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HIV / AIDS Pathology

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Prepared and presented by
Marc Imhotep Cray, M.D.

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Marc Imhotep Cray, M.D. 2
HIV and AIDS
Textbook of AIDS Pathology_Introduction
HIV Infection & Antiretroviral Agents
HIV/A...

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Marc Imhotep Cray, M.D.
Clinical Case: Make the Diagnosis
3
 A 40-year-old male was seen by his internist with chief
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HIV / AIDS Pathology

  1. 1. Prepared and presented by Marc Imhotep Cray, M.D.
  2. 2. Marc Imhotep Cray, M.D. 2 HIV and AIDS Textbook of AIDS Pathology_Introduction HIV Infection & Antiretroviral Agents HIV/AIDS Patient Animations HIV Science-Antiviral Drugs Animations Glossary HIV Related Terms_PDF Download
  3. 3. Marc Imhotep Cray, M.D. Clinical Case: Make the Diagnosis 3  A 40-year-old male was seen by his internist with chief complaints of fever, night sweats, increased episodes of diarrhea during the past month, and a 30-pound weight loss over the previous 4 months. On physical exam, he had oral thrush and cervical lymphadenopathy. Laboratory findings were significant for a CD4+ cell count of 100 cells/uL.
  4. 4. Marc Imhotep Cray, M.D. Acquired immunodeficiency syndrome (AIDS) Capsule AIDS is an infectious disease caused by human HIV AIDS is characterized by a profound suppression of immune system and susceptibility to opportunistic infections, neurologic disorders, and malignancies 4 Symptomatic phase and AIDS is end-stage HIV disease  Opportunistic protozoal, fungal, bacterial, & viral infections, Malignancies, Neurological disorders Other systems are also affected, including CV, Pulm, GI  AIDS is Dx for a person who is HIV-positive and has a T-cell count below 200 cells/ uL (or 200/ mm3) or presents with one of AIDS defining opportunistic infections /malignancies  AIDS is characterized by a CD4+ T lymphocyte count below 200 cells/mm3 (normal = 800– 1200/mm3)
  5. 5. Marc Imhotep Cray, M.D. AIDS Capsule cont. 5 Two genetically different, but closely related forms of human pathogens are recognized: HIV-1 and HIV-2  Both are RNA viruses belonging to retrovirus family (lentivirus genus)  HIV expresses cell surface protein gp120, which binds to CD4+ surface molecule of T helper lymphocytes  Proviral DNA synthesized by a reverse transcription in infected cells is integrated into host’s nuclear DNA Main characteristics of HIV
  6. 6. Marc Imhotep Cray, M.D. Acquired Immune Deficiency Syndrome (AIDS)  Infection with HIV causes a continuum of diseases, from acute (primary) HIV infection  prolonged periods of asymptomatic infection  full blown AIDS  Diagnosis of AIDS implies there has been significant damage to immune system and is a surveillance case definition established by Centers for Disease Control and Prevention (CDC) as part of classification of clinical status of HIV-infected patients  To date, two types of HIV, HIV-1 and HIV-2, have been identified as causative agents of AIDS  There are several subtypes (clades) of HIV-1 with varying distributions throughout world, whereas HIV-2 is more prevalent in Western Africa Important Epidemiology Note: “The Pandemic of HIV continues to be a serious international problem As of 2005, there were about 38.6 million people worldwide living with HIV/AIDS, with 2.8 million deaths in 2005 and 4 million people newly infected with HIV.” U.S. CDC (Centers for Disease Control and Prevention). HIV Surveillance Report Infographic / Full Report (2018). 6
  7. 7. Marc Imhotep Cray, M.D. Human Immunodeficiency Virus Etiology and Epidemiology: HIV-1 causes AIDS Transmission  Unprotected sexual intercourse o Homosexual contact is major mode of HIV-1 transmission in United States o Heterosexual transmission is most common in rest of world  Shared contaminated needles (IVDAs)  Contaminated blood transfusions  Vertical transmission from mother to child virus crosses placenta and is transmitted through breast milk 7
  8. 8. Marc Imhotep Cray, M.D. Prevalence of human immunodeficiency virus (HIV) infection among the adult population worldwide. 8World Health Organization (WHO) figures from 2006 demonstrate extent of HIV pandemic throughout world.
