Week 4 Flashcards
Immunity
protection against disease (not necessarily infection)
More rapid and greater response to subsequent exposure (e.g. vaccin)
“Natural” and acquired
Immunology
study of the mechanisms of immunity against infection and adverse effects of immune response
Components of immune function: (4)
1) Anatomic (skin, mucosal barriers)
2) Phagocytes (neutrophils, macrophages)
3) Cellular immunity (CD4+, CD8+ T cells, NK cells)
4) Humoral immunity (specific antibodies, B cells, complement)
HIV/AIDS:
what are the immune defects? (4)
1) Low CD4+ T cell number, decreased CD4+ T cell function
2) NK cell dysfunction
3) B cell dysfunction:
- Hypergammaglobulinemia, increased activation
- Decreased memory B cells
- Decreased response to new antigens
- High rates of autoimmunity
4) Phagocytic function: PMN and macrophages OK
3 stages of HIV/AIDs infection in terms of T cell number
Early stage = > 500
Intermediate = 200-500
Advanced, AIDS = < 200
Complement
Classical, Alternative, and Lectin converge at C3 → C5-C9 (MAC) and C5a
C1-C4 deficiency
classical pathway, present with PYOGENIC infections
C5-C9 deficiency
terminal pathway, show serious Neisseria infections
Most common complement deficienct
C2 deficiency
Antibody structure and function: Fc vs. Fab
Variable region F(ab): antigen binding region, each is unique
Constant region: Fc
- Defines isotype (IgG, IgM, IgA, IgE)
- Activates complement
- Binds phagocytes via Fc receptors
C5a
- potent chemoattractant
- promote anaphylactic activity
- recruit neutrophils and other inflammatory cells.
Classical complement pathway
Immune complex (IgG or IgM) + C1 activation —> C2, C3, C4 activation –> C5-C9
Alternative complement pathway
C3b + microbial surface, endotoxin, aggregated IgA –> C5-C9 activation
DOES NOT require C1, C4, or C2
C3 deficiency can predispose to what kinds of infections?
severe, recurrent pyogenic sinus and respiratory tract infections
increased risk for type III hypersensitivity reactions
Mannose-binding lectin pathway
mannose-binding lectin replaces C1 and does not require the presence of ab to be activated –> C2, C3, C4 –> C5-C9
Decay accelerating factor (DAF)
-responsible for what disease?
aka CD55
inhibits C3 and C5 convertases, prevents inappropriate complement activate
Paroxysmyl nocturnal hemoglobinuria due to GPI anchor defect that attaches DAF (CD55) and prevents complement activation –> complement mediated lysis of RBCs, WBCs, and platelets
Selective IgA deficiency
LOW IgA, NORMAL IgG, IgM
-can see increased airway and GI infections
- limited increase in infection due to protection by compensatory IgM
- majority asymptomatic
- Increased autoimmune +/- malignancy
- Increased risk of atopy and anaphylaxis
- Susceptible to transfusion reactions (with anti-IgA)
Primary immunodeficiency:
disease of adult (3) vs. childhood (3) presentation
Usually due to single gene defects
Most present in childhood:
1) X-Linked Agammaglobulinemia
2) SCID
3) Wiskott-Aldrich
Most common in adults:
1) CVID
2) IgG(2) subclass deficiency
3) Hyper-IgE syndrome (Job’s Syndrome)
Secondary immunodeficiency:
Developing country: Malnutrition, HIV/AIDS, Age (very young, very old), Measles
Developed country: chronic corticosteroids, chemotherapy, anti-TNF antibodies, HIV/AIDS, transplantation
Other causes: CLL (low Igs due to B “arrest”), multiple myeloma (high IgG but monoclonal, low IgM, IgA), renal and GI loss
Common variable immunodeficiency (CVID)
epidemiology
defect in what?
