Chapter 13- Failures of the Body's Defenses

Question 1

Primary immunodeficiency diseases

Answer 1

When there is a failure of immunological function as a result of a defect in one or more genes encoding components of the immune system. There are more than 350 primary immunodeficiencies, but most are very rare and occur in small populations that are geographically or culturally isolated

Question 2

Secondary immunodeficiency diseases

Answer 2

When there is a failure of immunological function as a result of infection or the use of immunosuppressive drugs, rather than a genetic defect

Question 3

How do immunologists study the immune system in the laboratory?

Answer 3

They knock out a selected gene and look at the immunodeficiency this causes. For some genes, their deletion from human and mouse genomes leads to similar phenotypes, while for other genes the phenotypes are different between the two species

Question 4

Carrier

Answer 4

A person who carries one copy of a recessive allele for a hereditary disease that does not show symptoms. The allele can be passed onto future generations

Question 5

X-linked diseases

Answer 5

Caused by recessive defects in genes on the X chromosome. Because males only have one X chromosome and females have two, the disease occurs in all males who inherit an X chromosome with a defective allele. Females must inherit 2 copies of the defective gene to develop the disease, so only females can serve as healthy carriers

Question 6

When are dominant immunodeficiencies most commonly seen?

Answer 6

When the defective gene encodes a protein that functions in a dimer or a larger protein complex. In these cases, the incorporation of one defective subunit can reduce or destroy the capacity of the complex to function. Before antibiotics were introduced in the 1950s, any dominant trait causing a severe immunodeficiency would have been eliminated from the population with the death of the first child carrying the mutation

Question 7

Interferon-γ

Answer 7

The main cytokine that activates macrophages. IFN-γ is important for defending against intravesicular bacteria, like mycobacteria. In the innate immune response, it is secreted by NK cells. In the adaptive immune response, it is secreted by TH1 CD4 T cells and cytotoxic CD8 T cells. When Interferon-γ binds to the Interferon-γ receptor on the surface of the macrophage, it induces changes in gene expression that better equip the macrophage for engulfing and killing bacteria

Question 8

Interferon-γ structure

Answer 8

IFN-γ is a dimer, composed of IFN-γR1 and IFN-γR2 polypeptides. The dimer associates with JAK1 and JAK2 tyrosine kinases. Functional IFN-γ is also dimeric, and binds to sites on 2 IFN-γR1 polypeptides, which cross-links them to initiate a signaling cascade

Question 9

Dominant allele

Answer 9

An allele that influences the phenotype in both homozygous and heterozygous individuals. Usually refers to disease-causing alleles that encode proteins with functional defects

Question 10

Recessive allele

Answer 10

An allele that expresses its phenotype only when a person inherits 2 copies. It may also be expressed if no other copy of the allele is present, as in the X chromosome in males

Question 11

Recessive mutations of IFN-γR1

Answer 11

People with these mutations produce a mutant chain that doesn’t reach the surface. Therefore, people who have inherited 2 mutant alleles only have IFN-γR2 at the surface, lack IFN-γR1, and can’t respond to IFN-γ. People who are heterozygous for this mutation produce enough wild-type IFN-γR1 chains to assemble enough functional receptors and respond to IFN-γ. Recessive disease is severe and presents at an early age

Question 12

Dominant mutations of IFN-γR1

Answer 12

A person who is heterozygous for a dominant mutation produces a truncated chain that lacks a signaling domain. This chain can assemble into a dimer and bind IFN-γ but can’t signal, even when it is cross-linked with a dimer that has a normal chain. A small amount of functional receptors composed of all normal chains can be made, but most aren’t functional. Monocytes of patients with a dominant mutation are more responsive to IFN-γ than the monocytes of patients with a recessive mutation, so the disease is less severe and detected at a later age

Question 13

IFN-γ receptor deficiency

Answer 13

Genetic immunodeficiency caused by a lack or low levels of the IFN-γ receptor on macrophages and monocytes. Dominant and recessive mutations have been observed. The disease is characterized by the inability to clear intracellular bacteria, especially mycobacteria

Question 14

What are the consequences of antibody deficiencies?

