens. Its clinical course resembles that of AIDS produced by HIV-1, but it is confined primarily to western Africa and is transmitted principally through heterosexual promiscuity. The subject recently infected with HIV may develop either no symptoms or an acute infectious mononucleosis-like condition. The principal symptoms include headache, sore throat, fever, rash, and malaise. This illness is apparent 2 to 6 weeks following infection but may occur between 5 d and 3 months. On examination, there is a macular or urticarial rash on the limbs, face and trunk, hepatosplenomegaly, generalized lymphadenopathy, and pharyngitis. The illness ranges from mild to severe, possibly requiring hospitalization. Acute HIV infection may also involve the nervous system and be associated with encephalitis, meningitis, cranial nerve palsies, peripheral neuropathy, and myopathy. In 3 to 6 weeks after infection with HIV-I there are high levels of HIV p24 antigen in the plasma (Figure 19.11). 1 week to 3 months following infection, there is an HIV-specific immune response resulting in the formation of antibodies against HIV envelope protein gp120 and HIV core protein p24. HIV-specific cytotoxic T lymphocytes are also formed. The result of this adoptive immune response is a dramatic decline in viremia and a clinically asymptomatic phase lasting from 2 to 12 years. As CD4+ T cell numbers decrease, the patient becomes clinically symptomatic. HIV-specific antibodies and cytotoxic T lymphocytes decline, and p24 antigen increases. HIV-2V possesses X-ORF and VPX, which are unique to it.

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FIGURE 19.11 AIDS serology.

AIDS-related complex (ARC) is the former term for the preamble to AIDS that consists of a constellation of symptoms and signs which include a temperature of greater than 38°C, a greater than 10% loss of body weight, lymphadenopathy, diarrhea, night sweats of greater than a 3month duration, and fatigue. Laboratory findings include CD4+ T lymphocyte levels of less than 0.4 × 109, a CD4:CD8 T lymphocyte ratio of less than 1.0, leukopenia, anemia, and thrombocytopenia. There may be a decreased response to PHA, principally a T cell mitogen, and anergy, manifested as failure to respond to skin tests. In contrast, there may be a polyclonal gammopathy. A diagnosis of ARC requires at least two of the clinical manifestations and two of the laboratory findings listed above. Changes in the nomenclature for disease associated with HIV caused AIDS-related complex (ARC) to be termed symptomatic HIV infection without an AIDS-defining condition. Progressive immune dysfunction is defined by manifestations of HIV-related symptoms. Patients experience persistent fever, night sweats, some weight loss, psoriasis, eczema, seborrheic dermatitis, diarrhea, herpes zoster, oral candidiasis, and oral hairy leukoplakia. The latter two indicate the development of AIDS. A few developed blood platelet counts less than 50,000µl. The CDC criteria for diagnosing AIDS include the development of selected opportunistic infections and tumors, HIV-induced wasting syndrome, HIV-related encephalopathy, and various other diseases indicative of AIDS based on laboratory findings. Subjects with a CD4 lymphocyte count below 200 cells/ml blood or a CD4 T lymphocyte level below 14% irrespective of clinical symptoms are considered to have AIDS. AIDS-defining illnesses also include recurrent bacterial pneumonia, pulmonary tuberculosis, and invasive cervical cancer. Opportunistic infections common in these individuals include cervical cancer, Pneumocystitis carnii pneumonia, disseminated toxoplasmosis,

cryptococcus, and Mycobacterial disease (including mycobacterium avium complex) and tuberculosis, the current herpes simplex infection, disseminated cytomegalovirus infection, and histoplasmosis. AIDS patients are also prone to developing staphylococcal and pneumococcal infections as well as Salmonella bacteremia. Lymphocytic interstitial pneumonitis and recurrent bacterial infections may have a higher incidence in children with AIDS than in adults. Kaposi’s sarcoma is the most frequently associated tumor with AIDS. It involves the endothelium and mesenchymal stroma but is a less frequent presenting illness than in the past. HHV-8 herpes virus may be the causative agent of Kaposi’s sarcoma. B cell lymphomas may also occur. Up to two thirds of AIDS patients may develop CNS signs and symptoms such as sustained cognitive behavior and motor impairment referred to as the AIDS dementia complex. This is believed to be associated with infection of microglial cells with the HIV-1 virus and could be due to the structural similarity of gp120 of HIV-1 to neuroleukin. Patients have memory loss, are unable to concentrate, have poor coordination of gait, and altered psychomotor function, among other symptoms. The subcortical white matter and deep gray matter degenerate; lateral and posterior spinal cord columns show white matter vacuolization; the gp120 of HIV serves as a calcium channel inhibitor causing toxic levels of calcium within neurons. AIDS enteropathy is a condition that may be seen in AIDS-related complex patients marked by diarrhea, especially nocturnal; wasting; possibly fever; and defective Dxylose absorption, leading to malnutrition. The small intestine may demonstrate atrophy of villi and hyperplasia of crypts. Both small and large intestines may reveal diminished plasma cells, elevated intraepithelial lymphocytes, and viral inclusions. AIDS encephalopathy refers to AIDS dementia. See AIDS dementia complex. AIDS dementia complex: Up to two-thirds of AIDS patients may develop CNS signs and symptoms such as sustained cognitive behavior and motor impairment believed to be associated with infection of microglial cells with the HIV-1 virus. This could be due to the structural similarity of gp120 of HIV-1 to neuroleukin. Patients have memory loss, are unable to concentrate, have poor coordination of gait, and have altered psychomotor function, among other symptoms. The subcortical white matter and deep gray matter degenerate; lateral and posterior spinal cord columns show white matter vacuolization; and the gp120 of HIV serves as a calcium channel inhibitor, causing toxic levels of calcium within neurons. Pneumocystis carnii (PCP) (Figure 19.12) is a protozoan parasite that infects immunocompromised subjects such as