  9. 9. Marc Imhotep Cray, M.D. HIV Structure (simplified) Ireland KA. Visualizing Human Biology, 3rd ed. New Jersey: Wiley & Sons, 2011. 9
  10. 10. HIV genes, gene products & structure of HIV-1 virion Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. 2014. Modified from: Hammer GD and McPhee JS, Eds. Pathophysiology of Disease : An Introduction to Clinical Medicine, 7th Ed. 2014 HIV is a group of related retroviruses, whose RNA encodes for nine genes
  11. 11. 11 Life Cycle of HIV Robbins Basic Pathology 10e, Elsevier, 2018. Fig. 4.19, Pg. 176.
  12. 12. 12 HIV Reproduction/ infection process Modified from: Ireland KA. Visualizing Human Biology, 3rd ed. New Jersey: Wiley & Sons, 2011 1. Virus attaches to host cell at CD4 receptor 2. Viral RNA is injected into cell and using reverse transcriptase makes a complementary DNA strand (cDNA) 3. Viral cDNA makes a second strand of DNA double-stranded viral DNA enters nucleus and is inserted into host DNA where it can remain dormant for many years as a provirus 4. Viral cDNA is transcribed into viral RNA and exported into cytoplasm 5. Viral RNA is translated into new viral particles 6. Assembled virus buds from cell membrane and is released Helper T- Lymphocyte (CD4+ Cell)
  13. 13. Marc Imhotep Cray, M.D. Human immunodeficiency virus-1 (HIV-1) seen budding from infected cells (arrows) Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012 13
  14. 14. HIV-1 pathogenesis  HIV-1 attaches via envelope glycoprotein gp120 to CD4 molecule and a second coreceptor (chemokine receptor) on helper T lymphocytes, monocytes-macrophages, and mucosal dendritic cells  HIV-1 may infect both activated and nonactivated CD4+ cells in draining lymph node  Virus remains latent in nonactivated (resting) T cells but replicates in and kills T cells activated by infection or cytokines or both Note: chemokine=any of a family of low molecular weight (8–10 kD) cytokines that induce chemotaxis or chemokinesis in leukocytes (or in particular populations of leukocytes). Robbins Basic Pathology 10e, Elsevier, 2018. Fig. 4.19, Pg. 178.
  15. 15. Marc Imhotep Cray, M.D. HIV /AIDS pathogenesis 15 AIDS is consequence of infection w HIV-1 which infects multiple cell lines, including lymphocytes, monocytes, macrophages, and dendritic cells  With HIV infection, there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4+ T-lymphocyte function and an associated increase in CD8+ cytotoxic T lymphocytes (CTLs)  “Reversal of the CD4/CD8 Ratio” A normal CD4/CD8 ratio is 2.0, with CD4 lymphocytes equal to or greater than 400/mm3 and CD8 lymphocytes equal to 200 to 800/mm3. If the ratio is higher than 2, it means the immune system is strong and HIV unlikely. If the ratio is less than 1, pt. may have HIV
  16. 16. Marc Imhotep Cray, M.D. HIV AIDS pathogenesis cont. 16  In addition to cell-mediated immune defects (T lymphocytes ) B-lymphocyte function (humoral- mediated immunity) is altered  such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses Resultant immunosuppression predisposes patients to constellation of opportunistic infections that characterizes AIDS
  17. 17. Marc Imhotep Cray, M.D. Human Immunodeficiency Virus 17 Clinical Manifestations: HIV disease is characterized by  an acute phase with a “flu-like” or infectious mononucleosis-like syndrome, followed by  an asymptomatic phase of clinical latency characterized by fatigue, weight loss, night sweats, or lymphadenopathy with a median time of 7-10 years to development of AIDS
  18. 18. Marc Imhotep Cray, M.D. Human Immunodeficiency Virus 18 Symptomatic phase and AIDS is end-stage disease  AIDS is characterized by a CD4+ T lymphocyte count below 200 cells/mL3 (normal = 800–1200/mL3)  Opportunistic protozoal, fungal, bacterial, & viral infections  Malignancies  Neurological disorders