Answer 14

These patients are predisposed to infection by pyogenic (pus-forming) bacteria. Encapsulated bacteria, such as Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus, are not recognized by the phagocytic receptors of macrophages and neutrophils. Therefore, they escape being immediately detected by the innate immune response. These infections are usually cleared when the bacteria are opsonized by specific antibody and complement, and are killed by phagocytes. However, patients with antibody deficiencies can’t clear the infections without antibiotics

Question 15

X-linked agammaglobulinemia (XLA)

Answer 15

An immunodeficiency disease due to a defect in Bruton’s tyrosine kinase protein (BTK). Males who inherit a BTK mutation on the X chromosome can’t produce functional B cells. This is because B cells are arrested at the pre-B stage.

Question 16

Bruton’s tyrosine kinase (BTK) function

Answer 16

Contributes to intracellular signaling from the B-cell receptor, and is necessary for the development and differentiation of pre-B cells. BTK is expressed in monocytes and T cells as well, but the functions of these cells don’t seem to be impacted in people with BTK mutations

Question 17

How are immunodeficiencies usually detected?

Answer 17

By a history of recurrent infections. The type of infection is usually suggestive of the defect- pus forming bacteria suggests a defect of antibody, complement, or phagocyte function. Recurrent fungal or viral infections indicate dysfunction of T cells

Question 18

Autosome

Answer 18

Any chromosome that is not a sex chromosome

Question 19

X-linked agammaglobulinemia (XLA) in females

Answer 19

Females who are heterozygous are healthy, but are considered carriers and pass on XLA to 50% of their sons. During development, cells in females randomly inactivate one X chromosome. Therefore, half of developing B cells in a female carrier are arrested at the pre-B cell stage because those cells inactivated the X chromosome that has a functional copy of BTK. The other half of the developing B cells become functional B cells because they inactivated the X chromosome that has the bad copy of BTK, and therefore use the good copy of the X chromosome

Question 20

Bronchiectasis

Answer 20

Chronic inflammation of the bronchioles of the lung, which can lead to chronic lung disease and death

Question 21

Long term effects of B cell deficiencies

Answer 21

Patients with diseases like XLA are able to successfully resist many pathogens, and can be treated with antibiotics when they develop infections. However, successive rounds of infection with pyogenic bacteria and antibiotic treatment may lead to permanent tissue damage caused by the excessive release of proteases from the infecting bacteria and defending phagocytes. May lead to bronchiectasis

Question 22

Treatment of XLA

Answer 22

Monthly injections of intravenous immunoglobulin- the immunoglobulin contains antibodies against all common pathogens and provides passive immunity against those pathogens

Question 23

CD40 ligand

Answer 23

CD40 ligand on activated T cells interacts with the CD40 on B cells. This interaction helps to stimulate B cell activation, the development of germinal centers, and isotype switching. Macrophage activation by effector CD4 T cells also depends on the interaction of macrophage CD40 and the CD40 ligand on T cells

Question 24

X-linked hyper-IgM syndrome (CD40 ligand deficiency)

Answer 24

An X linked condition, so most patients are males. Without CD40 ligand, no specific antibody is made against T cell-dependent antigens and there are no germinal centers in the secondary lymphoid tissues. There are abnormally high levels of circulating IgM and extremely low levels of IgG, IgA, and IgE. Patients are susceptible to infection with pyogenic bacteria and have to receive intravenous immunoglobulin infusions

Question 25

Neutropenia

Answer 25

Low numbers of neutrophils in the blood. This can be due to many causes, including genetic deficiencies in neutrophil production or autoimmunity directed against surface antigens on white blood cells. Causes severe sores and blisters in the mouth and throat. People with CD40L deficiency develop neutropenia because macrophage production of granulocyte-macrophage colony stimulating factor (GM-CSF) is impaired, so they can’t stimulate the development of neutrophils in the bone marrow and their release into circulation

Question 26

Leukocytosis

Answer 26

Increased numbers of leukocytes in the blood. In immunocompetent people, this is part of the immune response to infection

Question 27

Why does disruption of the mucosal tissues occur with neutropenia?

Answer 27

These tissues are always infected with bacteria. Their control requires constant surveillance by large numbers of neutrophils. In people with X-linked hyper-IgM syndrome, the disruption can cured by the IV administration of GM-CSF

Question 28

Importance of complement activation

Answer 28

All of the effector functions that antibodies carry out to clear pathogens and their products are facilitated by complement activation. Therefore, infections associated with antibody deficiency and complement deficiency can overlap

Question 29

Defects in C3

Answer 29

Cause susceptibility to pyogenic infections. This is because C3 is very important as an opsonin.