most common serious primary defect in adults (Onset in teens or 20’s)
Defect in B cell differentiation (many causes)
Common variable immunodeficiency (CVID)
labs and presentation
Recurrent PYOGENIC sinopulmonary infections (especially S. pneumoniae)
- bronchiectasis
- lymphoma
- increased risk of autoimmune disease
Chronic diarrhea with GI lymphoid hyperplasia and increased risk of bacteremia
Some PCP, fungi, mycobacteria, recurrent HSV
Labs: low IgG, IgM, IgA. NORMAL B cells, “NORMAL” T cells, LOW plasma cells
Chronic Granulomatous Disease (CGD)
sufficient phagocyte number but decreased function (NADPH oxidase deficiency = oxygen radicals decreased)
NBT negative
Chronic Granulomatous Disease (CGD)
increased susceptibility to…
Increased susceptibility to: “CATs Need PLACES to Belch Hairballs” = catalase + organisms
Nocardia Pseudomonas Listeria Aspergillus Candida E. Coli Serratio, Staph B. cepacia H. pylori
Recurrent skin abscesses, severe prolonged pneumonia, bone infections
If you have a cell mediated immunodeficiency, then you are more suscpetible to what bugs:
1) Bacterial (5)
2) Fungal (5)
3) Viral (4)
4) Protazoan (2)
5) Helminths (1)
*=TMP/SMX prophylaxis
Bacterial: Listeria, Nocardia, Mycobacterium, Salmonella*, Legionella
Fungal: Cryptococcus, Pneumocystis*, Aspergillus, Cocci. Immitis, Candida
Viral: HSV, Varicella, CMV, adenovirus
-Acyclovir prophylaxis for HSV and Varicella
Protozoan: Toxoplasma*, Cryptosporidium
Helminths: Strongyloides
TRECs
pieces of DNA cut out during intrathymic T-cell receptor gene rearrangement
V(D)J Recombination: take pieces of VDJ gene segments to generate a T cell receptor
D→ J and then V → DJ
SCID: Severe Combined Immunodeficiency
Possible defects: (2)
1) Defective IL-2R gamma chain (XR, most common)
2) Adenosine deaminase deficiency (AR)
Pediatric emergency to recognize SCID early: why?
Exposure to non-irradiated blood product transfusions, live vaccines, and common infections in patients in SCID can be life-threatening
Less complications, better prognosis, save money
Clinical presentation of SCID child
Failure to thrive, diarrhea, recurrent pulmonary infections
Opportunistic infections: viruses, fungi, intracellular bacteria
-PJP, Candida, Aspergillus, CMV, Enteroviruses, Mycobacteria
Absence of lymphoid tissue - ABSENT thymus
Alopecia, erythroderma, hepatosplenomegaly
Decreased TRECs
Genome structure of retroviruses
Structural proteins (4) Viral enzymes (3) Viral genome?
Structural proteins:
- Envelope (gp120, gp41)
- Gag = matrix (p17) and capsid (p24)
Viral enzymes:
- Reverse transcriptase: inefficient and error-prone
- Integrase: required for virus replication and transcription
- Protease: required for viral maturation
Viral genome: two RNA molecules
Retroviruses accessory proteins (6)
Tat (Tax): transactivator - required for viral gene transcription*
Rev (Rex): nuclear exporter
Vif: blocks APOBEC3G restriction
Vpr: multiple functions, nucleus importer
Vpu: multiple functions, virus assembly
Nef: multiple functions, host immune invasion
Long terminal repeats (LTRs)
cis elements required for reverse transcription, viral gene transcription, splicing, virus integration, and packaging
Life cycle of retroviruses (6 steps)
1) Binding and Entry
2) Reverse transcription
3) Genome integration
4) Viral gene transcription
5) Virus assembly and release
6) Viral maturation
Genome integration requires _______
Viral gene transcription requires ________
Virus assembly and release requires ______
Viral maturation requires _______
Genome integration (viral integrase)
Viral gene transcription (Tat transactivator)
Virus assembly and release: (Vpu required for virus release)
Viral maturation requires protease
protease in retroviruses
protease required for virus maturation and cleaves proteins in multi-linked chain to individual proteins
HERV: Human Endogenous Retrovirus
Comprises 8-10% of human genome
Most HERVs are defective and cannot produce infectious viruses but may be associated with human cancers
AIDS defining cancers: (3)
Kaposi sarcoma (HHV8) Non-hodgkin’s lymphoma (HHV8, EBV) Cervical cancer (HPV)
Non-AIDS defining cancers (7)
Anal cancer (HPV)
Hodgkin’s lymphoma (EBV)
Liver cancer (HBV, HCV)
Skin cancer (HPV?)