  19. 19. Marc Imhotep Cray, M.D. HIV W/U  Diagnostic Test:  Bloods: CBC, Lytes, LFTs, lipids, glucose, lymphocyte subsets  HIV specific: o Enzyme-linked immunosorbent assay (ELISA) o Western blot test o Immunofluorescence assay (IFA) o Nucleic acid testing  Virology screen: HIV antibody, HIV viral load, HIV genotype, hepatitis serology, cytomegalovirus (CMV) antibody, syphilis screen  Other infection, e.g. tuberculosis if indicated 19
  20. 20. Marc Imhotep Cray, M.D. Runge MS and Greganti MA. Netter's Internal Medicine 2nd Ed. Saunders, 2008 20 STI and HIV Lab Testing:
  21. 21. Marc Imhotep Cray, M.D. Natural History (NH) & Phases of HIV infection 1. Early, acute phase: Self-limited acute illness 3 to 6 weeks after infection  High level of virus production and widespread infection of lymphoid organs 2. Middle, chronic phase: No symptoms or persistent lymphadenopathy for several years 3. Minor infections 4. Final, crisis: Long-lasting fever, severe opportunistic infections, secondary neoplasms, and neurologic disorders  This usually develops after 7 to 10 years of chronic phase Four major stages of HIV infection: 21
  22. 22. Marc Imhotep Cray, M.D. Four major stages of HIV infection cont. 22 1) With acute HIV infection, individual may remain asymptomatic or develop an acute illness that resembles influenza or infectious mononucleosis Sx usually develop within 2 to 6 weeks after infection  During this stage, antibodies to HIV are generally undetectable 2) Seroconversion usually occurs during clinical latency, an asymptomatic period that would last approx. 7 to 10 years in an untreated patient  Low-level (but persistent) replication of HIV causes a gradual decrease in CD4+ T cells, and minor opportunistic infections may occur
  23. 23. Marc Imhotep Cray, M.D. Four major stages of HIV infection cont. 23 3) During crisis phase, escalation of viral replication leads to a more rapid T-cell decline  clinically apparent as weight loss, fever, fatigue, and lymphadenopathy 4) Acquired immunodeficiency syndrome (AIDS) is diagnosis for a person who is HIV-positive and has a T- cell count below 200 cells/ uL ( or 200/ mm3) or presents with one of AIDS defining opportunistic infections /malignancies
  24. 24. Marc Imhotep Cray, M.D. NH: Typical course of HIV infection (1) Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. Philadelphia: Saunders, 2014 Acute HIV infection may present as a self-limited, febrile viral syndrome characterized by:  fatigue  pharyngitis  myalgias  maculopapular rash  lymphadenopathy and  significant viremia  without detectable anti-HIV antibodies 24
  25. 25. Marc Imhotep Cray, M.D. NH: Typical course of HIV infection (2) Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012 25
  26. 26. NH: Typical course of untreated HIV infection (3)  During early period after primary infection, there is widespread dissemination of virus and a sharp decrease in number of CD4 T cells in peripheral blood  An immune response to HIV ensues, with a decrease in detectable viremia followed by a prolonged period of clinical latency • Sensitive assays for viral RNA show that virus is present in plasma at all times  CD4 T-cell count continues to decrease during following years until it reaches a critical level below which there is a substantial risk of opportunistic diseases 26 Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related disorders. In Longo DL, Fauci AS, Kasper DL, et al (editors). Harrison’s Principles of Internal Medicine, 18th ed. McGraw-Hill, 2012.