Question 30

Defects in C5-C9

Answer 30

These components of complement are the terminal parts of the membrane attack complex. However, defects in these molecules have relatively few effects. One effect is increased susceptibility to Neisseria infection, as the defense against Neisseria is complement-mediated lysis of extracellular bacteria. This requires many complement components, including C5-C9

Question 31

Immune-complex disease

Answer 31

A disease caused by the abnormal formation of antigen-antibody complexes and their deposition in tissues. This is often due to autoimmune diseases. Deposition of these complexes causes inflammation

Question 32

Deficiencies in complement components C1-C4

Answer 32

This impairs the formation of C4b and C3b, which creates an accumulation of immune complexes in the circulation. The complexes are then deposited in tissue, where they damage the tissue and activate phagocytes to induce inflammation

Question 33

How are immune complexes transported?

Answer 33

By erythrocytes. The erythrocytes use CR1 to bind to the C4b and C3b that are attached to the complexes

Question 34

Factor I deficiency

Answer 34

Leads to a deficiency in C3, which is the most important component of the complement system. The cleavage of C3 to make C3b continues in an uncontrolled manner if factor I isn’t present

Question 35

Infections caused by Neisseria bacteria (2)

Answer 35

1. N. meningitidis: meningitis, septicemia
2. N. gonorrhoeae: gonorrhea

Question 36

Factor P deficiency

Answer 36

Factor P is the plasma protein that stabilizes the C3 convertase of the alternative pathway. These patients are susceptible to Neisseria because they don’t have enough C3b to assemble the MAC and kill the bacteria

Question 37

IL-12 receptor deficiency

Answer 37

Patients exhibit impaired innate and adaptive immune responses to intracellular bacteria, such as mycobacterium tuberculosis.

Question 38

Defects in phagocytic function

Answer 38

Can include defects in the molecules cells need for trafficking (leukocyte adhesion deficiency), defects in the NADPH oxidase enzyme (chronic granulomatous disease), defects in other enzymes important for forming toxic molecules that destroy microbes taken up by phagocytosis. There may also be a defect in lysosomal trafficking protein (Chediak-Higashi syndrome)

Question 39

IL-12 function

Answer 39

IL-12 involved in the cross-talk between NK cells and macrophages. IL-12 is produced by macrophages and acts on the IL-12 receptor on NK cells, which causes the cells to secrete IFN-γ. IFN-γ then goes on to signal to the macrophage to kill the pathogens that were residing inside. It is also involved in TH1 CD4 T cell differentiation. When a naive T cell is responding to pathogens presented by the macrophage through MHC class 2, the IL-12 produced helps the cell to differentiate into a TH1 cell. The TH1 cell can then secrete IFN-γ, which can act on the macrophage or other cell types

Question 40

Can primary immunodeficiencies be cured?

Answer 40

Antibiotics and IVIG help to manage the disease, but not cure it. Some diseases can be cured by a bone marrow transplant. We ablate the person’s bone marrow and give them the new bone marrow from a healthy, matched donor. The immune system is repopulated with bone marrow that contains a functional copy of a gene. Gene therapy has also been done with certain forms of SCID, using an adenovirus vector containing a healthy form of the gene. The gene is then delivered to the cells of the body

Question 41

Severe combined immunodeficiency (SCID)

Answer 41

A severe immunodeficiency where neither antibody nor T cell responses are made. 15% of SCID cases are patients who have inherited a deficiency of adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP). There are also 2 forms of SCID that are X linked

Question 42

Treatment for SCID

Answer 42

The effects are so severe that infected infants will only survive if their immune system is replaced by hematopoietic stem-cell transplantation

Question 43

Adenosine deaminase (ADA) deficiency

Answer 43

One of the enzymes involved in purine degradation- it converts adenosine to inosine. The absence of these enzymes causes nucleotide metabolites (2’-deoxyadonsine and dATP) to accumulate in all cells, but is especially toxic to developing T cells. Children with this form of SCID have a poorly developed thymus that has few lymphocytes. The deficiency is inherited in an autosomal recessive manner