Head and neck cancer (HPV)
Lung cancer
Kidney cancer
What are the unique characteristics of HIV-positive cancers
- HIV associated cancers are more aggressive and progress faster
- Atypical pathology, higher tumor grade
- Poorer outcomes
- Higher rate of relapse
- Rapidly invasive
- Develops at a younger age
Significant improved survival rate of persons with HIV due to HAART → shift spectrum of HIV diseases from AIDS defining cancers to more Non-AIDS defining cancers
Antiretrovirals and chemotherapeutic agents have interactions and overlapping toxicities making therapy challenging
Potential contributing factors of HIV-positive cancers
1) Behavior risk factors
2) Direct effects of HIV:
- Transactivation of proto-oncogenes by HIV Tat
- Inhibition of tumor suppressor genes (p5s) by HIV
- Endothelial abnormalities by HIV (pro angiogenesis)
HTLV: Human T Cell Lymphocytic Virus
Oncovirus
Causes lymphoproliferative disorders
Epidemiology: Japan, Caribbean, South America, Africa, Iran
Lymphoproliferative disorders caused by HTLV
Adult T cell leukemia/Lymphoma (ATL)
HTLV-1-associated myelopathy (HAM)
Uveitis
Origins of AIDS epidemic
HIV entered human pop. from chimps in east central Africa
Markers of HIV disease and response to treatment: (2)
1) CD4+ lymphocytes = main host cell for HIV
CD4+ count correlates with disease progression
2) Plasma HIV RNA level - viral load is a measure of the extent of ongoing replication in lymphoid tissue
CCRH-d32 mutation
naturally occurring human genetic polymorphism
32 base pair deletion in CCR5 gene
Causes translational frameshift and protein truncation → CCR5 NOT expressed on cell surface
Initial infection with HIV presents with what symptoms?
acute febrile illness, mononucleosis-like illness +/- aseptic meningitis
Usually occurs 2-3 weeks after HIV exposure
Occurs in > 50% of patients (usually unrecognized)
Signs and Symptoms: fever, fatigue, maculopapular rash, myalgia, headache, pharyngitis, cervical lymphadenopathy, arthralgia, oral ulcers, odynophagia, weight loss, diarrhea, oral candidiasis, photophobia
Opportunistic infection
Infection that takes advantage of weakened immune system to cause an illness
Many only occur when CD4 < 200
Restoring CD4 count with antiretrovirals can minimize opportunistic infections
Opportunistic infection - 6 common ones with HIV/AIDS patients
1) Pneumocystis Pneumonia (PCP)
2) Kaposi Sarcoma
3) Thrush (mouth and esophagus)
4) CMV retinitis
5) CNS Toxoplasmosis (ring enhancing abscess)
6) Extrapulmonary TB
Effects of antiretroviral therapy:
- Virologic and immunologic effect (3)
- Clinical effects?
Virologic and immunologic effect:
- Potent inhibition of viral replication
- Early HIV → prevent immunologic deterioration
- Advanced HIV → allows immunologic recovery
Clinical effect:
- Prevent opportunistic infections, improve existing OIs
- Reduce hospitalizations, long-term care facility use, medications for OIs, and cost
Expected response to antiretroviral therapy (5)
- Reduces plasma HIV RNA levels (viral load)
- Increase CD4 count
- Improve existing OIs, prevent new OIs
- Decrease morbidity and mortality
- Reduced HIV transmission
HIV evolution
leads to increased pathogenicity, and drug resistance
-Genetic diversity (introduction of mutations)
Error-prone nature of viral replication → genetically distinct viral variants evolve from initial virus inoculum
Fast replication rate
Selective pressures (genetic bottlenecks)
Retroviral targets
1) Protease inhibitors
2) Entry inhibitors: target fusion, CD4, or CCR5
3) Reverse transcriptase (RT) inhibitors (includes NRTIs and NNRTIs)
4) Integrase inhibitors
HIV Prevention Strategies
Abstention and other behavioral changes
Male circumcision
Condoms
Pre-exposure prophylaxis
Post-exposure prophylaxis
ART in HIV+ patient
HIV vaccine
Microbicides
Diagnosis of HIV
initial ELISA, positive tests confirmed by Western blot
Viral load from qRT-PCR → help monitor efficacy of drug therapy
ELISA and Western Blot for diagnosis of HIV
False negative/False positive can be seen in what situations?