  27. 27. 27 HIV/AIDS Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013. Common Agents of Infection In Patients with AIDS As indicated above,  AIDS is characterized by a profound suppression of immune system and susceptibility to o infections o neurologic disorders & o malignancies
  28. 28. HIV/AIDS Consequences & Complications  Increased risk of opportunistic infections: o Toxoplasmosis o CMV, e.g. retinitis o Pneumocystis jiroveci pneumonia o Cryptococcal meningitis o Mycobacterium avium complex o Candida o Aspergillosis  Increased risk of malignancies: o Kaposi’s sarcoma o Non-Hodgkin’s lymphoma o Cervical cancer o Anal cancer 28
  29. 29. Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012  HIV-1 mediated destruction of cellular immune system results in  AIDS  Infectious and neoplastic complications of AIDS can affect practically every organ system Consequences of HIV infection and AIDS
  30. 30. HIV-AIDS Revised Surveillance Case Definition, 2014.*  Candidiasis of bronchi, trachea, lungs, or esophagus  Cervical cancer, invasive  Coccidioidomycosis, disseminated or extrapulmonary  Cryptococcosis, extrapulmonary  Cryptosporidiosis, chronic intestinal (>1 month duration)  Cytomegalovirus disease (other than liver, spleen, or nodes; including cytomegalovirus retinitis with loss of vision)  Encephalopathy, HIV related  Herpes simplex: chronic ulcers (>1 month duration) or bronchitis, pneumonitis, or esophagitis  Histoplasmosis, disseminated or extrapulmonary  Isosporiasis, chronic intestinal (>1 month duration)  Kaposi’s sarcoma  Leukoencephalopathy, progressive multifocal  Lymphoma, Burkitt’s (or equivalent form),  immunoblastic (or equivalent form), or primary of brain  Mycobacterium avium complex or M. kansasii,  disseminated or extrapulmonary  Mycobacterium tuberculosis, pulmonary or  extrapulmonary  Mycobacterium, other species or unidentified species,  disseminated or extrapulmonary  Pneumocystis carinii  Pneumonia, recurrent  Salmonella septicemia, recurrent  Toxoplasmosis of brain  Wasting syndrome due to HIV *Patients infected with HIV and who have a CD4+ T-cell count <200 or CD4+ percent <14% are classified as having AIDS. HIV-AIDS Revised Surveillance Case Definition, 2014. 30
  31. 31. Pneumocystis jiroveci (carinii). HIV-associated Kaposi sarcoma in nodular stage. HIV-associated Kaposi sarcoma in macular stage. Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013. 31
  32. 32. Marc Imhotep Cray, M.D. HIV/AIDS Clinical Manifestations  HIV affects all body systems, particularly integumentary, pulmonary, gastrointestinal (GI), neurologic, and ocular systems  GI manifestations develop in nearly all persons with HIV b/c of major effect of HIV infection on GI system  Pulmonary and cutaneous symptoms develop in ~ 50% to 75% of all persons with HIV, and  Neurologic Sx develop in 50% to 60% 32
  33. 33. Marc Imhotep Cray, M.D. HIV/AIDS One of most significant systemic symptoms is malnutrition or wasting syndrome  In Africa, HIV is known as “slim disease” b/c of wasting Malnutrition is defined as unintended, involuntary loss of greater than 10% body weight Systemic symptoms attributable to HIV infection malnutrition include major muscle wasting, weight loss, and loss of vitamins, minerals, and other nutrients 33
  34. 34. Marc Imhotep Cray, M.D. Wasting syndrome cont. 34 HIV malnutrition is result of a combination of factors, including  an elevated metabolic rate with increased resting energy expenditure (REE)  chronic inflammation  malabsorption  anorexia  decreased intake of food, and  effect of multiple opportunistic insults
  35. 35. Marc Imhotep Cray, M.D.  LYMPHOPENIA  Predominantly caused by selective loss of CD4+ helper T-cell subset DECREASED T-CELL FUNCTION IN VIVO  Preferential loss of activated and memory T cells  ↓ delayed-type hypersensitivity  Susceptibility to opportunistic infections  Susceptibility to neoplasms ALTERED T-CELL FUNCTION IN VITRO  ↓ proliferative response to mitogens, alloantigens, and soluble antigens  ↓ cytotoxicity  ↓ helper function for B-cell antibody production  ↓ IL-2 and IFN-γ production  ↓ capacity to present antigen to T cells Major Abnormalities of Immune Function in AIDS 35