Question 44

X-linked SCID

Answer 44

Caused by a mutation in the X-chromosome gene that encodes the common gamma chain (γC). This chain is a signaling component of the cell surface receptors for multiple cytokines that are key for B and T cell development, including IL-2, IL-7, and IL15. When one of the cytokines binds to its receptor, γC interacts with the protein kinase JAK3 to produce intracellular signals, If the γ chain of the receptor isn’t functional, none of the 5 cytokines induces signaling when it binds to the receptor. T cells are more dependent on IL-7 than B cells, so patients do not make any T cells. B cell numbers are normal but can only make T-cell independent antibody responses

Question 45

Rag1/Rag 2 deficiency

Answer 45

Another form of autosomal recessive SCID where there is a complete lack of Rag1/Rag2. These enzymes play a critical role in creating B cell and T cell receptors. The deficiency results in no VDJ recombination and a complete lack of T and B cells

Question 46

Omenn syndrome

Answer 46

A reduced amount of RAG1/RAG2. In this case, B cells are not produced, but a small amount of T cells are produced

Question 47

DiGeorge syndrome

Answer 47

Impacts the development of the thymus. Without the thymus, T cell development cannot occur. In the absence of T cells, only T-independent B cell responses can occur. These responses are low affinity and typically involve IgM

Question 48

Bare lymphocyte syndrome

Answer 48

Type 1- no MHC class 1 is produced, usually caused by a TAP1 or TAP2 defect. There is also a type 2 of the syndrome- no MHC class 2, caused by a defect in the C2TA transcription activator. It regulates the expression of molecules that is needed to form MHC class 2

Question 49

Defect in B cell development

Answer 49

These patients have an increased susceptibility to extracellular bacteria with polysaccharide capsules. There is no ability to opsonize and a reduced ability to fix complement on those pathogens, which causes the increased susceptibility. Patients also have an increased susceptibility to some viruses. Antibodies are responsible for neutralization of the virus, so if there are no antibodies, there is no neutralization

Question 50

CD45 phosphatase defect

Answer 50

CD45 phosphatase downregulates T cell responses. This leads to a defect in peripheral T cells

Question 51

Wiskott-Aldrich syndrome

Answer 51

Caused by a defect in the Wiskott-Aldrich syndrome protein (WASP), which is activated during T cell receptor signaling. It causes a reorganization of the cytoskeletal proteins that allows for the synapse to form between the helper T cell and B cell/APC. Without WASP, the synapse doesn’t form, and it’s difficult for the synapse to be fully activated and allow for T cell responses. A mutation also leads to a platelet defect (clotting disorder)

Question 52

CD3 complex defects

Answer 52

CD3 plays an important role in transferring signals through its ITAMs domain. Without CD3, thymocytes fail to progress to the double positive stage because they don’t get the interaction between the TCR and the MHC molecule. This is another defect that causes SCID

Question 53

Pre-T cell receptor

Answer 53

A receptor that is present on the surface of some immature thymocytes. It’s made of a TCRβ chain associated with PTα. To form it, each heterodimer superdimer assembles with the CD3 complex and ζ chain

Question 54

Pre-T cell receptor signaling

Answer 54

This receptor generates intracellular ligands rather than using an exogenous ligand. The signals are mediated by the CD3 complex and Lck. Assembly of the pre-T cell receptor signals the thymocyte to stop the rearrangement of the β, γ, and δ chains. Once a thymocyte has passed the pre-T cell receptor developmental checkpoint, it becomes a pre-T cell and moves on to the next stage of development.

Question 55

Immunoreceptor tyrosine-based activation motifs (ITAMs)

Answer 55

Phosphorylated tyrosine residues in the cytoplasmic tails of CD3 proteins form part of short sequences known as ITAMs. Enzymes and other signaling molecules bind to the phosphorylated tyrosines and they too become activated. Therefore, the extracellular binding of antigen to TCRs triggers the pathways of intracellular signaling that drive T cell differentiation. They are found on CD3 gamma, delta, epsilon, and zeta chains. Phosphorylated ITAMS recruit and activate the kinase ZAP-70

Question 56

Wiskott-Aldrich syndrome symptoms (6)

