Midterm 2 Flashcards
(227 cards)
1
Q
How does undernourishment modify the immune system?
A
Insufficient energy to generate effective immunity -> more prone to microbial infections
2
Q
How does overnourishment modify the immune system?
A
Creates an impaired or overractive immune system -> more prone to microbial infections, excess inflammation
3
Q
What part of the innate immune system is impact the most by Protein-Energy Malnutrition (PEM)?
A
The innate immune system (reduces epithelial and physiological barriers; reduces function of neutrophils, macrophages, and natural killer cells)
4
Q
Which common micronutrient deficit causes the following:
- Decrease in pro-inflammatory cytokines (TNFalpha/IL6)
- Inhibits T cell proliferation
- Diminishes Thymic function
A
Iron deficiency
5
Q
How can an iron overload be bad?
A
Iron is essential for bacterial, protozoal, and viral infections (known as the host-pathogen battle for iron)
6
Q
What is the role of iron in bacteria, viruses, and protozoa?
A
- Bacteria- iron genes concentrated in high-pathogenic regions
- Viruses- high iron status promotes HIV progression
- Protozoa- Malaria-induced redistribution promotes bacterial co-infections
7
Q
How does a Vitamin A deficiency impact the immune system?
A
- Skews the immune system towards Th1 response (reduces Th2)
- Increases mortality and morbidity (can reverse with supplementation)
8
Q
How does obesity impact the immune system?
A
Causes low grade chronic inflammation, alters T cell subsets (increases TNF-alpha), enhances thymic aging
9
Q
What infection risks are elevated in obese patients?
A
- Secondary infections
- Surgical site infections and wound complications
- Pulmoary aspiration and community-related RTIs
- Risk for influzena related death
- Peridontal infections
10
Q
Why do obese patients have an elevated risk of death from influenza?
A
- Response to influenza requires functioning DC, CD4, and CD8 T cells
- In obese patients, all of these inflammatory markers decrease after respiratory infection (elevated before)
11
Q
Why don’t doctors vaccinate infants when they are very young (less than 1 week)?
A
Because the maternal antibodies can interrupt with B cell stimulation
12
Q
Why are many immune deficiencies not recognized until after the first few months of life?
A
Because maternal IgG antibodies make up for the lack of response in the infant
13
Q
Why is the cell-mediated immunity in neonates atypical?
A
Because the innate immune cells do not produce IL12, the Th1 response is prevented (and Th2/Th17 prevail)
14
Q
Why is B cell class switching and CD8 T cell levels decreased in neonates?
A
Because ofthe deficiency in co-stimulatory molcules (T helpers) in first few months of life
15
Q
At what age do lymphocyte numbers and serum IgG/IgM reach “adult levels”?
A
Age 6
16
Q
What T cell imbalance exists in elderly people?
A
There is an over-representation of effector/memory T cells vs. naive T cells
17
Q
What are the effects of old age on T helper cells and B cells?
A
- There is a defect in the function of CD4+ T cells upon antigen stimulation
- There is a decrease in B cell lymphopoesis and a general reduction in the quantity/quality antibody response
18
Q
What is the effects of old age on the innate immune system?
A
- Macrophages reduce expression of MHC II
- Impairs the function of neutrophils and NK cells
- TLR signaling pathways can be reduced
19
Q
Chonric low-grade inflammation _____ (inc/dec) with age?
A
Increases!
20
Q
What is the definition of vaccine?
A
A substance designed to induce potent and protective immune response, by exposing the host to antigenic (non-pathogenic) material
21
Q
What is the difference between active and passive immunity?
A
- Active- body’s response to a potential pathogen, hopefully leading to long-term protective response
- Passive- created via transfer of pre-formed antibodies to an individual (short-lived)
22
Q
When is passive immunization useful?
A
- When immediate protection is needed
- When host is unable to produce an adquate immune response
- When no safe or effective vaccine is available
23
Q
What is pneumocephalus?
A
Air in the skull
24
Q
What is the difference between rabies immune globulin (RIG) and rabies vaccine?
A
- Rig provides passive immunity (now)
- Rabies provides active immunity (later)
- Both would be provided to the patient in the event of an animal bite
25
Why is Respiratory Syncytial Virus (RSV) treated with passive immunization?
Because it can cause chronic lung disease and there is no safe or effective vaccine (monoclonal antibody preparation is available)
26
What are some commune situations in which passive immunization is used?
* Protection against toxins (tetanus, botulism, diptheria, snake venom)
* Use of Rho-Gam (pregnancy)
* Sever deficiencies of the humoral immune system (IVig)
* Directed against specific viral antigens (HepA, CMV, rabies, RSV)
* Various infections for autoimmune diseases
27
What is a common immunization now used during pregnancy (for of passive immunity)?
Pertussis, because it can prevent whooping cough!
28
What is the difference between inactivated and attenuated vaccines for bacteria/viruses?