  36. 36. Marc Imhotep Cray, M.D. Major Abnormalities of Immune Function in AIDS cont.  POLYCLONAL B-CELL ACTIVATION  Hypergammaglobulinemia and circulating immune complexes  Inability to mount de novo antibody response to new antigens  Poor responses to normal B-cell activation signals in vitro ALTERED MONOCYTE OR MACROPHAGE FUNCTIONS  ↓ chemotaxis and phagocytosis  ↓ class II HLA expression 36
  37. 37. Marc Imhotep Cray, M.D. Most important determinants of progression of HIV infection CD4+ T-cell count indicates damage that has occurred to immune system, and how close patient is to progressing to AIDS  A high count is ideal  Normal count ranges from 500 to 1500 cells/mm3 (500 to 1500/ mm3) Viral load is an indication of pace at which damage is occurring  A low viral load is ideal  Viral load serves as a marker for disease progression and drug therapy effectiveness by measuring amount of actively dividing HIV virus  CD4 count better for disease staging  Viral load better proxy for disease progression or monitoring response to therapy 37
  38. 38. 38 How is clinically suspected diagnosis of AIDS confirmed  Laboratory tests are performed to detect antibodies against HIV proteins  Seroconversion (presence of antibodies against HIV in a previously nonreactive individual) usually occurs within 6 months of exposure to HIV  Detection of infection during serologic window before seroconversion requires detection of viral antigens or viral RNA The diagnosis of symptomatic acute antiretroviral syndrome during the window period with antigen- antibody testing and HIV viral load https://www.sciencedirect.com/science/article/pii/S2 214250918300982?via%3Dihub#sec0005
  39. 39. Marc Imhotep Cray, M.D. Common opportunistic infections in AIDS Opportunistic infections account for vast majority of deaths in patients These infections include:  P. jiroveci pneumonia  C. albicans infections of the mouth, esophagus, vagina, and lungs  Cytomegalovirus enteritis and pneumonitis  Atypical mycobacterial infection (M. avium-intracellulare) of GIT  Cryptococcus neoformans meningitis  Cryptosporidium enteritis 39
  40. 40. Marc Imhotep Cray, M.D. Most common neoplasms associated with HIV infections and AIDS  Kaposi sarcoma  Non-Hodgkin lymphoma  Carcinoma of uterine cervix  Squamous cell carcinoma of skin 40
  41. 41. Marc Imhotep Cray, M.D. Neurologic consequences of HIV infection and AIDS Involvement of central nervous system is common (clinically 40%–60%) and may present in several forms: HIV-related diseases  Aseptic meningitis  AIDS dementia complex Opportunistic infections:  viral (cytomegalovirus and herpes simplex virus)  fungal(Coccidioides and Cryptococcus), and protozoal (Toxoplasma gondii) Neoplasms (lymphoma) 41
  42. 42. Marc Imhotep Cray, M.D. What is “PCP pneumonia”  PCP refers to Pneumocystis carinii pneumonia (the preferred name is now Pneumocystis jirovecii pneumonia)  P. jirovecii pneumonia is most common significant opportunistic infection in HIV patients o yeast-like fungus originally classified as protozoan and now classified as a fungus  typically occurs in patients with a CD4+ count of below 200  Pneumocystis jirovecii causes a diffuse interstitial pneumonia 42
  43. 43. Marc Imhotep Cray, M.D. PCP (2)  Transmission: Inhaled  Most infections are asymptomatic  Immunosuppression (e.g., AIDS) predisposes to disease  Clin. Findings:  Patients typically present with fever, nonproductive cough, and dyspnea  Radiographic studies show bilateral diffuse infiltrates, most pronounced in perihilar regions o Diffuse, bilateral ground-glass opacities on CXR/CT  Diagnosed by lung biopsy or lavage Disc-shaped yeast forms on methenamine silver stain of lung tissue  Patients with CD4+ counts below 200/mm3 should be started on TMP- SMX prophylaxis 43
  44. 44. Question A 23-year-old man presents to the emergency department with symptoms of malaise, dry cough, and dyspnea for several weeks. Physical examination reveals tachypnea, tachycardia, and fever, with crackles on auscultation. On further questioning, the patient admits to IV drug abuse. The chest x-ray findings (top) prompt the clinician to order a chest CT study, from which is a representative section in the coronal plane is shown in the bottom figure. What is the most likely diagnosis? A. Pneumocystis pneumonia (PCP) B. Pneumococcal pneumonia C. Miliary tuberculosis (TB) D. Cytomegalovirus (CMV) pneumonia E. Pulmonary edema Studdiford, JS and Tully AS. USMLE Images for the Boards: Philadelphia. Saunders,2013 44