Answer 56

1. Low IgA- B cells aren’t properly activated and don’t return to the germinal center to undergo isotype switching and affinity maturation
2. Low IgM- even the initial B cell response is impacted
3. Low platelets- clotting defect
4. Eczema
5. Blood diarrhea
6. Recurrent bacterial infections

Question 57

Hyper IgE syndrome symptoms (6)

Answer 57

1. Eczema
2. Recurrent infections, like S. aureus, sinus infections and ear infections, and pneumonia
3. Normal lymphocytes and neutrophils, but high eosinophils
4. Normal levels of IgG and IgA, slightly elevated IgM
5. Abnormally high IgE
6. Skeletal and dental abnormalities- facial asymmetry (broad nose, deep set eyes), scoliosis, bone fractures, and hyperextensibility of joints. STAT3 is also utilized in other cells for other functions

Question 58

Hyper IgE syndrome (Job’s syndrome)

Answer 58

Caused by a defective STAT3. Patients exhibit impaired signaling for IL-6, IL-22, and IL-23, which controls differentiation into TH17 cells. Without the correct signaling, RORγT will not be expressed which is the key transcription factor for TH17 cell differentiation. Patients exhibit a reduced ability to mount inflammatory responses, an increased susceptibility to S. aureus and C. albicans (fungal) infections, facial asymmetry (broad nose, deep set eyes), scoliosis, bone fractures, and hyperextensibility of joints

Question 59

JAK/STAT cytokine signaling pathway

Answer 59

Once the cytokine binds to the receptor, JAK becomes activated. JAK recruits and phosphorylates the STAT molecules. The STATs dimerize and travel from the cytoplasm into the nucleus to turn on genes. People with a defective STAT3 molecule (as in hyper IgE syndrome) have impaired signaling for IL-6, IL-22, and IL-23, which controls differentiation into TH17 differentiation

Question 60

Public health burden of measles

Answer 60

One of the most contagious diseases known to humankind- there were 2.6 million deaths yearly prior to the development of the MMR vaccine. Measles is still a critical health concern due to the lack of access to vaccination and refusal to get vaccinated. It still infects more than 7 million people and kills more than 100,000 each year worldwide. 20% of people in the US who get infected with measles require hospitalization. Complications include brain damage as well as vision and hearing loss

Question 61

Which immune cells does measles infect?

Answer 61

The measles virus can infect dendritic cells and monocytes. The virus is then able to travel to lymphoid tissues, where it can also interact with memory T and B cells

Question 62

Measles immune amnesia

Answer 62

A resetting of the immune system that can occur in infected patients. Measles virus replaces the old memory cells of its host with new MV-specific lymphocytes (T cells and B cells). Patients lose 11-73% of pre-existing antibodies to pathogens the individual had been exposed to

Question 63

How was HIV discovered?

Answer 63

HIV was discovered in the early 1980s in the United States. Physicians in New York and California made the first observations of a new infectious disease in homosexual men. There was also a sudden appearance of a rare skin cancer called Kaposi’s sarcoma. Other complications included atypical pneumonia caused by Pneumocystis carinii, CMV infections, Candiasis, and other observed opportunistic infections

Question 64

History of HIV and AIDS

Answer 64

All observed individuals suffered from immune suppression. In 1981, the syndrome was named gay-related immunodeficiency (GRID), but it was renamed to AIDS in 1982. By 1983, there were 2304 AIDS deaths. In 1985, Rock Hudson announced he had AIDS and died. In 1991, Magic Johnson tested positive for HIV

Question 65

When was HIV isolated?

Answer 65

In 1984, two research teams (one in the US, one in Europe) described a retrovirus isolated from cultured T cells from the lymph node biopsy of an AIDS patient

Question 66

HIV transmission

Answer 66

HIV is present in blood, semen, vaginal fluids, breast milk, saliva (low levels), and tears (low levels). It can be transmitted through sex without a condom, from mother to baby during delivery, sharing injecting equipment, or contaminated blood transfusions and organ transplants. HIV an enveloped virus that is fragile, and can only pass in fluids.

Question 67

HIV cases worldwide

Answer 67

There are new cases of HIV every year, although this number has decreased over time. The highest proportion of cases occur in parts of Africa, eastern Europe, and the Asian pacific.