* **Inactivated-** grow large number of bacteria/virus and kill using heat or chemical fixation
* **Attenuated, live**- repeated passages through cell culture until non-virulent organism is isolated
29
What is the benefit of inativated bacterial and viral vaccines?
* Inactivated bacterial vaccines provide limited, short-lived protection and are not used in the US
* Inactivated viral vaccines produce some protection and include influenza, rabies, polio
30
What is the benefit of attenuated viral and bacterial vaccines?
* Attenuated bacterial vaccines are rarely used
* Attenuated viral vaccines can generate effective, long-term protection (sometimes need boosters)
31
What are the common live, attenuated viral vaccines?
* Measels, Mumps, Rubella
* Chickenpox
* Rotavirus
* Live influenza vaccine (oral)
32
Why are some vaccines a concern for patients with immune deficiency?
Because some vaccines contain live organisms
33
What is the usefulness of toxoids and purified polysaccharide antigens?
* **Toxoids-** very effective immunogens, inactivated toxins (diptheria, tetanus)
* **PPA-** not longterm effective, used in conjugate vaccines, very safe
* Both of these have a short shelf-life and fail to stimulate the CTL because they are recognized as exogenous antigens
34
What are sythetic/recombinant antigen vaccines?
Active part is synthesized protein/AA (Hep B)
35
What are the advantages/disadvantages of combination vaccines (polyvalent)?
* Advantage- reduction in the number of injections
* Disadvantage- not all vaccines can be combined (interference with immune response)
36
What are the components of a vaccine?
* **Adjuvants**- added to improve/stimulate immune response (aluminum salts)
* **Diluent**- water/saline
* **Stabilizers**- maintain vaccine potency
* **Antibiotics**
* **Preservatives** (thermosal)
37
What are 2 principles that increase the effectiveness of a vaccine?
* Microorganisms are invariant in their surface structures
* Limited to human hosts (no animal reservoirs)
38
What is the only immunization given on day 1?
Hepatitis B
39
What is herd immunity?
Large percentage of individuals in community are immunized:
* Microorganism has difficulty surviving
* Low probability that unimmunized individual will contact pathogen
40
What are the 3 most common reactions to vaccines?
* Local reactions
* Mild systemic reactions
* Allergic reactions
41
What is a primary immunodeficiency?
A genetic mutation that may occur at any phase of the immune response (most present in childhood)
42
What are the most common forms of primary immune deficiency (PID)?
Humoral (B cell) immune deficiencies
43
What 4 questions do you need to ask to diagnose immune deficiency?
* Is there enough B cells, T cells, and complement?
* Do the cells work?
* How about innate cells (PMNs, macrophage)?
* Can cells travel where they need to go?
44
What are the common signs/symptoms of humoral/antibody defects?
* Pyogenic Infections (sinusitis, pneumonia, cellulitis, meningitis)
* Frequent viral infections
* Chronic Diarrhea
\**Pyogenic= causes local purulent*\*
45
How many infections are to many in adults/children?
* **Children**- 4 courses of antibotics per year
* **Adults-** 2 courses of antibiotics per year
* *Pneumonia twice over any time is concerning*
46
What disease is associated with a defect in germinal centers?
(XLA) X-linked agammaglobulinemias
47
What is the most common primary immunodeficiency?
IgA deficiency (1:500) (usually asymptomatic)
48
Why is it dangerous for patients with severe IgA deficiency to receive IVigA?
Because they might have antibodies for IgA (no IgA in body normally) and can end up in anaphylaxis
49
What is the second most common immunodeficiency (and most common ***_symptomic_*** immunodeficiency)?
(CVID) Common Variable Immunodeficiency
50
What humoral immune deficiency has normal antibody, B cell, and T cell numbers?
Specific Antibody Deficiency (impaired vaccine response)
51
What are the classic encapsulated organisms? (Some Killers Have Pretty Nice Capsules)
* Streptococcus pnemoniae & pyogenes
* Staph aureus
* Klebsiella
* Haemophilus influenzae
* Pseudomonas aeruginosa
* Neisseria meningitidis
* Crytococcus neoformans
52
What immune deficit has low IgG (but normal specific antibodies) and usually resolves by age 4?
Transient Hypogammaglobulinemia of Infancy
53
What is the standard order of evaluations for humoral immune system diagnosis?
1. CBC with differential
2. Age-adjusted quantitative immunoglobulins
3. Specific antibody titers
4. Complement pathway (functional assay)
5. Lymphocyte markers (B cell)
54
How do you test the specific antibody production of a patient?
Use a vaccine booster to see secondary response a few months later (if no big response, that means there is no antibody response)
55
How can disorders with T cells impact humoral immune system?
Causes problems with Ig synthesis (need T helper cells)
Often called **combined immunodeficiencies**
56
What are the signs/symptoms of T cell dysfunction?
* Failure to thrive
* Anergy to recall antigens
* Graft vs. host disease (eczema)
* Increased B cell malignancies
* Eosinophelia, thrombocytopenia
* Thrush
57
What rare disease (ID) is associated with the following symptoms?