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AIDS patients, transplant recipients, lymphoma and leukemia patients, and others immunosuppressed for one reason or the other. It is diagnosed in tissue sections stained with the Gomori-methenamine silver stain. A mannose receptor facilitates the organism’s uptake by macrophages. Approximately one half of those hospitalized with a first infection by PCP die. The organism has two major forms: a trophozoite and a cyst. A trophic form is the smaller form (1 to 4 µm), is pleomorpic, and is present in clusters. The cyst stage is larger (5 to 8 µm) and contains as many as eight intracystic bodies. There are two groups of P. carnii antigens, i.e., a large surface complex, designated major surface glycoprotein (MSG); and gpA or gp120 discovered in organisms derived from human subjects, with a mol wt of 95 to 140 kDa. MSG facilitates the microorganism’s interaction with the host. The other major antigen complex is a glycoprotein of 35 to 45 kDa in human P. carnii. Cytomegalovirus (CMV) (Figure 19.13) is a herpes (DNA) virus group that is distributed worldwide and is not often a problem except in individuals who are immunocompromised, such as the recipients of organ or bone marrow transplants, or individuals with acquired immunodeficiency syndrome (AIDS). Histopathologically, typical inclusion bodies that resemble an owl’s eye are found in multiple tissues. CMV is transmitted in the blood. AIDS treatment: Two classes of antiviral drugs are used to treat HIV infection and AIDS. Nucleotide analogs inhibit reverse transcriptase activity. They include azidothymidine-AZT, dideoxyinosine, and dideoxycytidine. They may diminish plasma HIV RNA levels for considerable periods, but often fail to stop disease progression because of development of mutated forms of reverse transcriptase that resist these drugs. Viral protease inhibitors are now used to block the processing of precursor proteins into mature viral capsid and core proteins. Currently, a triple-drug therapy consisting of protease inhibitors (Figure 19.14 to Figure 19.16), together with two separate reverse transcriptase inhibitors, are used to reduce plasma viral RNA to very low levels in patients treated for more than

FIGURE 19.12 Pneumocystis carnii.

FIGURE 19.16 Nelfinavir mesylate.

FIGURE 19.13 CMV nuclear and cytoplasmic inclusions in the lung.

FIGURE 19.17 Zidovudine. FIGURE 19.14 Saquinavir mesylate.

FIGURE 19.15 Indinavir sulfate.

1 year. It remains to be determined whether or not resistance to this therapy will develop. Disadvantages include their great expense and the complexity of their administration. Antibiotics are used to treat the many infections to which AIDS patients are susceptible. Whereas viral resistance to protease inhibitors may develop after only a few days,

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resistance to the reverse transcriptase inhibitor zidovudine may occur only after months of administration. Three of four mutations in the viral reverse transcriptase are necessary for resistance to zidovudine, yet only one mutation can lead to resistance to protease inhibitors. Many advances have been made in AIDS treatment. Although no drug is curative, zidovudine (azidothymidineAZT), ddC (dideoxycytidine), and ddI (dideoxyinosine) are effective in delaying progression of the disease. Many experimental preparations are under investigation, such as DAB/486 IL-2, which is cytotoxic for high-affinity IL-2 receptors expressed on HIV-infected T lymphocytes. Zidovudine (3′-azido-3′-deoxythymidine) or AZT (Figure 19.17) is a reverse-transcriptase inhibitor that is a thymidine analog. It is FDA approved for the treatment of AIDS. The mechanism of action includes phosphorylation of the drug in vivo to 3′-azido-3′-deoxythymidine triphosphate. This combines with human immunodeficiency virus