  45. 45. 45 Studdiford, JS and Tully AS. USMLE Images for the Boards: Philadelphia. Saunders,2013 ANSWER: Pneumocystis pneumonia (PCP)  The Chest x-ray and Chest CT show a diffuse ground-glass pattern throughout the lungs. The term ground-glass refers to the edge of a microscope slide that can be written on with pencil, and it means that although the area remains transparent, one cannot see detail through it This pattern is characteristic of pneumocystis pneumonia, commonly known as PCP  The patient tested positive for HIV infection, likely acquired through the sharing of contaminated needles, and he is severely immunosuppressed.  Sputum obtained during bronchoalveolar lavage was positive for PCP.
  46. 46. Marc Imhotep Cray, M.D. Other opportunistic pathogens and malignancies: Major cause of death in AIDS Common opportunistic infections at notable CD4+ counts:  Toxoplasma encephalitis at <100  Cryptococcal meningitis at <100  Mycobacterium avium complex at <50  Cytomegalovirus retinitis at <50 o CMV retinitis is treated with ganciclovir, a competitive guanosine analog • In event that ganciclovir fails foscarnet (viral DNA polymerase inhibitor) is used 46
  47. 47. Marc Imhotep Cray, M.D. Select HIV Infection and AIDS Gross and Microscopic Pathology Plates and Radiographs 47
  48. 48. Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 Pneumocystis pneumonia, microscopic  Granular pink alveolar exudate ( ) of Pneumocystis jiroveci pneumonia (left panel) consists of edema fluid, protein, Pneumocystis organisms, and dead inflammatory cells  Mononuclear cells infiltrate interstitium  Gomori methenamine silver (GMS) stain on bronchoalveolar lavage fluid (right panel) shows 4- to 8-μm dark cyst walls of organisms appearing as crushed Ping-Pong balls 48
  49. 49. Studdiford, JS and Tully AS. USMLE Images for the Boards: Philadelphia. Saunders ,2013 Pneumocystis pneumonia, CXR  Chest x-ray show a diffuse ground- glass pattern throughout lungs  Term ground-glass refers to edge of a microscope slide that can be written on with pencil, and it means that although area remains transparent, one cannot see detail through it  This pattern is characteristic of pneumocystis pneumonia, commonly known as PCP 49
  50. 50. Progressive multifocal leukoencephalopathy, microscopic  PML lesions have perivascular monocyte infiltrates, astrocytosis with bizarre or enlarged astrocytes (with occasional mitotic figures), and central lipid-laden macrophages  Virus preferentially infects oligodendrocytes in white matter, leading to demyelination  Shown here at periphery of lesions are large “ballooned” oligodendrocytes infected with JC polyoma virus that have enlarged dark pink, ground-glass nuclei (arrowhead) containing viral antigen Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 50
  51. 51. Progressive multifocal leukoencephalopathy, MRI  PML occurs in immunocompromised patients, such as those with AIDS, from reactivation of JC polyomavirus infection  Shown here are areas of markedly increased signal intensity in left hemisphere (right panel) with T2 weighting, fat saturation  Extensive white matter involvement is subtle with T1 weighting, postgadolinium (left panel)  multifocal lesions may also involve cerebellum Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 51
  52. 52. Kaposi sarcoma, gross  Epidemic form of KS seen with AIDS usually appears in men who have sex with men and is rare in other groups at risk for HIV infection  Risk factor for KS is infection with human herpesvirus 8 (HHV-8), known as the Kaposi sarcoma–associated herpesvirus (KSHV), which can be sexually transmitted o seroprevalence of HHV-8 is 5% to 10% of general population, but 20% to 70% in men who have sex with men  Lesions can start as small reddish to red-purple plaques or patches on one or more areas of skin  Over time lesions may become nodular, larger, and more numerous  In patients who test positive for HIV, KS is diagnostic of AIDS  Use of antiretroviral therapy markedly decreases incidence of KS Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 52
