Homework # 2

1. Homework # 2 A2 Subsection Dr. Sandra Navarra USTFMS

2. 1. List the elements of the immune response to HIV and give an example of each element.

3. Elements of the Immune Response to HIV Humoral immunity Cell-mediated immunity Helper CD4 T lymphocytes Class I MHC–restricted cytotoxic CD8 T lymphocytes CD8 T cell–mediated inhibition (noncytolytic) ADCC Natural killer cells • Binding antibodies • Neutralizing antibodies • Type specific • Group specific • Antibodies participating in antibody-dependent cellular cytotoxicity (ADCC) • Protective • Pathogenic (bystander killing) • Enhancing antibodies • Complement Harrison’s Principle of Internal Medicine 17th Edition

4. Humoral immune response

5. Binding antibodies Harrison’s Principle of Internal Medicine 17th Edition

6. Neutralizing antibodies • The only viral proteins that elicit neutralizing antibodies are the envelope proteins gp120 and gp41 • Most of the anti-envelope antibodies are directed toward: • an epitope in the gp41 region comprising amino acids 579-613, or • a hypervariable region in the gp120 molecule, known as the V3 loop region, comprising amino acids 303-338 Harrison’s Principle of Internal Medicine 17th Edition

7. Neutralizing antibodies • Two forms: • Type-specific • Group-specific Harrison’s Principle of Internal Medicine 17th Edition

8. Type-specific neutralizing antibodies • Generally directed to the V3 loop region • Neutralize only viruses of a given strain and are present in low titer in most infected individuals Harrison’s Principle of Internal Medicine 17th Edition

9. Group-specific neutralizing antibodies • Capable of neutralizing a wide variety of HIV isolates • 2 forms: • Those binding to amino acids 423-437 of gp120, which lie close to CD4 binding site • Those binding to amino acids 728-745 of gp41, which lie proximal to the viral membrane Harrison’s Principle of Internal Medicine 17th Edition

10. Antibodies participating in antibody-dependent cellular cytotoxicity (ADCC) • NK cells that bear Fc receptors are armed with specific anti-HIV antibodies • Bind to and destroy cells expressing HIV antigens • Antibodies to both gp120 and gp41 Harrison’s Principle of Internal Medicine 17th Edition

11. Antibody enhancement • Antibodies directed to gp41, when present in low titer, have been shown in vitro to be capable of facilitating infection of cells through an Fc receptor-mediated mechanism • The same regions of the envelope protein of HIV that give rise to antibodies capable of mediating ADCC also elicit the production of antibodies that can facilitate infection of cells in vitro Harrison’s Principle of Internal Medicine 17th Edition

12. By-stander killing • Anti-gp120 antibodies that participate in the ADCC killing of HIV-infected cells might also kill uninfected CD4+ T cells if the infected cells had bound free gp120 Harrison’s Principle of Internal Medicine 17th Edition

13. Complement system • HIV alone is capable of directly activating the complement cascade • However, the resulting lysis is weak due to the presence of host cell regulatory proteins captured in the virion envelope during budding • It is possible that complement-opsonized HIV virions have increased infectivity Harrison’s Principle of Internal Medicine 17th Edition

14. Cellular Immune Response

15. T-cell immunity • Two major categories: • Helper/inducer CD4+ T cells • Cytotoxic/immunoregulatory CD8+ T cells Harrison’s Principle of Internal Medicine 17th Edition

16. HIV-specific CD4+ T cells • Can be detected in majority of HIV-infected patients through: • Flow cytometry - measure intracellular cytokine production in response to MHC class II tetramers pulsed with HIV peptides • Lymphocyte proliferation assays utilizing HIV antigens such as p24 Harrison’s Principle of Internal Medicine 17th Edition

17. HIV-specific CD4+ T cells • May be preferential targets of HIV infection by HIV-infected antigen-presenting cells • However, they are also likely to undergo clonal expansions in response to HIV antigens, thus, survive as a population of cells • In the setting of high viral loads: • CD4+ T cell responses to HIV antigens appear to shift from one of the proliferation and IL-2 production to one of IFN-γ production Harrison’s Principle of Internal Medicine 17th Edition

18. MHC class I-restricted, HIV-specific CD8+ T cell • CTLs – produce perforins • T cells – can be induced by HIV antigens to express an array of cytokines such as IFN-γ Harrison’s Principle of Internal Medicine 17th Edition

19. CTLs • Bind to and cause the lytic destruction of target cells bearing autologous MHC class I molecules associated with HIV antigens • Two types: • Spontaneous CTL activity - directly lyses appropriate target cells in culture without prior in vitro stimulation • Precursor frequency of CTLs - can be demonstrated by stimulation of CD8+ T cells in vitro with a mitogen such as phytohemagglutinin or anti-CD3 antibody Harrison’s Principle of Internal Medicine 17th Edition

20. CD8+ T cells • Driven to in vivo expansion by HIV antigen • Multiple HIV antigens (Gag, Env, Pol, Tat, Rev, and Nef) can elicit CD8+ T cell responses Harrison’s Principle of Internal Medicine 17th Edition

