Chapter 13- Failures of the Body's Defenses Flashcards
Primary immunodeficiency diseases
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
Secondary immunodeficiency diseases
When there is a failure of immunological function as a result of infection or the use of immunosuppressive drugs, rather than a genetic defect
How do immunologists study the immune system in the laboratory?
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
Carrier
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
X-linked diseases
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
When are dominant immunodeficiencies most commonly seen?
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
Interferon-γ
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
Interferon-γ structure
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
Dominant allele
An allele that influences the phenotype in both homozygous and heterozygous individuals. Usually refers to disease-causing alleles that encode proteins with functional defects
Recessive allele
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
Recessive mutations of IFN-γR1
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
Dominant mutations of IFN-γR1
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
IFN-γ receptor deficiency
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
What are the consequences of antibody deficiencies?
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
X-linked agammaglobulinemia (XLA)
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.
Bruton’s tyrosine kinase (BTK) function
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
How are immunodeficiencies usually detected?
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
Autosome
Any chromosome that is not a sex chromosome
X-linked agammaglobulinemia (XLA) in females
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
Bronchiectasis
Chronic inflammation of the bronchioles of the lung, which can lead to chronic lung disease and death
Long term effects of B cell deficiencies
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
Treatment of XLA
Monthly injections of intravenous immunoglobulin- the immunoglobulin contains antibodies against all common pathogens and provides passive immunity against those pathogens
CD40 ligand
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
X-linked hyper-IgM syndrome (CD40 ligand deficiency)
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
Neutropenia
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
Leukocytosis
Increased numbers of leukocytes in the blood. In immunocompetent people, this is part of the immune response to infection
Why does disruption of the mucosal tissues occur with neutropenia?
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
Importance of complement activation
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
Defects in C3
Cause susceptibility to pyogenic infections. This is because C3 is very important as an opsonin.
Defects in C5-C9
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
Immune-complex disease
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
Deficiencies in complement components C1-C4
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
How are immune complexes transported?
By erythrocytes. The erythrocytes use CR1 to bind to the C4b and C3b that are attached to the complexes
Factor I deficiency
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
Infections caused by Neisseria bacteria (2)
- N. meningitidis: meningitis, septicemia
- N. gonorrhoeae: gonorrhea
Factor P deficiency
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
IL-12 receptor deficiency
Patients exhibit impaired innate and adaptive immune responses to intracellular bacteria, such as mycobacterium tuberculosis.
Defects in phagocytic function
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)
IL-12 function
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
Can primary immunodeficiencies be cured?
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
Severe combined immunodeficiency (SCID)
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
Treatment for SCID
The effects are so severe that infected infants will only survive if their immune system is replaced by hematopoietic stem-cell transplantation
Adenosine deaminase (ADA) deficiency
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
X-linked SCID
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
Rag1/Rag 2 deficiency
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
Omenn syndrome
A reduced amount of RAG1/RAG2. In this case, B cells are not produced, but a small amount of T cells are produced
DiGeorge syndrome
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
Bare lymphocyte syndrome
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
Defect in B cell development
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
CD45 phosphatase defect
CD45 phosphatase downregulates T cell responses. This leads to a defect in peripheral T cells
Wiskott-Aldrich syndrome
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)
CD3 complex defects
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
Pre-T cell receptor
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
Pre-T cell receptor signaling
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.
Immunoreceptor tyrosine-based activation motifs (ITAMs)
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
Wiskott-Aldrich syndrome symptoms (6)
- Low IgA- B cells aren’t properly activated and don’t return to the germinal center to undergo isotype switching and affinity maturation
- Low IgM- even the initial B cell response is impacted
- Low platelets- clotting defect
- Eczema
- Blood diarrhea
- Recurrent bacterial infections
Hyper IgE syndrome symptoms (6)
- Eczema
- Recurrent infections, like S. aureus, sinus infections and ear infections, and pneumonia
- Normal lymphocytes and neutrophils, but high eosinophils
- Normal levels of IgG and IgA, slightly elevated IgM
- Abnormally high IgE
- 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
Hyper IgE syndrome (Job’s syndrome)
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
JAK/STAT cytokine signaling pathway
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
Public health burden of measles
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
Which immune cells does measles infect?
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
Measles immune amnesia
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
How was HIV discovered?
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
History of HIV and AIDS
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
When was HIV isolated?
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
HIV transmission
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.
HIV cases worldwide
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.
Human immunodeficiency virus (HIV) structure
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
The life cycle of HIV in human cells (8)
- 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
- The viral envelope fuses with the cell membrane, and the viral genome and proteins enter the cell
- Reverse transcriptase copies the viral RNA genome into double stranded cDNA
- Viral cDNA migrates from the cytoplasm into the nucleus and randomly integrates into the host cell genome
- T cell activation induces some transcription of provirus
- RNA transcripts are splices to allow the synthesis of the early proteins Tat and Rev
- Tat amplifies transcription of viral RNA. Rev increases transport of RNA to the cytoplasm
- Gag, Pol, and Env are made and assembled with viral RNA into virions, which bud from the cell
Immune response to HIV
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.
Adaptations to HIV-2 vs HIV-1
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
Extinction of CD4 cells during HIV infection
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
AIDS
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
HIV progression to AIDS
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
How was HIV antiviral therapy developed?
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.
Types of HIV antiviral therapy (7)
- Non-nucleoside (RTNNI) or
- Nucleoside reverse transcriptase (RTNI) inhibitors of HIV RT; addition of faulty nucleotides; competitive substrate inhibitors
- Protease inhibitors
- Fusion inhibitors
- Integrase inhibitors
- CCR5 (co-receptor) blocking inhibitor- blocks viral attachment
- Pharmacokinetic enhancers- improves the bioavailability of other drugs given to the patient
HIV protease inhibitors
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
HIV fusion inhibitors
Block HIV fusion of viral gp41 protein and the host cell membrane
HIV integrase inhibitors
Block HIV p32 activity, abolishing integration of the proviral DNA copy of HIV into the host cell chromosome
Undetectable viral load
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
How do anti-retroviral drugs increase the number of CD4 T cells?
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
Human resistance to HIV
- 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
- Individuals who are heterozygous for the defective CCR5Δ32 gene progress more slowly to AIDS- must inherit 1 defective copy
How did human resistance to HIV come about?
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
Cure for AIDS
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
Why is an HIV vaccine challenging to develop?
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
Non-infectious factors that can suppress immune function (4)
- Alcohol exposure- lymphocyte proliferation, phagocytosis are impacted
- Heavy metals (lead, cadmium)- reduced antibody production
- Malnutrition- impacts a wide range of physiological functions, including immune responses
- Statins- decreased inflammatory responses
How did scientists discover that measles can induce immune amnesia?
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
Provirus
The HIV genome once it has integrated into the host cell genome. It can be transcribed just like host cell DNA
Diagnosis of HIV
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