  53. 53. Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 Mycobacterium avium complex infection, gross  Seen here in this cross-section of spleen are numerous small white nodules representing ill-formed granulomas  This patient had disseminated Mycobacterium avium complex (MAC) infection, and organs of mononuclear phagocyte system are often involved  MAC infection is most likely to occur in immunocompromised persons, such as those with HIV infection with CD4 count< 50 53
  54. 54. Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 Cytomegalovirus pneumonia, microscopic  Note very large cells that have large violet intranuclear inclusions surrounded by a small clear halo  This Cowdry type A bodies are typically referred to as “owl’s eyes” due to their microscopic appearance  Basophilic stippling (arrow ) can be seen in cytoplasm of these cytomegalic cells  Endothelial and epithelial cells can become infected  Though infection may begin in lungs, dissemination to other organs is common=CMV retinitis 54
  55. 55. Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 HIV encephalitis, microscopic  HIV infection often involves brain through macrophages that are carried there from reservoirs of infection within lymphoid tissues  Shown here is an encephalitis with a focal lesion (microglial nodule) showing perivascular multinucleated cells (arrow), which can be infected by HIV  There are few lymphocytes because of markedly reduced number of CD4 lymphocytes with progression of HIV infection  Brain injury is potentiated by microglial activation and cytokine release  Encephalitis can lead to progressive loss of cognitive and motor function, termed HIV- associated dementia  Aseptic meningitis may also occur with acute HIV infection 55
  56. 56. Primary central nervous system lymphoma, MRI  There is one large periventricular mass (L arrow ), with smaller masses, showing increased signal intensity with gadolinium enhancement  Areas of lower signal intensity (R arrow ) represent tumor necrosis, and there is diminished intensity of surrounding brain from edema  These lesions often involve deep gray matter, but also white matter and cortex  Periventricular spread is common  They often have extensive central necrosis  Most are aggressive diffuse large cell B- cell lymphomas arising with Epstein-Barr virus infection in immunocompromised persons those with HIV infection Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 56
  57. 57. Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 Cryptosporidiosis, microscopic  Small round pale blue objects (arrow ) at luminal border or within a vacuole in peripheral enterocyte cytoplasm are Cryptosporidium parvum organisms  Organisms rarely invade or disseminate  There is no inflammation, necrosis, or hemorrhage  This infection most frequently affects immunocompromised patients, particularly those with AIDS  Immunocompetent patients may develop only a mild watery diarrhea; but with diminished cell- mediated immunity, cryptosporidiosis produces a copious watery diarrhea  Diagnosis is typically made by examination of a stool specimen, and organisms can be highlighted with an acid-fast stain 57
  58. 58. Cryptococcal meningitis, gross and microscopic  coronal section shows a thick mucoid exudate within the subarachnoid space ( ), ventricles ( ), and brain parenchyma ( ) in an immunocompromised patient with Cryptococcus neoformans meningitis  Perivascular collections of organisms can cause small cystic spaces within the brain  An India ink stain of CSF (right panel) reveals thick, clear capsule of these organisms surrounding these yeasts  CSF may have a mild to moderate leukocytosis, elevated protein, and decreased glucose Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 58
  59. 59. Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 Toxoplasma encephalitis, CT image  Toxoplasma gondii infection can be congenital in neonates or an opportunistic infection of immunocompromised adults  This CT scan shows several ring- enhancing lesions (arrowhead) with darker areas of surrounding edema that are typical of toxoplasmosis producing multiple abscesses in adults  Vascularity in organizing wall of an abscess leads to the observed bright ring enhancement with CT and MRI 59