Can be falsely negative in first 1-2 months post HIV infection
Can be falsely positive in infants born to HIV+ mothers (anti-gp120 crosses placenta)
Diseases seen when CD4 < 500 (6)
1) Candida albicans
2) EBV
3) Bartonella Henselae
4) HHV-8
5) Cryptosporidium
6) HPV
Diseases seen when CD4 < 500
EBV vs. Candida
Candida albicans: oral thrush (scrapable plaque)
EBV: oral hairy leukoplakia (unscrapable plaque on lateral tongue)
Diseases seen when CD4 < 500
Bartonella Henselae vs. HHV-8
Bartonella Henselae: bacillary angiomatosis with neutrophilic inflammation on biopsy
HHV-8: Kaposi sarcoma, lymphocytic infiltrate on biopsy
Diseases seen when CD4 < 500
Cryptosporidium
- sx?
- what do you see in stool?
chronic, watery diarrhea, acid-fast oocysts in stool
Diseases seen when CD4 < 500
HPV
resulting in squamous cell carcinoma (anus or cervix)
Diseases seen when CD4 < 200 (3)
1) Pneumocystis jirovecii
2) JC virus reactivation
3) HIV dementia
Diseases seen when CD4 < 200
Pneumocystis jirovecii
- sx?
- appearance on imaging?
- increased value on what lab?
pneumonia, ground-glass appearance on imaging, elevated serum lactate dehydrogenase
Diseases seen when CD4 < 200
JC virus reactivation
- disease it causes?
- appearance on MRI?
resulting progressive multifocal leukoencephalopathy with nonenhancing areas of demyelination on MRI
Diseases seen when CD4 < 100 (8)
1) Aspergillus fumigatus
2) Histoplasma capsulatum
3) Candida albicans
4) Cryptococcus neoformans
5) CMV
6) Mycobacterium avium-intracellulare (MAC)
7) EBV
8) Toxoplasma gondii
Diseases seen when CD4 < 100
Aspergillus fumigatus
- sx
- appearance on chest imaging?
hemoptysis, pleuritic pain, cavitation or infiltrates on chest imaging
Diseases seen when CD4 < 100
Histoplasma capsulatum
- sx?
- appearance on histology?
nonspecific symptoms - fever, weight loss, fatigue, cough, dyspnea, nausea, vomiting, diarrhea
Oval yeast cells within macrophages
Diseases seen when CD4 < 100
Candida albicans
sx?
appearance on microscopy?
esophagitis, white plaques on endoscopy, yeast/pseudohyphae on microscopy
Diseases seen when CD4 < 100
Cryptococcus neoformans
sx?
appearance on microscopy?
meningitis, thickly encapsulated yeast on India ink stain on microscopy
Diseases seen when CD4 < 100
CMV
retinitis, esophagitis
Retinitis → cotton-wool spots on fundoscopy
Esophagitis → linear ulcers on endoscopy
Biopsy with intranuclear (owl eye) inclusion bodies
Diseases seen when CD4 < 100
Mycobacterium avium-intracellulare (MAC)
- sx?
- which two labs will be elevated?
anemia, increased alk phosphatase, increased lactate dehydrogenase, hepatosplenomegaly
Diseases seen when CD4 < 100
EBV
- sx?
- appearance on brain imaging?
B cell lymphoma with single or multiple ring enhancing lesions on brain imaging (fewer that Toxoplasma)
Diseases seen when CD4 < 100
Toxoplasma gondii
-appearance on MRI?
brain abscesses that appear as multiple ring-enhancing lesions on MRI
HHART includes what combination of drugs?
2 NRTIs + Integrase inhibitor, protease inhibitor, or NNRTI
Nucleoside reverse transcriptase inhibitors (NRTIs):
Mechanism of action
prodrug activated by cellular kinases to triphosphorylated active form → inhibit reverse transcription by competing with host cell triphosphate nucleotides for access to active site of HIV reverse transcriptase
→ Prevents genome replication and establishment of provirus
Nucleoside reverse transcriptase inhibitors (NRTIs):
Mechanism of resistance
high rate of resistance, associated with mutations in amino acid positions of HIV reverse transcriptase CROSS RESISTANCE within class is common
Nucleoside reverse transcriptase inhibitors (NRTIs):
what happens if levels are too low? too high?
Levels fall too low → increase resistance developing, levels too high → toxicity
Nucleoside reverse transcriptase inhibitors (NRTIs):
Drug names (6)
1) *Tenofovir AF
2) *Emtricitabine
3) Abacavir
4) *Lamivudine
5) Stavudine
6) Zidovudine (formerly AZT)
*Tenofovir AF
mechanism? ADR? metabolism?
TDF vs. TAF?