21. CD8+ T cell-mediated suppression of HIV replication • Ability of CD8+ T cells from an HIV-infected patient to inhibit the replication of HIV in tissue culture in a noncytolytic manner • No requirement for HLA compatibility • Effector mechanism is nonspecific and appears to be mediated by soluble factors • CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP1β (CCL4) Harrison’s Principle of Internal Medicine 17th Edition

22. ADCC • Involves killing of HIV-expressing cells by N cells armed with specific antibodies directed against HIV antigens Harrison’s Principle of Internal Medicine 17th Edition

23. NK cells • Capable of killing HIV-infected target cells in tissue culture • Directed towards nonspecific surveillance for neoplastic transformation and viral infection through recognition of altered class I MHC molecules Harrison’s Principle of Internal Medicine 17th Edition

24. 2. Classification of HIV and Expanded AIDS Surveillance Case Definition

25. Category A consists of one or more of the conditions listed below in an adolescent or adult (greater than or equal to 13 years) with documented HIV infection. Conditions listed in Categories B and C must not have occurred. • Asymptomatic HIV infection • Persistent generalized lymphadenopathy • Acute (primary) HIV infection with accompanying illness or history of acute HIV infection

26. Category B • Category B consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical Category C. • Shouldmeet at least one of the following criteria • the conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity • the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. • Conditions in clinical Category B include, but are not limited to: • Bacillary angiomatosis • Candidiasis, oropharyngeal (thrush) • Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy • Cervical dysplasia (moderate or severe)/cervical carcinoma in situ • Constitutional symptoms, such as fever (38.5 C) or diarrhea lasting greater than 1 month • Hairy leukoplakia, oral • Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome • Idiopathic thrombocytopenic purpura • Listeriosis • Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess • Peripheral neuropathy

27. Category C includes the clinical conditions listed in the AIDS surveillance case definition. • Once a Category C condition has occurred, the person will remain in Category C

28. Category C conditions • Candidiasis of bronchi, trachea, or lungs • Candidiasis, esophageal • Cervical cancer, invasive * • Coccidioidomycosis, disseminated or extrapulmonary • Cryptococcosis, extrapulmonary • Cryptosporidiosis, chronic intestinal (greater than 1 month's duration) • Cytomegalovirus disease (other than liver, spleen, or nodes) • Cytomegalovirus retinitis (with loss of vision) • Encephalopathy, HIV-related

29. Category C Conditions • Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, pneumonitis, or esophagitis • Histoplasmosis, disseminated or extrapulmonary • Isosporiasis, chronic intestinal (greater than 1 month's duration) • Kaposi's sarcoma • Lymphoma, Burkitt's (or equivalent term) • Lymphoma, immunoblastic (or equivalent term) • Lymphoma, primary, of brain • Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary • Mycobacterium tuberculosis, any site (pulmonary * or extrapulmonary) • Mycobacterium, other species or unidentified species, disseminated or extrapulmonary • Pneumocystiscarinii pneumonia • Pneumonia, recurrent * • Progressive multifocal leukoencephalopathy • Salmonella septicemia, recurrent • Toxoplasmosis of brain • Wasting syndrome due to HIV

31. 3. List possible conditions to explain this patient’s cervical lymphadenopathy. • HIV infection • Kaposi's sarcoma • Tuberculosis • MulticentricCastleman’s disease • Lymphoma • Toxoplasmosis • Cryptococcus • Bacillary angiomatosis • Cytomegalovirus infection

32. 3. List possible conditions to explain this patient’s cervical lymphadenopathy. a. HIV infection • Disorders of the hematopoietic system including lymphadenopathy are common throughout the course of HIV infection and may be the direct result of HIV, manifestations of secondary infection or neoplasms. • Persistent generalized lymphadenopathy serve as its early clinical manifestation. • This condition is defined as the presence of enlarged lymph nodes (>1cm) in two or more extrainguinal sites for >3 months without an obvious cause • The lymphadenopathy is due to marked follicular hyperplasia in the node in response to HIV infection

33. 3. List possible conditions to explain this patient’s cervical lymphadenopathy. a. HIV infection • In HIV patients with CD4+ T cell counts > 200/uL, the differential diagnosis of lymphadenopathy includes Kaposi sarcoma, tuberculosis, castleman’s disease and lymphoma. • In HIV patients with more advanced disease, lymphadenopathy may also be due to toxoplasmosis, systemic fungal infection or bacillary angiomatosis.

34. 3. List possible conditions to explain this patient’s cervical lymphadenopathy. b. Kaposi sarcoma Immunocompromised patients with HHV-8 infection may present with fever, splenomegaly, lymphoid hyperplasia, pancytopenia or rapid onset KS. c. Tuberculosis Lymphadenopathy is the most common presentation of extrapulmonary TB which occurs more commonly in immuno-compromised patients especially those infected with HIV due to the impaired cell-mediated immunity essential for defense against TB.