* Eczema
* Thrombocytopenia with small platelets
Wiskott Aldrich Syndrome (problem with actin polymerization)
58
What is order of diagnostic evaluations for combined immunodeficiencies (T cell)?
1. CBC with differential
2. Age-adjusted quantitative immunoglobulins
3. Specific Antibody Titers
4. Lymphocyte Markers (all)
5. Lymphocyte mitogen proliferation assays
6. Antigen reactivity (candida, tetanus)
7. DTH to candida
8. Nucleic acid enzyme assays (AICDA)
59
What ID is characterized by recurrent soft tissue infections with no pus formation?
***Hint:*** Innate immune system
Leukocyte Adhesion Deficiency-1 (LAD-1) because neutrophils cannot migrate or adhere
60
What diagnostic tests should you consider for defects of innate immunity?
1. CBC with differential
2. Neutrophil function (NBT, chemotaxis, Leukocyte phenotypes)
3. Assays for complement (AH50, CH50, MBL)
61
What PID is associated with onset of birth to 3 months?
* Phagocytic cell defects
* Complement defects
* DiGeorge syndrome
62
What PID is associated with onset of 3-6 months?
* Severe combined immunodeficiency (SCID)
63
What PID is associated with onset of 6-18 months?
* X-linked agammaglobulinemia (XLA)
* Transient hypogammaglobulinemia
64
What PID is associated with onset of 18 months-adulthood?
* Common Variable Immunodeficiency (CVID)
* Complement Defects
65
What Physical Examination observations should you examine for PID?
* Growth measurements
* Inspection of tonsils
* Thrush? (in adults)
* Palpation of lymph nodes
* Organomegaly
* Skin lesions
66
What are some common treatments for humoral/antibody deficiency?
* Avoidance of high rate exposure to infection
* Antibiotic therapy
* IV or SQ IgG
67
What are some common treatments for combined immunodeficiency?
* Stem Cell transplantation
* Enzyme replacement
* Thymic transplant (DiGeorge)
* Gene Therapy (ADA, XL-SCID)
* IVIG
* Avoidance of live viral vaccines
* Irradiation of blood products
* Phrophylactic antibiotics
68
What are some common treatments for defects of phagocytic cells?
* Prophylactic antibiotics
* Gamma intereferon in CGD
* Bone marrow transplants (some patients)
69
What are some common treatments for complement immunodeficiency?
* Symptomatic care
* Frequent use of antibiotics
* Immunizations with bacterial polysacccharide vaccines
70
What is acquired immunodeficiency?
Defects in immune system not arising from genetic abnormalities (from infection, nutritional deficits, medical condition/treatment, external stimuli)
71
How does biochemical homeostasis cause acquired immunodeficiency and what are 3 examples?
Disorders cause chronic imbalance of hormones, nutrients, and toxic metabolic waste products
* Diabetes mellitus
* Dialysis and uremia
* Cirrhosis
72
How does diabetes mellitus impact immune system?
* Decreased neutrophil function (related to high blood glucose)
* Poor peripheral circulation
* Can lead to disseminated candidiasis
73
What are the immune risks with 2 types of dialysis?
* **Hemodialysis**- redued T cell function & Ig production, compromised neutrophil and dendritic function
* **CAPD-** changes in peritoneum and removal of opsonic factors
* *General presence of foreign body (catheter) increases risk of infection*
74
What are the immune impacts of cirrhosis?
* Risk for bacterial sepsis and peritonitis
* Higher endogenous glucocorticoids
* Low complement (made in liver)
75
What are some of the main causes of protein loss?
* Nephrotic syndrome (kidneys, urine)
* Protein losing enteropathies (GI tract, stool)
* Severe dermatitis (skin)
* Peritoneal dialysis
76
Why is IgM levels near normal, but IgA and IgG low in disorders of protein loss?
IgM is too big for the body to lose it!
77
How do you determine if IgG levels are low due to protein loss or low B cell/decreased production?
* **Urinalysis** (check for protein in urine)
* **IVIG-** know the half lift of Ig and check for presence at time points!
78
How does trauma cause ID?
Depends on the degree of tissue injury, but massive release of inflammatory cytokines due to activation of monocytes/macrophages (due to necrosis)
79
Why is burn trauma worse than mechanical trauma?
It has a greater immune suppression effect, disrupts nonspecific defense (skin) and results in increased loss of fluids/proteins
80
How does ionizing radiation impact the immune system?
* Damages DNA-\>impair cell division-\>impair immune function
* May induce apoptosis
* Dose-dependent decline in CBC (B cells impacted more!)
* Primary antibody responses diminished
* Nodes and spleen affected (homing and recirculation)
81
Why is the spleen such a key player in getting rid of encapsulated bacteria?
The macrophages in the marginal zone of the spleen are the best at taking out encapsulated bacteria that have been opsonized
82
What are some possible etiologies of splenectomy/hypospenism?
