Acquired Immunodeficiency Syndrome 12
What the USMLE Requires You To Know
•The receptors and coreceptors of HIV
•The immunologic results of systematic TH-cell eradication
•The mechanisms through which HIV evades the immune response
Of allthe newly emerging pathogens of the past century, none so efficiently and in exorably eradicates the functioning ofthe immunesystem as the human immunode ficiency virus (HIV). This D-type retrovirus attaches to CD4 receptors on host cells (TH cells, macrophages, and microglia) and utilizes several chemokine receptors on these cells as coreceptors. Early in the infection, thevirus uses the CCRS chemokine receptor and is thus predominantly macrophage-tropic, whereas late in the infec tion, the virus uses the CXCR4 chemokine receptor and becomes T cell-tropic.
HIV infection ultimately results in impaired function of both adaptive and innate immune systems. The most prominent defects arise in cell-mediated immunity, but because TH cells and macrophages are infected and destroyed, all aspects of immunity are eventually affected.
In a Nutshell
•HIV infects CD4+ cells.
•CXCR4 and CCRS chemokine receptors are coreceptors.
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Chapter 12 • Acquired Immunodeficiency Syndrome
Chapter Summary
•HIV infects CD4+ cells (TH cells and macrophage lineages) using CCRS and CXCR4 chemokine coreceptors.
• HIV destroys cell-mediated and humoral immune responses by eradicatingTH cells.
•HIV evades the immune response through glycosylation of surface antigens and antigenic drift.
•HIV is diagnosed using ELISA and Western blot for anti-HIV antibodies.
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Section I • Immunology
Review Questions
1. A 27-year-old woman who was 5 months pregnant presented forprenatal care. A routine evaluation was performed, which included testing for HIV antibody. The patient was reported to be negative for RPR but positive for HIV antibody by the EIA assay. The HIV Western blot only demonstrated the presence of an antibody to the HIV p24 antigen. How should this patient be counseled?
(A)That she and her baby are both infected with HIV
(B)That she is negative for HIV because the RPR is more specific (C) That she is positive for the HIV virus
(D)That she should have an HIV polymerase chain reaction (PCR) test per formed
(E)That this is a confirmed false-positive HIV result
2. A neonate born to a known HIV-positive mother is evaluated for HIV status. What would be the assay of choice?
(A)CD4 cell count
(B)EIA for the detection of HIV antibody
(C)Polymerase chain reaction (PCR) for the detection of HIV DNA
(D)gpl20 antigen assay
(E)Western blot
3.The attachment of HIV to a TH cell is initiated by the binding of the HIV gpl20 molecule to the CD4 receptor. Then gpl20 undergoes a conformational change and binds to a second molecule. What is the second molecule on the surface of the CD4 lymphocyte that acts as a coreceptor and binds with the lymphotropic HIV?
(A)The chemokine receptor CCRS expressed on dendritic cells
(B)The chemokine receptor CXCR4 expressed on T cells
(C) The chemokine receptor CXCRS expressed on T cells
(D)The complement receptor CR2 (CD21) on B cells
(E)The cytokine receptor CCRS expressed on T cells
4.A male exotic dancer in San Francisco has been HIV-positive for 10 years. Because of his low income, he can only irregularly afford the antiretroviral drugs prescribed to him at the AIDS clinic. When he presents to the clinic for a checkup, his CD4 cell count is found to be 390/mm3. Which of the following immunologic parameters is likely to be most profoundly depressed at this stage of his infection?
(A)Cell proliferation in response to pokeweed mitogen
(B)Delayed-type hypersensitivity to Candida antigens
(C)IgA production
(D)Intracellular killingofbacteria
(E)Rejection of allogeneic skin grafts
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Chapter 12 • Acquired Immunodeficiency Syndrome
5. Patients with HIV infection begin to display an immunologic deviation toward TH2 responses relatively early in the course of their disease. Which of the fol lowing cytokines would be increased in a patient with a CD4 count of 500/ mm3?
(A)IFN-y
(B)IL- 1
(C)IL-2
(D)IL-10
(E)TNF-
Answers and Explanations
1.The correct answer is D. A patient who is HIV EIA-positive must always have the result confirmed by a confirmatory assay, e.g., HIV Western blot. The HIV Western blot is considered positive when the patient demonstrates the presence of antibody to at least 2 of 3 important HIV antigens, which are gpl20, gp41, and p24. If no reaction is observed, then the patient is considered negative, but any reaction that is not consistent with a positive is reported as indeterminate.
This patient is considered indeterminate. The physician can wait 6 months and retest by the EIA assay, with a reflex to the Western blot assay ifthe EIA result is positive. If the Western blot results are identical to the previous, then the patient is reported as negative or the patient can be tested by another confirmatory test such as the PCR assay. A negative PCR in this situation would classify this patient as negative; however, it would be wise to retest the patient in 3 to 6 months if she has risk factors.
That she and her baby are both infected with HIV (choice A) is not correct. Approximately 30% of the babies from untreated and <8% from treated HIV positive mothers willbe infected.