35. 3. List possible conditions to explain this patient’s cervical lymphadenopathy. d. MulticentricCastleman’s disease - abnormal overgrowth of lymph nodes with high fevers, anemia, weight loss, loss of appetite, and low white blood cell counts due to the overproduction of interleukin 6. e. Lymphoma - higher incidence among HIV patients characterized by lymphadenopathy, fever of unknown origin, weight loss, pruritus, anorexia, fatigue

36. 3. List possible conditions to explain this patient’s cervical lymphadenopathy. f. Toxoplasmosis - a parasitic disease caused by Toxoplasmagondii presenting with swollen lymph nodes, or muscle aches and pains that last for a month or more. Immunocompromised patients, such as those with HIV/AIDS may develop severe toxoplasmosis which can cause damage to the brain (encephalitis) or the eyes (necrotizing retinochoroiditis). g. Cryptococcus infection - most commonly present with meningoencephalitis, headache, nausea, dementia, irritability caused by Cryptococcus neoformans

37. 3. List possible conditions to explain this patient’s cervical lymphadenopathy. h. Bacillary angiomatosis - characterized by the proliferation of blood vessels, resulting in tumour-like masses in the skin and other organs (lymph nodes, brain, bone marrow, spleen, liver) caused by Bartonellahenselae or Bartonellaquintana i. Cytomegalovirus infection - CMV is an important pathogen when CD4+ cell counts fall below 50-100/uL, producing lymphadenopathy, retinitis, colitis, and disseminated disease.

38. 4. Enumerate rheumatologic conditions in HIV-infected individuals

39. HIV-associated Rheumatic Diseases • disorders of the joints and muscles that can result from the HIV infection. • Painful joints and muscles are usually the first and most common complaints. • HIV-associated Rheumatic Diseases are: • Reactive arthritis – Reiter’s syndrome, Psoriatic Arthritis • HIV-associated arthropathy • Painful articular syndrome • Diffuse infiltrative lymphocytosis syndrome (DILS) • Fibromyalgia, septic arthritis, vasculitis Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

40. Reiter’s Syndrome • a triad of arthritis, urethritis & conjunctivitis • usually develops following an intestinal or a genital/urinary tract infection Psoriatic Arthritis • type of inflammatory arthritis that affects 10-30% of people suffering from the chronic skin condition psoriasis • exact cause unknown; genetic cause? Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

41. Reiter’s Syndrome & Psoriatic Arthritis • Occur with increasing frequency as the competency of the immune system declines • Related to an increase in infections with organisms that trigger a reactive arthritis with progressive immunodeficiency or to a loss of important regulatory T cells. Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

42. HIV-associated Arthropathy • Characterized by subacuteoligoarticular arthritis developing over a period of 1-6 weeks and lasting 6 weeks to 6 months • Generally involves the larger joints (knees and ankles) • Non-erosive with only a mild inflammatory response • NSAIDs are marginally helpful • Intra-articularglucocorticoids have been more useful in pain relief Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

43. Painful Articular Syndrome • 10% of AIDS patients • Presents as acute severe sharp pain in the affected joint (knees, elbows and shoulders) • Episodes last 2-24 hrs • Cause is unclear; however, it may be a result from a direct effect of HIV on the joint. • Condition is reminiscent of the fact that other lentiviruses (caprine arthritis-encephalitis virus) are capable of causing arthritis Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

44. Diffuse Infiltrative Lymphocytosis Syndrome (DILS) • Autoimmune disease that occurs with an increased frequency in HIV patients • Parotid gland enlargement, dry eyes, dry mouth associated with lymphocytic infiltrates of the salivary gland and lung • Infiltrates predominantly CD8+ T cells Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

45. Other Rheumatologic Disorders associated with HIV Patients • There have been reports of leukocytoclastic vasculitis in the setting of zidovudine therapy. • CNS angiitis and polymyositis have also been reported. • Septic arthritis = due to S. aureus, systemic fungal infections Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

46. 5. Describe the features/treatment of TB in the HIV patient, which may differ from that in a non-HIV patient

47. TB in an HIV Patient • A new TB infection acquired by an HIV infected patient may evolve to active disease in weeks rather than months or years. • When CMI is only partially compromised, pulmonary tuberculosis presents in a typical manner. • In late stages of HIV infection, a primary tuberculosis-like pattern, with diffuse interstitial or miliary infiltrates, little or no cavitation, and intrathoraciclymphadenopathy is more common. • Sputum smears may be positive less frequently.

48. TB in an HIV Patient • Extrapulmonary TB is more common (lymphatic, disseminated, pleural and pericardial are the most common) • Atypical radiographic findings, lack of classic granuloma formation in late stages, negative TST.

49. Treatment Regimen

50. Treatment • Standard treatment are equally efficacious, with more pronounced adverse effects. • Increased frequency of drug interactions between antiretroviral therapy and rifamycins • Development of of Rifampin monoresistance. • Substitute rifabutin to rifampin.