* Congenital asplenia
* Post spenectomy (trauma)
* Atrophy/non-functional spleen (sickle cell)
83
Why is immune system reduced during pregnancy?
Depressed cellular immunity is a "survival benefit" for the fetus
84
What cell populations does stress typically effect?
* Natural killer cells (reduced activity)
* Lymphocytes (reduced mitogen responses)
85
What are the immune alterations induced by measles?
* Superinfections with respiratory viruses are common (Staph. aureus or pnemonia)
* T cell lymphopenia
* Dimished T cell proliferation (in vitro)
* Diminished antibody production
* *Measles is a direct infection of T cells and dendritic cells*
86
What immune alterations are induced by herpes viruses?
Transient depression of cell-mediated immunity (especially noted with CMV)
87
How extreme is the immune suppression by protozoan infection?
***More extreme*** than infection by any other class of microbe (excluding HIV)
* Decreased cell-mediated immunity (malaria)
* Increased susceptibility to infections
* Delayed graft rejection
* High rate of various malignancies
88
What are the immune alterations induced by superantigens?
* Can cause immune suppression
* Initial stimulation, followed by T cell decrease (number and activity)
* Neutrophil function is also decreased
89
What are the diagnostic assays for infectious disease (low -\> high sensitivty)
* Light Microscopy
* Cell Culture (and viral)
* Immunoassays
* Nucleic Acid Amplification Tests (NAATs)
90
What is the problem with viral cultures?
Requires eukaryotic host cells and is more labor, expertise, time and money intensive!
91
What are the 4 main forms of immunoassays (involving antigens and antibodies)?
1. ELISA
2. Western Blots
3. Rapid immunochromatographic strip tests
4. Particle agglutination tests
92
The secondary antibody detects which part of the primary antibody in antigen detection tests?
The Fab portion of the secondary antibody binds the Fc portion of the primary antibody (which is attached to the antigen via its own Fab portion)
93
What is serum always looking for in tests?
Antibodies
94
How can ELISA tests detect past vs. present infections?
* Indirect= past infections are detected by antibody tests (serologic tests)
* Direct= present infections are detected by antigen tests
95
What are some benefits of Nucleic Acid Amplification Tests (NAATs)?
* Targets are microbial DNA or RNA
* Enzymatic amplification of target molecules
* Most sensitive
* Does not require live organisms
* Increased sensitivity may allow use with non-invasive specimens
96
What is the main drawback of Nucleic Acid Amplification Tests (NAATs)?
* Detection of dead organisms impacts timing of test culture (DNA)
97
How do microbiologists think about sensivity and specificity?
* Sensitivity- test recognizes very small amount of organism
* Specificity- test recognizes a particular pathogen (not closely related ones)
98
Are viral genomes always RNA?
No, they can be ssRNA, dsRNA or dsDNA
99
What are the main structures in a virus?
* Virion- entire virus particle
* Envelope
* Capsid
* Nuecleocapsid
* Capsomere
* Genome (nucleic acid)
100
How do viruses obtain an enveloped structure?
Envelope is derived from host cell membranes (but can contain virally encoded proteins, glycoproteins)
101
What are the main functions of the capsid (protein) coat on a virus?
* Protect viral nucleic acid
* Interact specifically with viral nucleic acid for packaging
* Interact with host receptors for cell entry
* Allow for release of nucleic acid upon entry
* Assist in viral/host gene regulation
102
How does protein coat shape influence virus nucleic acid packaging?
* Icosahedral (**spherical**)- amount packaged is limited by size of particle (closed)
* Helical (**rod-shaped**)- no limit to the amount packaged (open)
103
What is not encoded in the viral genome?
* Protein synthesis machinery
* Energy metabolism
* Membrane biosynthesis
104
What are some characteristics of enveloped viruses?
* Outer evelope with phospholipids, proteins, glycoproteins
* Sensitive to heat, acids, drying
* Not associated with GI tract
* **Examples include**: Herpesvirus, influenza, measeles, mumps, RSV
105
What are some characteristics of non-enveloped viruses?
* Outer covering is capsid protein
* Resistant to heat, acids, drying
* Survive in GI tract
* **Examples include:** norovirus, rotavirus, adenovirus, papillomavirus, parvovirus
106
What are some of the characteristics of DNA viruses?
* They can incorporate themselves into the cellular genome and establish latency
* They are less prone to replication errors
* Use more host enzymes
107
What is an arbovirus?
Airborne transmission
108
What are the main herpesviruses?
* Herpes Simplex Virus Type 1 (HSV-1)
* HSV-2
* Varicella-Zoster Virus (VZV)
* Cytomegalovirus (CMV)
* Epstein-Barr Virus (EBV)
* Human Herpesvirus 8 (HHV-8 or KSV)
109
What are some characteristics of all herpesviruses?
* dsDNA genome (capcity to establish latency)
* icosahedral (sphereical) capsid
* enveloped
110
Why is influenza A virus so dangerous?