Question 68

Human immunodeficiency virus (HIV) structure

Answer 68

HIV is an enveloped retrovirus- has an RNA genome that is converted to DNA. The envelope contains gp120 and gp41 proteins, which are important for the infection process. HIV also contains enzymes such as reverse transcriptase, which it uses to convert its genome to DNA

Question 69

The life cycle of HIV in human cells (8)

Answer 69

1. The virion gp120 protein binds to CD4 and a co-receptor (CCR5 or CXCR4) on T cells. The binding to both receptors causes a conformational change that allows gp41to mediate viral fusion
2. The viral envelope fuses with the cell membrane, and the viral genome and proteins enter the cell
3. Reverse transcriptase copies the viral RNA genome into double stranded cDNA
4. Viral cDNA migrates from the cytoplasm into the nucleus and randomly integrates into the host cell genome
5. T cell activation induces some transcription of provirus
6. RNA transcripts are splices to allow the synthesis of the early proteins Tat and Rev
7. Tat amplifies transcription of viral RNA. Rev increases transport of RNA to the cytoplasm
8. Gag, Pol, and Env are made and assembled with viral RNA into virions, which bud from the cell

Question 70

Immune response to HIV

Answer 70

The virus is recognized as foreign when it engages PRRs, and patients make an innate and adaptive response against the virus. High amounts of virus are made in the infected individual for the first 4-8 weeks. HIV-specific CD8 killer T cells and CD4 T cells, as well an neutralizing antibodies are produced, but these are not sufficient to clear the virus. This is because the virus is mutates rapidly, as well as “hides” inside cells.

Question 71

Adaptations to HIV-2 vs HIV-1

Answer 71

There are 2 versions of HIV- HIV-1 and HIV-2. HIV-1 has the highest infectivity rate and the highest virulence, and is found globally. HIV-2 has lower infectivity and a slower progression to AIDS (greater than 20 years). It is restricted to parts of western Africa

Question 72

Extinction of CD4 cells during HIV infection

Answer 72

HIV causes immunosuppression by infecting CD4 T cells and killing them. The virus starts off infecting macrophages and monocytes before going on to infect CD4 T cells. In the first 2-6 weeks of infection, the patient experiences flu-like symptoms (sometimes), and there is a dramatic decrease in CD4 T cells. Afterwards, there is a slight rebound in CD4 T cells as the virus becomes latent. However, the number of CD4 T cells gradually decreases over time. Once the count drops below 500, the individual starts experiencing symptoms. Once it drops below 200, the person is considered to have AIDS

Question 73

AIDS

Answer 73

Once established, HIV infection usually leads to AIDS. Hemophiliacs were another population prone to HIV due to their reliance on blood products, which could not be screened for HIV. The likelihood of a HIV+ hemophiliac developing AIDS increased with age due to their inability to generate new T cells. HIV+ hemophiliacs born before 1943 exhibited a much more rapid progression to AIDS than those born after 1943

Question 74

HIV progression to AIDS

Answer 74

Individuals with AIDS are prone to all types of infections- parasitic, bacterial, fungal, and viral. They are also prone to malignancies, including Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and primary lymphoma of the brain. The virus may also travel to the CNS and impact the nervous system, causing dementia due to viral infection of the brain, failure to thrive in children, and premature aging diseases (associated with the elderly) appear sooner, such as heart disease and osteoporosis. May be due to the chronic inflammation or due to decades taking antiviral drugs

Question 75

How was HIV antiviral therapy developed?

Answer 75

Zidovudine (AZT), a thymine analog, was the RT inhibitor first approved for HIV-1 treatment. As the HIV reverse transcriptase begins to work and convert the RNA to DNA, it incorporates the thymine analog, which blocks additional DNA synthesis. However, drug resistance to AZT emerged as the virus begins to mutate- HIV cannot be treated with only one drug. In 1996, David Ho developed HAART, Highly Active Retroviral Therapy. It uses a cocktail of at least 3 compounds simultaneously to block HIV RT, protease, entry/fusion, integrase, etc.

