HIV / AIDS Pathology by Marc Imhotep Cray, M.D.

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

HIV and AIDS

Marc Imhotep Cray, M.D.

Textbook of AIDS Pathology_Introduction HIV Infection & Antiretroviral Agents HIV/AIDS Patient Animations HIV Science-Antiviral Drugs Animations Glossary HIV Related Terms_PDF Download

Clinical Case: Make the Diagnosis ď&#x201A;§ 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.

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 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) Marc Imhotep Cray, M.D.

AIDS Capsule cont. Main characteristics of HIV 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

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). 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 Marc Imhotep Cray, M.D.

Prevalence of human immunodeficiency virus (HIV) infection among the adult population worldwide.

Health Organization (WHO) figures from 2006 demonstrate extent of HIV pandemic throughout world. MarcWorld Imhotep Cray, M.D.

HIV Structure (simplified)

Ireland KA. Visualizing Human Biology, 3rd ed. New Jersey: Wiley & Sons, 2011. Marc Imhotep Cray, M.D.

HIV genes, gene products & structure of HIV-1 virion HIV is a group of related retroviruses, whose RNA encodes for nine genes

Modified from: Hammer GD and McPhee JS, Eds. Pathophysiology of Disease : An Introduction to Clinical Medicine, 7th Ed. 2014

Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. 2014.

Life Cycle of HIV

Robbins Basic Pathology 10e, Elsevier, 2018. Fig. 4.19, Pg. 176.

HIV Reproduction/ infection process 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 DNAď&#x192; 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 TLymphocyte (CD4+ Cell)

Modified from: Ireland KA. Visualizing Human Biology, 3rd ed. New Jersey: Wiley & Sons, 2011

Human immunodeficiency virus-1 (HIV-1) seen budding from infected cells (arrows)

Rubin R and Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 2012

Marc Imhotep Cray, M.D.

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.

HIV /AIDS pathogenesis 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 Marc Imhotep Cray, M.D.

HIV AIDS pathogenesis cont.  In addition to cell-mediated immune defects (T lymphocytes ) B-lymphocyte function (humoralmediated 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 Marc Imhotep Cray, M.D.

Human Immunodeficiency Virus  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

Marc Imhotep Cray, M.D.

Human Immunodeficiency Virus 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

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 Marc Imhotep Cray, M.D.

STI and HIV Lab Testing:

Marc Imhotep Cray, M.D.

Runge MS and Greganti MA. Netter's Internal Medicine 2nd Ed. Saunders, 2008

Natural History (NH) & Phases of HIV infection Four major stages of HIV infection: 1. Early, acute phase: Self-limited acute illness 3 to 6 weeks after infection ď&#x201A;§ 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 ď&#x201A;§ This usually develops after 7 to 10 years of chronic phase Marc Imhotep Cray, M.D.

Four major stages of HIV infection cont. 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 Marc Imhotep Cray, M.D.

Four major stages of HIV infection cont. 3) During crisis phase, escalation of viral replication leads to a more rapid T-cell decline ď&#x201A;§ 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 Tcell count below 200 cells/ uL ( or 200/ mm3) or presents with one of AIDS defining opportunistic infections /malignancies Marc Imhotep Cray, M.D.

NH: Typical course of HIV infection (1) 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 Marc Imhotep Cray, M.D.

Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. Philadelphia: Saunders, 2014

NH: Typical course of HIV infection (2)

Marc Imhotep Cray, M.D.

Rubin R and Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 2012

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

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. 26

HIV/AIDS As indicated above, ď&#x201A;§ AIDS is characterized by a profound suppression of immune system and susceptibility to o infections o neurologic disorders & o malignancies

Common Agents of Infection In Patients with AIDS

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

HIV/AIDS Consequences & Complications  o o o o o o o

Increased risk of opportunistic infections: Toxoplasmosis CMV, e.g. retinitis Pneumocystis jiroveci pneumonia Cryptococcal meningitis Mycobacterium avium complex Candida Aspergillosis

 o o o o

Increased risk of malignancies: Kaposi’s sarcoma Non-Hodgkin’s lymphoma Cervical cancer Anal cancer

Consequences of HIV infection and AIDS  HIV-1 mediated destruction of cellular immune system results in  AIDS  Infectious and neoplastic complications of AIDS can affect practically every organ system

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012

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.

Pneumocystis jiroveci (carinii).

HIV-associated Kaposi sarcoma in macular stage.

HIV-associated Kaposi sarcoma in nodular stage.

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

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% 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 Marc Imhotep Cray, M.D.

Wasting syndrome cont. 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 Marc Imhotep Cray, M.D.

Major Abnormalities of Immune Function in AIDS  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 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

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 Marc Imhotep Cray, M.D.

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 antigenantibody testing and HIV viral load https://www.sciencedirect.com/science/article/pii/S2 214250918300982?via%3Dihub#sec0005 38

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 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

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) 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

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 TMPSMX prophylaxis Marc Imhotep Cray, M.D.

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

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. Studdiford, JS and Tully AS. USMLE Images for the Boards: 45 Philadelphia. Saunders,2013

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

Marc Imhotep Cray, M.D.

Select HIV Infection and AIDS Gross and Microscopic Pathology Plates and Radiographs

Marc Imhotep Cray, M.D.

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

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 48

Pneumocystis pneumonia, CXR  Chest x-ray show a diffuse groundglass 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, Studdiford, JS and Tully AS. USMLE Images for the Boards: Philadelphia. Saunders ,2013 commonly known as PCP 49

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