* The genome is negative sense, ssRNA in segments
* This creates the possibility of co-infections creating a new influenza virus (take some segments of the ssRNA)
111
What is the role of the Fb portion of immunoglobulin antibody?
* Fragment, antigen binding
* Determines idiotype: unique antigen binding pocket (only 1 per cell)
* Contains some of the heavy chain and light chain
112
What is the role of the Fc region in immunoglobulin anitbodies?
* Constant (only heavy chain)
* Carboxy terminal
* Complement binding
* Carbohydrate side chains
* Determines isotype (IgM, IgD, etc.)
113
What are the upregulated acute phase reactants (APRs)?
* C-reactive protein (opsonin)
* Ferritin (binds and sequesters iron)
* Fibrinogen (coagulation factor)
* Hepicidin (decrease iron absorption/realease)
* Serum amyloid A
114
What are the downregulated acute phase reactants (APRs)?
* Transferrin (help macrophages sequester iron)
* Albumin (conserves AA)
115
What are the 6 general steps of the virus life cycle?
1. Attachment
2. Entry
3. Uncoating
4. Synthesis of protein and nucleic acid
5. Assembly
6. Release
116
What is the difference between eclipse period and latent period in virus replication?
* **Eclipse-** no intracellular virions detectable
* **Latent**- no extracellular infectious virus detectable
117
What are some specific viruses that use receptor-mediated endocytosis?
* Adenovirus
* Orthomyxoviruses
* Rhabdoviruses
118
What are some specific viruses that use membrane fusion?
* Herpesviruses
* HIV
* parainfluenza
119
Why are retroviruses special?
They use a reverse transcriptase to create dsDNA from parental ssRNA (+) strand
120
Where are the typical DNA and RNA virus replication sites?
* **DNA**- replicate in nucleus (except Poxviruses)
* **RNA**- replicate in cytoplasm (except retrovirus and influenza)
121
What is nucleocapsid formation?
Accumulation of structural proteins in same cellular compartment where replication of progeny genome occurs *(naked viruses are infectious after this point!*)
122
What additional maturation steps are required for enveloped viruses?
* Internal envelopment and exocytosis (herpesviruses, coronaviruses, bunyaviruses, poxviruses)
**_OR_**
* Cell surface development (rhabdoviruses, togaviruses, orthmyxoviruses, paramyxoviruses, retroviruses)
123
What is CPE?
**Cytopathic effect-** the alteration in appearance of infected cells, or even cell death, by a virus (visualized under microscope)
## Footnote
*Can even be seen as visible plaques*
124
What special enzymes are needed for Human Retroviruses?
* Reverse transcriptase (RNA -\> DNA)
* Integrase (proviral DNA into host genome)
125
What are some examples of Human Retroviruses?
* Oncoviruses (Human T cell leukemia viruses)
* Lentiviruses (HIV-1 and HIV-2)
126
What are some characteristics of lentiviruses?
* Infect non-dividing cells
* Specific to species
* HIV-1 more common and more pathogenic than HIV-2
127
What are the important structures of the HIV virus that you should know?
* **GP120-** main envelope of HIV
* **GP41**- always coupled with GP120, transmembrane
* **P24**- main outer capsid antibody (important for diagnosis)
* **Protease, Integrase, Reverse Transcriptase**
128
HIV entry requires CD4 receptor, this means that it infects which cells?
* Mostly T helper lymphocytes
* Also macrophages
* And microglial cells
129
In addition to CD4 receptor, what else does HIV require for cell entry?
A co-receptor (CCR5 or CXCR4)
130
What are the 3 general steps of HIV attachment for entry into cell?
1. GP120 interacts with CD4
2. CD4-GP120 changes conformation, GP120 interacts with chemokine co-receptor
3. Conformation change occurs again and GP41 starts fusion
131
What is the difference between co-receptors CCR5 and CXCR5 in HIV?
* **CCR5**- used by most virus strains, prevalent early
* **CXCR4**- associated with disease progression
132
What are the 3 main jobs of the RNA transcriptase?
1. Transcribe ssRNA to proviral ssDNA
2. Degrade the ssRNA
3. Create a second strand of DNA to form dsDNA that can enter nucleus
133
What is one pro and one con of the vast number of mutations created during HIV genome replication?
* **PRO-** many of these mutations will lead to a non-functioning form of the virus
* **CON-** these mutations can lead to drug resistance
134
What is the difference in replication patterns for viruses with:
* dsDNA
* +ssRNA
* -ssRNA
* **dsDNA**- can enter nucleus and use DNA pol
* **+ssRNA**- doesn't enter nucleus, uses ribosomes (like an mRNA)
* **-ssRNA**- virus needs to have own polymerase to create positive strand
135
What is the main drug for Herpesvirus and what is its MOA?
**Acyclovir (ACV)**- chain terminator of the viral DNA synthesis (lacks 3' hydroxyl)
136
What drug can be used in place of ACV for sever CMV related infections?