Question 76

Types of HIV antiviral therapy (7)

Answer 76

1. Non-nucleoside (RTNNI) or
2. Nucleoside reverse transcriptase (RTNI) inhibitors of HIV RT; addition of faulty nucleotides; competitive substrate inhibitors
3. Protease inhibitors
4. Fusion inhibitors
5. Integrase inhibitors
6. CCR5 (co-receptor) blocking inhibitor- blocks viral attachment
7. Pharmacokinetic enhancers- improves the bioavailability of other drugs given to the patient

Question 77

HIV protease inhibitors

Answer 77

Inhibit HIV maturation by blocking an HIV-specific protease, resulting in noninfectious virus. HIV contains proteases that chop up the virus polyproteins into smaller and more functional pieces, so blocking this protein impacts the viral life cycle

Question 78

HIV fusion inhibitors

Answer 78

Block HIV fusion of viral gp41 protein and the host cell membrane

Question 79

HIV integrase inhibitors

Answer 79

Block HIV p32 activity, abolishing integration of the proviral DNA copy of HIV into the host cell chromosome

Question 80

Undetectable viral load

Answer 80

Anti-retroviral therapy reduces bloodborne HIV to undetectable levels. The viral load is undetectable and CD4 T cell counts increase, making HIV a chronic inflammatory disease to be managed. If a person stops taking the drugs, their CD4 T cell counts will decrease again, and they would be at risk of progressing to AIDS

Question 81

How do anti-retroviral drugs increase the number of CD4 T cells?

Answer 81

Productive infection of CD4 T cells accounts for more than 99% of the virus in the plasma. Since infected cells are short-lived, HIV must continually infect new cells. However, if virus production is blocked by a drug, the virus can be rapidly cleared from the blood. CD4 T cells then rapidly increase, replacing those lost by infection

Question 82

Human resistance to HIV

Answer 82

1. Individuals who are homozygous for a defective CCR5Δ32 gene (no CCR5 co-receptor) are virtually resistant to HIV infection. An individual must inherit 2 defective copies
2. Individuals who are heterozygous for the defective CCR5Δ32 gene progress more slowly to AIDS- must inherit 1 defective copy

Question 83

How did human resistance to HIV come about?

Answer 83

The theory is that CCR5Δ32 led to increased survival during smallpox outbreaks that occurred in 14th century Europe. European populations are between 5-14% heterozygous for CCR5Δ32. Some populations are 1% homozygous, including Caucasian North Americans. However, the CCR5Δ32 allele is almost absent in African, Asian, Native American, and Middle Eastern populations

Question 84

Cure for AIDS

Answer 84

The “Berlin” patient was diagnosed with HIV in 1995 and then developed acute myeloid leukemia in 2006. He needed a bone marrow transplant to survive, and received bone marrow from a CCR5Δ32 donor. His levels of HIV plummeted while his CD4 T cell count increased, and he remains off antiretroviral therapy and is considered cured. Experimental gene therapy is under development to induce the CCR5 mutation in a patient’s T cells

Question 85

Why is an HIV vaccine challenging to develop?

Answer 85

An AIDS patient harbors 100 million genetically distinct variants of HIV. HIV variants can escape both antibody and T cell immune responses, so we must design a vaccine to cope with this degree of antigen variability. Some patients produce broadly neutralizing antibodies, which recognize 4 conserved epitopes of the HIV envelope glycoprotein. They are found in a minority of HIV infected individuals

Question 86

Non-infectious factors that can suppress immune function (4)

Answer 86

1. Alcohol exposure- lymphocyte proliferation, phagocytosis are impacted
2. Heavy metals (lead, cadmium)- reduced antibody production
3. Malnutrition- impacts a wide range of physiological functions, including immune responses
4. Statins- decreased inflammatory responses

Question 87

How did scientists discover that measles can induce immune amnesia?

Answer 87

Patients were given the tuberculin antigen and made a response. After they were infected with measles and developed the measles rash, they were given the antigen again. There was no zone of induration at week 1, a reduced zone of induration at weeks 2 and 3. Even at week 4, the zone of induration was below that seen at baseline. This suggests that the measles infection was doing something to inhibit an antigen-specific T cell response

Question 88

Provirus

Answer 88

The HIV genome once it has integrated into the host cell genome. It can be transcribed just like host cell DNA

Question 89

Diagnosis of HIV

Answer 89

While HIV-specific antibodies are not sufficient to clear the virus, they are still useful diagnostically. Blood samples can be used for an ELISA or western blot to determine whether a person is producing antibodies against the virus, which would indicate infection. You can also do molecular tests to confirm the presence of viral RNA