(HIV reverse transcriptase), which leads to cessation of DNA elongation. Lamivudine is the (-) enantiomer of a dideoxy analog of cytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. Zidovudine and lamivudine are combined as the active ingredients in Combivir®. Ziagen® is a carbocyclic synthetic nucleoside analog. It is FDA approved for the treatment of HIV. The mechanism of action includes activation of abacavir to carbovir triphosphate, which inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Abacavir is the active component of the drug. Azidothymidine is a synonym for zidovudine. AZT (3′-azido-3′-deoxythymidine). See zidovudine. BI-RG-587 is a powerful inhibitor of reverse transcriptase in humans. This dipyridodiazepinone can prevent the replication of HIV-1 in vitro. It can be used in conjunction with such nucleoside analogs as zidovudine, ddI, and ddC, as well as in subjects whose HIV-1 infection no longer responds to these drugs. ddC (dideoxycytidine) is an inhibitor of reverse transcriptase used in AIDS treatment. It resembles ddI. ddI (2′,3′-dideoxyinosine) is a purine analog that blocks HIV-1 in vivo. It is transformed into a triphosphorylated substance, ddATP, which blocks HIV reverse transcriptase and suppresses the replication of HIV by inhibiting viral DNA synthesis. Administration of ddI may be followed by an elevation in the CD4+ T helper cells and a significant decrease in p24 antigen, an indicator of HIV activity in the blood. AIDS patients tolerate ddI better than they do zidovudine. Epivir® is a synthetic nucleoside analog. It is FDA approved for the treatment of HIV. The mechanism of action includes phosphorylation of the drug to its active 5′-triphosphate metabolite, which inhibits reverse transcriptase via DNA chain termination after incorporation of the nucleoside analog. Lamivudine is the active component of the drug. Highly active anteretroviral therapy (HAART) describes the combined use of reverse transcriptase inhibitors and a viral protease inhibitor for HIV infection. This type of therapy can diminish virus titers to undetectable levels for more than 1 year and slow the progression of HIV disease. Norvir® is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. It is FDA approved for the treatment of HIV. The mechanism of action includes inhibition of HIV protease, rendering the enzyme incapable of processing the gag-pol polyprotein precursor, which leads to production

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of noninfectious immature HIV particles. Ritonavir is the active component of the drug. Retrovir® is a synthetic nucleoside analog of thymidine, in which the 3′-hydroxy group is replaced by an azido group. It is FDA approved for the treatment of HIV. The mechanism of action includes the conversion of zidovudine to its active metabolite zidovudine 5′-triphosphate, which inhibits the activity of the HIV reverse transcriptase by both competing for utilization with the natural substrate and its incorporation into viral DNA. Zidovudine is the active component of the drug. Sustiva® is an HIV-1 specific, nonnucleoside, reversetranscriptase inhibitor. It is FDA approved for the treatment of HIV. The mechanism of action includes noncompetitive inhibition of HIV-1 reverse transcriptase by efavirenz. Efavirenz, the active component of the drug, has no inhibitory effect on HIV-2 reverse transcriptase. Videx® is a synthetic purine nucleoside analog. It is FDA approved for the treatment of HIV. The mechanism of action includes the activation of didanosine to dideoxyadenosine 5′-triphosphate, which inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate and by its incorporation into viral DNA. Didanosine is the active component of the drug. Viracept® is an inhibitor of the HIV-1 protease that prevents cleavage of the gag-pol polyprotein, resulting in the production of noninfectious virus. It is FDA approved for the treatment of HIV. Nelfinavir mesylate is the active component of the drug. Serpins are a large family of protease inhibitors. Viramune® is a nonnucleoside reverse-transcriptase inhibitor. It is FDA approved for the treatment of HIV. Nevirapine, the active component of the drug, binds directly to reverse transcriptase and blocks the RNAdependent and DNA-dependent polymerase activities by causing disruption of the enzyme’s catalytic site. Nevirapine has no inhibitory effect on HIV-2 reverse transcriptase. Pentamidine isoethionate is a substance useful in the treatment of Pneumocystis carnii pneumonia in AIDS patients who have failed to respond to trimethoprimsulfamethoxazole therapy. It is administered by aerosol and has diminished P. carnii pneumonia by 65%. Adverse effects include azothemia, arrythmia, hypotension, diabetes mellitus, pancreatitis, and severe hypoglycemia. Ribavarin (1-8-5-D ribofuranosyl-1,2,4-triazole-3carboxamide) (Figure 19.18) is a substance that interferes with mRNA capping of certain viruses, thereby restricting the synthesis of viral proteins. It is used as an aerosol to treat severe respiratory syncytial virus infection in children.