**Ganciclovir (GCV)**- note that it has greater adverse effects (BM toxicity)
137
What are the requirements of using a drug for prophylaxis?
The drug should be used well before any noticable symptoms of the outbreak, otherwise the use of drug is too late (symptoms are a result of immune reaction and virus is no longer replicating)
138
What are the two DNA polymerase inhibitor drugs used against Herpesviruses that cause nephrotoxicity?
Foscarnet and Cidofovir
139
What is the interaction between viral load and mutations?
A higher viral load (in an immunosuppressed patient) results in more mutations and this can cause faster drug resistance
140
What is the main drug for Influenza, what is its MoA, and when is it effective?
* Oseltamivir (Tamiflu)
* Neuraminidase inhibitor (prevents receptor cleavage for virus release)
* Need to use within 24-36 hours of infection
141
What are the 4 main goals of antiretroviral therapy (HIV)?
1. Maintain or improve health
2. Preserve or restore immune function
3. Suppress HIV replication
4. Limit toxicity
142
How many drugs are SOC in HIV treatment?
3 drugs should be used, most common MoA are:
* Reverse Transcriptase Inhibitors
* Integrase Inhibitors (tegra)
* Protease Inhibitors (navir)
143
What are the 4 HIV antiretroviral drugs that you need to know?
1. Zidovudine (Retrovir, AZT)
2. Lopinavir/Ritonavir (Kaletra)
3. Raltegravir
4. Maraviroc
144
What is the MoA for Zidovudine (AZT)?
It is an NRTI: competitive binding of reverse transcriptase (terminates chain elongation)
## Footnote
*\*It was the first ARV drug developed\**
145
What is the MoA for Lopinavir/Ritonavir?
PI: Protease Inhibitor
146
What is the MoA for Raltegravir?
Integrase Inhibitor
147
What is the MoA for Maraviroc?
Unique mechanism- inhibits co-receptor
148
What is the difference between PEP and PrEP in HIV prevention?
* **PEP-** Post exposure prophylaxis
* **PrEP**- Pre exposure prophylaxis
149
For which adverse effects should ARV therpay be stopped?
Hypersensitivty (extreme fever) because this is life-threatening
150
What is main goal of a virus (needs to do this in order to propagate)?
Make mRNA!
151
Where does HIV get the nucleotides in order to create dsDNA?
From the host! (this process occurs in the cytoplasm)
152
How do CTL kill target cells?
* Release granzymes and perforin, which activates caspase cascade (apoptosis)
* Also FAS ligand that can bind to FAS on target cell and trigget apoptosis
153
Which immunoglobulin is a dimer?
IgA
154
Which immunoglobulin is a pentamer?
IgM
155
What percentage of the human genome is endogenous retrovirus?
one percent
156
What are the two main groups of HIV-1?
HIV-1 M and HIV-1 O
157
How many people in the world are currently living with HIV/AIDS?
36.7 million people living with HIV/AIDS (25 million of them in Africa)
158
How many new infections and deaths were there due to HIV in 2016 worlwide?
1.8 million new infections, 1 million deaths
159
What are the two main risk factors associated with transmission of HIV in the USA?
* Male to Male sexual contact
* Black/African American
160
What is the innate immune response to HIV?
* Langerhans cells in vaginal and foresking epithelia
* Macrophage, dendritic cells, and NK cells in subepithelia
* These restrict virus early, but contribute to spread of virus as it moves onto adaptive response
161
What is the adaptive immune response to HIV?
* p24 antigen appears, then decreases
* Neutralizing antibody for envelope proteins (GP120 and GP41) and core protein antigens
* CD8+ T cells activate (CTLs)
* CD4+ T helper cells stimulate cytokines (IL2, IFN-gamma, TNF)
162
Why does the CD4+ T cell response and antibody response decrease over time with HIV?
Really high mutation rate of HIV
163
What is the time general time course for HIV infection?
* 2 days- innate immune cell response
* 3 days- entrance into the lymph nodes
* 3 weeks- highest viral load and explosion into organs
164
Why is the MALT severely affected in acute HIV?
Because there is a large amount of mucosal CD4+ T cells (especially in GI tract). This destruction of the mucosa is not able to be recovered fully (usually GI problems with HIV)
165
What is the relationship between HIV progression and:
* Risk of transmission
* Viral diversity
* Risk of transmission is highest within the first few weeks (high viral load) and lowest during early years (increases again with time)
* Viral diversity steadily increases with time (more mutations occur)
166
What immune action corresponds with the decrease in viral load after a few weeks?
An increase in CD8+ T cells (CTL)
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Why are infants/children at higher risk for more rapid progression of HIV?
Don't yet have a full immune system!
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What is an "elite-controller" in regards to HIV?
A subset of the population with much higher CD4+ T cells that are Anti-HIV specific and tend to keep a low viral load despite HIV infection
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What is the relationship between HIV specific CD4+ and CD8+ T cells?