That she is negative for HIV because the RPR is more specific (choice B) is not correct because RPR is not a test for HIV but a test for syphilis.
That she is positive for the HIV virus (choice C) is not correct because her Western blot was indeterminate, and a confirmatory test (e.g., Western blot or PCR) must confirm the EIA assay before the patient can be reported positive.
That this is a confirmed false-positive HIV result (choice E) may eventually be proven to be correct, but with the present data one does not know ifthe patient has been detected in the early stages of seroconversion or is simply a patient who is false positive.
2.The correct answer is C. The neonate could not be tested for anti-HIV anti
bodies because the known HIV-positive mother passively transmits anti-HIV IgG antibodies to the baby through the placenta. Allbabies born to HIV positive mothers will be anti-HIV antibody-positive. Because of the sensitivity of HIV antibody testing, an HIV antibody test on a specimen from a baby born to an HIV-positive mother should not be believed until 15 months of age. The test of choice is to detect the DNA of the virus by PCR.
CD4 cell count (choice A) is not correct because this assay is used to measure the progression of the disease and the destruction ofthe target CD4+ cells. It is not a diagnostic test for the presence of the virus or antiviral antibodies.
EIA for the detection of HIV antibody (choice B) is incorrect because maternal antibodies can be detected in babies who are from known HIV-positive moth ers for up to 12 months after birth. The HIV EIA assay is an antibody-screening test, whereas the HIV Western blot is a confirmatory test for the presence of anti-HIV antibody.
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Section I • Immunology
pl20 antigen assay (choice D) is incorrect because there is no such test as an HIV gpl20 antigen assay. The ELISA (EIA) tests for p24 antibody.
Western blot (choice E) is incorrect because maternal antibodies can be detect ed in babies who are from known HIV-positive mothers for up to I2 months after birth. The HIV EIA assay is an antibody-screening test, whereas the HIV Western blot is a confirmatory test for the presence of anti-HIV antibody.
3.The correct answer is B. The HIV envelope, derived from the host-cell mem brane, displays viral glycoproteins gpI20 and gp41. The gpI20 glycoprotein has
a high affinity for CD4 and is thus important in the attachment of the virus to the cell. Allcells expressing CD4 are potential targets for infection with HIY. After the gpI20 of the HIV binds to the CD4, it undergoes a conformational change and must then bind to a second molecule, a coreceptor, on the surface of the target cell. The variation of the gpI20 molecule determines the tropism of the HIV and thus dictates which CD4+ cell can be infected. Lymphotropic HIV virions use the CXCR4 chemokine receptor (coreceptor) expressed on T cells and require a high density of CD4 on the surface of the cell. Macrophage tropic HIV uses the CCRS chemokine receptor and requires only a low level of CD4 expression on the target cell.
The CCRS chemokine receptor expressed on dendritic cells (choice A) is not correct. The question is addressing the infection of TH, not dendritic, cells.
The CXCRS chemokine receptor expressed on T cells (choice C) is not correct. The chemokine receptor on T cells is CXCR4, not CXCRS.
The complement receptor CR2 (CD2I) on B cells (choice D) is not correct. CR2 (CD2I ) is found on B cells and is not the coreceptor on TH cells for the attachment of HIY. CR2 is the receptor for EBV.
The CCRS cytokine receptor expressed on T cells (choice E) is not correct. Chemokines are small cytokines of relatively low molecular weight released from a variety ofcells involved in inflammatory responses; however, the receptor on the T cells is CXCR4. The CCRS is found on macrophages and dendritic cells.
4.The correct answer is B. At this stage of this patient's infection, TH cell num bers are depressed to the point that TH-dependent immune responses will be depressed. Because delayed-type hypersensitivity is a purely THI -mediated response, it will be impaired at this stage of infection.
Cell proliferation in response to pokeweed mitogen (choice A) is incorrect because pokeweed mitogen is a B-cell mitogen. These responses will remain within normal limits until the end of life in an HIV-positive patient.
IgA production (choice C) is not correct because these antibodies will not begin to fall untillater in the infection. IgA is a TH2-dependent antibody, but at this stage ofinfection, there should still be B memorycells capable ofmounting this response.
Intracellular killingof bacteria (choice D) is mediated by phagocytic cells. Although THI cytokines contribute to phagocyte activation, the intracellular killingmechanisms themselves should be unaffected in this patient.
Rejection of allogeneic skin grafts (choice E) is a CD8+ cell-mediated response and should not begin to be depressed until later in the course of HIV infection. Although cytotoxic T lymphocytes are stimulated by the cytokines ofTH1 cells, this response should remain relatively normal at this stage of the disease.
5.Thecorrect answeris D.Most patients willbegin to show immune deviation of TH responses toward the TH2 arm around 600 CD4+ cells/mm3. As the TH2 response is augmented, IL-4 and ILIO will be produced, which further inhibit the THI response. Over time this leads to more and more profound skewing of the immune response toward a humoral response and more and more produc tion of TH2 cytokines, such as IL-10 and IL-4.