whether or not they can effectively prevent disease. Several experimental AIDS vaccines are under investigation. HIV-2 inoculation into cynomologus monkeys apparently prevented them from developing simian AIDS following injection of the SIV virus. ALVAC is an experimental AIDS vaccine developed for the first test of a human AIDS vaccine in Africa. The vaccine has undergone safety testing in the U.S. and France with no serious side effects reported and is being used in Uganda, where AIDS has killed nearly half a million people and left one million children orphaned. gp160 vaccine is a vaccine that contains a cloned segment of the envelope protein of HIV-1. It activates both humoral and cellular immunity against HIV products during early infection with HIV-1. It diminishes the rate at which CD4+ T lymphocytes are lost. FIGURE 19.18 Ribavirin.

FIGURE 19.19 Foscarnet.

Foscarnet (Figure 19.19) is an investigational drug used to combat cytomegalovirus-induced pneumonia, hepatitis, colitis, and retinitis in AIDS patients rendered nonresponsive to gancyclovir, which is a frequently used treatment for cytomegalovirus infection. Gancyclovir (9-[2-hydroxy-1(hydroxymethyl) ethoxymethyl] guanine) is an antiviral drug used for the therapy of immunocompromised patients infected with cytomegalic inclusion virus. Five days of gancyclovir therapy has proven effective for clearing CMV from the blood, urine, and respiratory secretions. It has been used successfully to treat CMV retinitis, gastroenteritis, and hepatitis. Drug resistance may develop. The drug may induce neutropenia and thrombocytopenia as side effects. It has not proven very effective in AIDS or bone marrow transplant patients. Development of an AIDS vaccine always has been made difficult by the genetic potential of HIV for extensive antigenic variations. Whereas many of the viral gene products capable of inducing humoral immunity are known, humoral immunity is insufficient to prevent HIV disease. By contrast, viral products that can induce effective cellmediated immunity require investigations to determine

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Pediatric AIDS describes AIDS in infants who are infected vertically, i.e., from mother to young through intrauterine or intrapartum infection. They show symptoms usually between 3 weeks and 2 years of age. They develop lymphadenopathy; fever; increased numbers of B lymphocytes in the peripheral blood; thrombocytopenia; and increased levels of IgG, IgM, and IgD in the serum. They may develop lymphoid interstitial pneumonia, chronic otitis media encephalopathy, recurrent bacterial infections, and Candida esophagitis. Epstein-Barr virus infection may produce interstitial pneumonia and salivary gland inflammation. They may also have bloodborne infections with such microorganisms as Hemophilus influenzae or pneumococci. The adult age pattern of either opportunistic infections or Kaposi’s sarcoma is rarely seen in HIV-1-infected infants. These children have a 50% 5-year mortality. SIV (simian immunodeficiency virus) is a lentivirus of primates that resembles HIV-1 and HIV-2 in morphology and attraction to cells that bear CD4 molecules such as lymphocytes and macrophages. SIV also shares with these human viruses the additional genes lacking in other retroviruses, which include vip, rev, upr, tat, and nef. The SIV virus induces the classic cytopathologic alterations of the type produced by HIV, and it can also induce chronic disease following a lengthy latency. SIVmac239 is an SIV clone that induces a disease resembling AIDS in monkeys. Simian immunodeficiency virus (SIV) causes a disease resembling human AIDS in rhesus monkeys. The SIV sequence reveals significant homology with HIV-2, a cause of AIDS in western Africa. SAIDS (simian acquired immunodeficiency syndrome) describes an immunodeficiency of rhesus monkeys induced by retrovirus group D. The animals develop opportunistic infections and tumors. Their CD4+ lymphocytes decrease.

They suffer wasting and develop granulomatous encephalitis. The sequence homology between SIV and HIV-1 is minimal, but the sequence homology between SIV and HIV-2 is significant.

access to the nucleus and activates viral proliferation. Additional retroviral genes become activated. Mesenchymal tumors may be induced by the tat genes in experimental animals.

SRV-1 is a simian AIDS virus type D that shows little similarity with HIV-1. However, they both contain genes that resemble one another. This strain was responsible for an infection among a colony of macaques in California.

MAIDS is an abbreviation for (1) murine acquired immunodeficiency syndrome and (2) monoclonal antiidiotypic antibodies.

tat gene is a retrovirus gene found in HIV-1. The tat transactivating protein, which this gene encodes, gains

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Mycoplasma–AIDS link is a mechanism postulated by L. Montagnier for AIDS development. HIV-1 virus binds to cells first activated by Mycoplasma infection.

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