HIV specific CD4+ T cells are lost early in infection and this progressive loss causes a decrease in CD8+ CTL (which are present in high numbers early)
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What are the 3 anti-viral effect of CTLs in HIV?
1. Lysis of virus-infected cell (before virions released)
2. Inhibition of viral replication (IFN-gamma)
3. Inhibition of viral entry (block CCR5)
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Why are CD4+ T cells unable to be replaced in HIV?
* Thymic dysfunction
* Bone marrow dysfunction
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What are the key signs/symptoms of acute HIV?
* 60-90% of patients will have symptoms similar to mono (fever, sore throat, lymph nodes, faint rash, mucosal ulcers)
* Typically begin 1-4 weeks post-exposure
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What are things allow for HIV progression to chronic infection?
* High rate of viral replication, error prone RT, rapid recombination (these allow HIV to escape immune control)
* Switch in CCR5 usage to CXCR4
* Accessory gene function (nef)
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What is the difference between clinical and virological latency?
* Clinical Latency (incubation)- no symptoms/signs (but still presence/replication of virus)
* Virological Latency (dormant)- no symptoms/signs ***and*** no replication of virus
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What does a Western Blot test for?
Presence of antibody
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What is the best assay to use for diagnosis of HIV?
* 4th generation HIV-1/2 immunoassay
* Detection of HIV p24 antigen
* Detection of antibody to HIV-1 group or HIV-2
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What are some other common tests for HIV screening?
* HIV1/2 Rapid Oral Test (detection/differentiation of HIV1/2 antibodies)
* HIV DNA PCR (infants)
* HIV RNA PCR (viral load)
* HIV antibody (ELISA or western blot)
* p24 virus protein
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Why shouldn't doctors use the standard HIV antibody test when screening an infant?
Because the test may pick up the mom's antibodies (need to do PCR instead until 18 months of age)
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At what point is p24 observable in HIV?
Around 20 days
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What is the difference in CD4+ T cell increases from initial vs. gradual immune reconstitution?
* **Initial (1-6 months)**- mostly memory CD4+ T cells, cannot replace lost T cell specificity
* **Gradual**- mostly naive CD4+ T cells (derive from Thymus), can replace T cell specificity
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What is Immune Reconstitution Inflammatory Syndrome?
When a patient feels and appears worse after starting drug therapy (due to increase in immune system function)
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Can you use a lower dose than recommended for HIV drugs if patient is not tolerating well?
No, because the schedules and dosages are needed for effective therapy and to decrease transmission risk.
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At what number and percent of CD4 T cells is the patient in stage 3 (AIDS)?
Less than 200 T cells or 15%
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What are 3 cofactors that significantly increase risk for HIV transmission?
* Anal (compared to vaginal sex)
* STI (compared to no STI)
* Uncircumcised (compared to circumcised)
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What is the risk of utero, vaginal birth, and breast feeding transmission of HIV to child?
* Utero (30%)
* Birth (60-70%)
* Breast feeding (20%)
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What is HAART (3 drug minimum)?
**H**ighly **A**ctive **A**nti**R**etroviral **T**herapy
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Are HIV negative infants exposed to HIV (maternal) "normal"?
* There can be structural changes (growth) and immunology changes
* Increased morbidity and mortality in developing nations
* Neutrophil, CD4+ T cell, cytokine, and vaccine responses
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What are some of the common infections in HIV+ individuals when CD4 cell count is above 200?
* Streptococcus Pneumonia
* M. tuberculosis
* Herpes Simplex and Shingles
* Syphilis
* Salmonella
* Staph. aureus
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What is the anomaly with TB occurence in individuals with HIV?
* They do not show the classic upper lobe cavities (extra-pulmonary TB)
* PPD skin tests may be negative (anergy)
* Very common in HIV
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What are some common **fungi** infections in AIDS (CD4 count below 200)?
* Pneumocystis jiroveci pneumonia (PJP or PCP) is most common
* Candida
* Cryptococcus
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What are some signs/symptoms of penumocystis (PJP)?
* Shortness of breath (no cough or fever)
* Hypoxemia or O2 desaturation
* LDH is elevated
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What are some common **viral** infections in AIDS (CD4 count below 200)?
* Cytomegalovirus (CMV), espcieally retinitis
* HSV-1 or HSV-2
* HHV-8 (Karposi's sarcoma), causing vascular nodules in skin
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What are some common **protozoal** infections in AIDS (CD4 count below 200)?
* Toxoplasma gondii
* Cryptosporidia
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What is mycobacterium avium complex (MAC or MAI)?
* Diffuse infection of multiple organs (GI tract, liver, spleen, bone marrow)
* Usually occurs with severe AIDS (CD4 \< 100)
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What cancers are typically associated with HIV/AIDS?
* Karposi's sarcoma (HHV-8)
* Non-Hodgkins Lymphoma (EBV)
* Hodgkin's Lymphoma (EBV)
* Primary effusion lymphoma (HHV-8)
* Human papilloma virus related cancers
* Hepatocellular carcinoma
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What are some of the common treatment preventions for opportunistic infections in AIDS?