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Chapter 12 • Acquired Immunodeficiency Syndrome
Interferon-y (choice A) is a product of THI cells that stimulates the effector cells of cell-mediated immunity and inhibits the TH2 cell.'This cytokine would be decreasing in the patient at this point.
IL- I (choice B) is a product of activated macrophages. Macrophages are acti vated by THI cytokines, so interferon-y production should begin to decrease at this time.
IL-2 (choice C) is a product of THO and THI cells. Its levels would probably be unaffected at this point in an infection.
Tumor necrosis factor- (choiceE) is a product ofTHI cells that stimulates the effector cells of cell-mediated immunity. This cytokine would be decreasing in the patient at this point.
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Section I • Immunology
In a Nutshell
In all hypersensitivity reactions:
•First exposure sensitizes.
•Subsequent exposures damage.
•Reaction is Ag-specific
In a Nutshell
Type I Hypersensitivity
•lgE-mediated
•Protective response to helminths
•Atopic/allergic individuals develop this response to inappropriate stimuli
What the hypersensitivity reactions have in common:
•The first exposure to the antigen "sensitizes" lymphocytes.
•Subsequent exposures elicit a damaging reaction.
•The response is specific to a particular antigen or a cross-reacting substance.
TYPE I (IMMEDIATE) HYPERSENSITIVITIES
This is the only type of hypersensitivity mediated by IgE antibodies and mast cells. It is manifested within minutes ofthe reexposure to an antigen. The IgE response is the normal protective response against many metazoan parasites, which are too large to be phagocytized or killed by other cytopathic mechanisms. Twenty percent ofallindi viduals in the United States, however, display this immune response against harmless environmental antigens, such as pet dander or pollen: We call these responses atopic or allergic responses.
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Chapter 13 • Diseases Caused by Immune Responses: Hypersensitivity and Autoimmunity
1First exposure to allergen
2 TH2 release of IL-4 and IL-1 3stimulates B cell to produce
Ir.. lgE; class switching occurs
)(lgE Antibody
3B cell produces lgE immunoglobulin; it attaches to Fe receptor on mast cell
4Second exposure to allergen
5Allergen cross-links several lgE molecules on mast cell and cell degranulates, releasing powerful chemicals
Figure 1-1 3-1 . Development of the Immediate-Hypersensitivity Reaction
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Chapter 13 • Diseases Caused by Immune Responses: Hypersensitivity and Autoimmunity
In some types oftype II hypersensitivities, complement is activated and/or ADCC is ac tive (e.g., hemolytic disease ofthenewborn [HDNB]).In othertypes oftype II hypersen
sitivities, cellfunction isalteredintheabsence ofcomplementactivationand ADCC (e.g., myasthenia gravis and Graves disease). Eventually, as these diseases progress, complexes ofantigen and antibody may cause localized damage, but these complexes do not circu late so the damage is localizedto the specific tissue.
An important example oftype II hypersensitivityis HDNB, also known as erythroblas tosis fetalis. In the fetus, this disease is due to transport ofIgG specific for one ofthe Rhesus (Rh) protein antigens (RhD) across the placenta. About 85% ofpeople are Rh+.
Ifa pregnant woman is Rhand the father is Rh+, there is a chance that the fetus will also be Rh+. 1his situation willpose no problem in the first pregnancy, as the mother's immune system willnot usually encounterfetalblood cell antigens until placentalsepa ration atthe time ofbirth.Atthat time, however, Rh+ fetal red blood cells willenterthe maternal circulation and stimulate a T-dependentimmuneresponse, eventually result ing in the generation of memory B cells capable of producing IgG antibody against RhD. In a subsequent pregnancy with another Rh+ fetus, this maternal IgG can be transported acrosstheplacenta, reactwithfetal Rh+ red cells, andactivatecomplement, producing hemolytic disease. Hemolytic disease ofthe newborn can be prevented by treating the Rhmother with RhoGAM™, a preparation ofhuman anti-RhD IgG an tibody, at 28 weeks of gestation and again within 72 hours after birth. 1his antibody effectivelyeliminates the fetal Rh+ cellsbeforetheycan generate RhD-specificmemory B cells inthemother. Anti-RhD antibodyshouldbegivento anyRhindividualfollow ing anytermination ofpregnancy.
RhDMother
Maternal
Erythrocytes
RhD
Antigen
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Fetal |
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Delivery of |
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RhD+ Baby |
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RhD |
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Antigen |
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Fetal |
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erythrocytes |
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Subsequent Pregnancy |
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Crosses Placenta to |
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React with Baby RhD+ |
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In a Nutshell
Hemolytic Disease ofthe Newborn (HDNB)
•Erythroblastosis fetalis
•Anti-RhD+ lgG
•Formed in Rhmother carrying Rh+ child
•First pregnancy sensitizes
•Ab crosses placenta and injures sub sequent fetuses
•Prevent with RhoGAM™
Baby RhD+ RBCs Coated with |
Maternal Anti-RhD+ Antibody |
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Produced in Response to Fetal |
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Maternal Anti-RhD+ Antibody |
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RhD Erythrocytes |
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Figure 1-13-3. Hemolytic Disease of the Newborn |
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