  60. 60. Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 Toxoplasmosis, microscopic  T. gondii infection can result in formation of pseudocysts, which occur within an infected cell, with cell membrane forming the cyst wall  Pseudocysts ( ) are visible in left panel within the cerebrum in a microglial nodule of a patient with AIDS  In right panel immunohistochemical staining with antibody to T. gondii highlights brown bradyzoites within the pseudocyst and adjacent free tachyzoites ( )  Organisms become progressively harder to detect as abscessing lesions become more chronic and organized 60
  61. 61. Marc Imhotep Cray, M.D. HIV 1 Infection Summary What is HIV?  HIV is an RNA retrovirus of the lentivirus genus  This virus causes acquired immunodeficiency syndrome (AIDS) Cause HIV-1: o Type M: A-J prevalent in Europe, America, Australia and sub-Saharan Africa Type o Type O: mainly in Cameroon 61
  62. 62. Marc Imhotep Cray, M.D. HIV Infection Summary cont. Transmission  Unprotected sexual intercourse  Shared contaminated needles  Contaminated blood transfusions  Vertical transmission from mother to child Virus crosses placenta and is transmitted through breast milk 62
  63. 63. Marc Imhotep Cray, M.D. HIV Infection Summary cont.  Genes required for viral replication Remember PEG  pol : encodes reverse transcriptase and integrase  env : encodes envelope proteins, e.g. gp120  gag : encodes viral structural proteins 63
  64. 64. Marc Imhotep Cray, M.D. HIV Infection Summary cont. Infection process  gp120 antigen on HIV binds to CD4+ receptors on T cell This process produces a conformational change and need to bind to a co- receptor: CCR5 or CXCR4 (no binding=person resistant to HIV)  gp41 binds to co-receptor This binding causes ‘six-helix bundle formation’ and fusion of the viral and host membranes  Disintegration of viral capsid occurs causing viral RNA to be released into human cell  Double-stranded RNA is produced and this process is catalyzed by viral reverse transcriptase  Double-stranded RNA is integrated into host DNA using integrase enzyme  Host cell now manufactures new virions by long terminal repeat 64
  65. 65. Marc Imhotep Cray, M.D. HIV Infection Summary cont. Investigations  Bloods: CBC, Electrolytes, BUN/Cr LFTs, lipids, glucose  HIV specific: o Enzyme-linked immunosorbent assay (ELISA) o Western blot test o Immunofluorescence assay (IFA) o Nucleic acid testing  Virology screen: HIV antibody, HIV viral load, HIV genotype, hepatitis serology, cytomegalovirus (CMV) antibody, STIs screen  Other infection, e.g. tuberculosis if indicated 65
  66. 66. Marc Imhotep Cray, M.D. HIV Infection Summary cont.  Complications  Increased risk of opportunistic infections: o Toxoplasmosis o CMV, e.g. retinitis o Pneumocystis jiroveci pneumonia o Cryptococcal meningitis o Mycobacterium avium complex o Candida o Aspergillosis  Increased risk of malignancies: o Kaposi’s sarcoma o Non-Hodgkin’s lymphoma o Cervical cancer o Anal cancer 66
  67. 67. HIV Antiretroviral therapy Stages in life cycle of HIV in which antiretroviral therapy is effective are shown. Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013. 67
  68. 68. 68 THE END See next slide for links to tools and resources for further study.
  69. 69. Marc Imhotep Cray, M.D. Sources and further study: 69  Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.  Dipiro JT et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 8th Ed. New York: McGraw-Hill, 2011.  Kishiyama JL. Ch. 3 Disorders of the Immune System, Pgs. 31-59 and Bloch KC. Ch. 4 Infectious Diseases, Pgs. 61-87 In: Hammer GD and McPhee eds. JS. Pathophysiology of Disease : An Introduction to Clinical Medicine, 7th Ed. New York: McGraw-Hill Education, 2014 eLearning (Cloud) o Infectious Disease Pathology o BMS HIV/AIDS Folder Textbooks:  Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010.  Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York: McGraw-Hill, 2016.

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