NRTI
Mechanism: nucleoTIDE reverse transcriptase inhibitor
-*Does NOT require intracellular phosphorylation to be active
ADRs: Fanconi syndrome
Renal excretion
Lower systemic exposure than TDF because action primarily intracellular
*Emtricitabine
Best tolerated NRTI
Also active against HBV
Renal excretion
Abacavir
-metabolism?
- ADRs?
- what can you screen for to prevent ADR?
NRTI
Hepatic metabolism
ADRs: hypersensitivity reactions
HLAB*57:01 screening performed prior to initiating treatment with abacavir to avoid Type IV hypersensitivity reaction
*Lamivudine
Best tolerated NRTI
Also active against HBV
Renal excretion
Zidovudine
-main use?
NRTI
(formerly AZT):
Can be given prophylactically after birth along with Nevirapine to decrease risk of HIV acquisition from mom
NRTIs:
Adverse Drug Reactions common to all the drugs in this class (4)
1) Some activity against mitochondrial DNA polymerase → Myopathy, anemia, granulocytopenia, neuropathy
2) Lactic acidosis
3) Hepatic steatosis
4) Renal impairment potential
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs):
Mechanism
bind and directly inhibit reverse transcriptase (non-competitive inhibition)
Do NOT require phosphorylation to be active
Do NOT compete with nucleotides
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs):
Mechanism of resistance
single AA substitutions in binding site of NNRTIs on HIV reverse transcriptase Resistance to one NNRTI → resistance to remaining class members
**Must be used with as least two other antiretroviral agents to prevent acquisition of strain resistance
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs):
ADRs (2)
rash, hepatotoxicity
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs):
Drug names (3)
1) *Efavirenz
2) Nevirapine
3) Delavirdine
*Efavirenz
2 ADRs unique to this drug
contraindicated in who?
NNRTI
vivid dreams, CNS symptoms
CONTRAINDICATED in pregnancy
Nevirapine can be given with Zidovudine to do what?
Can be given prophylactically after birth along with Zidovudine to decrease risk of HIV acquisition from mom
Nevirapine
ADRs (3)
potential for severe hepatotoxicity, hepatic failure, and death - not used really anymore
NNRTI
Delavirdine
NNRTI
CONTRAINDICATED in pregnancy
Least potent NNRTI, rarely used
Fusion inhibitors
mechanism?
interfere with binding, fusion, and entry of HIV virion into CD4 cells
Fusion inhibitors
2 drug names?
1) *Enfuvirtide
2) *Maraviroc
Enfuvirtide
Mechanism?
blocks gp41 conformational change → prevent fusing with CD4 cells
Enfuvirtide
Mechanism of resistance?
gp41 mutations
Maraviroc
Mechanism?
CCR5 antagonists → prevent fusion between viral gp120 and CCR5 receptors on macrophages → prevent viral entry
Maraviroc ADRs (1)
hepatotoxicity (with high dose treatment)
Maraviroc
mechanism of resistance?
mutations in gp120, no cross resistance
Maraviroc has no activity against what strain of HIV?
No activity against “X4” or “dual tropic” HIV-1 strains - HIV-1 virions that target CXCR4, associated with later stages of HIV infection and disease progression
Means CXCR4 used over CCR5 to enter cell
Integrase inhibitors:
mechanism?
prevent insertion of viral dsDNA into host genome via reverse transcription of RNA, no action against human DNA polymerase
Integrase inhibitors:
Mechanism of resistance
lower genetic barrier to resistance, single point mutation
Integrase inhibitors:
Drug names? (3)
*Raltegravir
Elvitegravir
Dolutegravir
Integrase inhibitors
ADRs (2)
hypercholesterolemia, increase in creatine kinase
Generally well tolerated
Protease inhibitors
Mechanism of action
bind and prevent virally encoded proteases (HIV-1 protease, pol gene) from cleaving polyproteins into mature proteins
Protease inhibitors:
Mechanism of resistance
single AA substitution, typically SPECIFIC for individual protease inhibitors
Resistance development is rapid when used as a single drug → must combine
Protease inhibitors:
ADRs
1) Lipodystrophy (fat redistribution, central fat accumulation)
2) Hyperglycemia, hyperlipidemia, hyperinsulinemia
3) GI intolerance
4) QT prolongation
5) Hepatotoxicity
6) **Rifampin (CYP450 inducer) CONTRAINDICATED with protease inhibitors
Protease inhibitors:
Drug names (4)
(-navir)
Darunavir
Atazanavir
Fosamprenavir
Ritonavir