* CD4 count below 200? Bactrim/Septra prophylaxis (prevent pneumocystis)
* CD4 count below 50? Azithromycin prophylaxis (prevent MAI)
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What are the 4 clinical categories for HIV?
* N (asymptomatic)
* A (mild)
* B (moderate)
* C (severe)
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What are the two main things doctors observe to determine degree of HIV?
* Viral load
* CD4 count and percentage
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Conjugate vaccines allow us to....
Immunize against carbohydrate base materials (polysaccharide)
200
What is an autograft "autologous transplant"?
One between different sites on same individual (no immunologoical problems)
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What is an isograft "syngeneic tranplantation"?
Inbred strain of animals or monozygotic twin (same genes)
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What is allograft "allogeneic transplantation"?
One between non-identical humans (most of the immune problems with transplants)
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When is hematopoietic stem cell transplant (SCT) often used?
Used with *curative* intent to eradicate hematologic malignancy (high risk leukemia)
Should be used alongside chemotherapy and radiation (to kill tumor)
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How do enveloped vs. non-enveloped viruses enter the cell?
* **enveloped-** fusion
* **nonenveloped-** endocytosis (requires receptor)
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Why is donor/recipient tolerance not the goal of SCT?
Because the graft contains donor-derived immune cells that can target the cancer
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What causes an increase of hematopeoitic stem cells in the blood in the donor (prior to donation)?
G-CSF
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What is the main reason for chemotherapy before SCT?
To immunosuppress the patient (not kill cancer)
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What increases the likelihood of leukemia relapse after SCT?
* T-cell depletion of allograft increases relapse
* Syngeneic Transplants increase relapses (twins)
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How can you cure leukemia after relapse post-SCT?
Infusion of donor lymphocytes
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What is the difference between myeloablative conditioning (MAC) and reduced intensity conditioning (RIC)?
* MAC has less relapse risk compared to RIC
* Survival with RIC/MAC is comparable
* Both are better than no SCT, but need SCT (to get return of T cells)
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What are the odds of a sibling vs. parent being an HLA match with a patient?
* Sibling = 1/4
* Parent = 1/2
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What is the current HLA matching goal for SCT?
* 12/12 HLA match (HLA-A, HLA-B, HLA-C, HLA-DR)
* Will tolerate up to one A/B/C/DR match plus DQ match
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What are the options for SCT if no HLA match can be found?
* Umblicial cord blood transplant (low dose)
* HLA mis-match (haplo-identical) needs to have some T cell depletion
* Use of bone marrow instead of peripheral stem cells
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Can SCT be performed across ABO incompatabilities?
Yes if you do the following:
* Plasma deplete donor SC product (removes antibodies)
* Completeley remove RBC (if needed)
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What is Graft Versus Host Disease (GVHD)?
* Donor-derived, T-cell mediated activity against recipient tissues
* Treat with immunosuppressive drugs
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What is the difference between acute and chronic GVHD?
**Acute** (first 3 months)- affects skin, colon, liver
**Chronic** (after 6 months)- affects skin, eyes, GI tract, liver
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What are some of the common immunosupressive drugs used to treat GVHD?
* Tacrolimus, Cyclosprine, Sirolimus (Inhibit T cell activity)
* Methotrexate, Cyclophosphamide (Inhibit T cell proliferation)
* Anti-thymocyte globulin, Alemtuzumab (T cell depletion AB)
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Why are males better suited to be donors of stem cells?
There is a possibility of Y-antigen mediated reactivity in female donors
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What is the goal of solid organ transplant?
Long-term tolerance (graft accepts host and host accepts graft)
220
Why is chronic immunosuppression essential in solid organ transplant?
Becasue HLA disparities are almost universal and cause humoral and cellular mediated rejection
221
What is the one exception to the common HLA disparities of solid organ transplant?
Sibling renal transplant
222
How can a person become alloimmunized against foreign HLA?
Blood transfusions and pregnancies can induce antibody response
223
What is hyperacute graft rejection?
* Graft rejection due to blood type (can happen with HLA too)
* Preformed antibodies attack within hours
* Results in complement fixation, vascular damage, thrombosis
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What is direct allorecognition?
Recipient T cells recognize HLA complexes on the donor (graft) APC an causes generation of CD8+ T cells against donor (graft)
225
What is indirect allorecognition?
Recipient APC processes donor proteins and present donor HLA, generates CD4+ T cell cytotoxicity (via FAS/FasL)
226
What is the difference between acute and chronic organ rejection?
* **Acute** (7-21 days)- cell mediated toxicity, humoral rejection (not preformed antibodies)
* **Chronic** (after 21 days)- Interstitial fibrosis, mononuclear cell infiltration, ischemia
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What are the ranking factors in organ allocation?
* Risk of hyperacute rejection (ABO and HLA antibodies)
* Illness of patient (how badly do they need)
* Size paring of organ-patient
* Distance of organ
