Module 7 Infection and Immunity Flashcards
1
Q
Mucins
A
Mucins are gigantic glycoproteins that endow the mucus with properties to protect the epithelial surfaces
- Glycoprotein.
- Secreted by the epithelium.
- Their polypeptide chains reaching length of more than 10,000 amino acids, but constructed from simple sequence motifs repeated it many times over; the motives are rich in serine and threonine Reza juice
- Polypeptides are glycosylated with short negatively charged glycans
2
Q
Why is the mucous constantly hydrated?
A
It is intertwining of these gigantic proteins makes mucus viscous, and physically, impede the movement of microorganisms. The extensive glycosylation of Mucins causes mucus to be heavily hydrated and protect epithelial surfaces by retaining water and preventing dehydration
3
Q
How does Mucous expel microorganisms?
A
The free cysteine residues of the mucin polypeptides can be used to form covalent disulfide bonds with molecules of secreted IgA and defensins. The former are used to bind microorganisms approaching a mucosal surface; the latter are used to kill them
4
Q
Five ways in which the commensal gut microbiota benefit their human hosts?
A
- Synthesis of essential metabolites (vitamin K: essential for clotting)
- Breakdown of the plant fibers into digestible food.
- Inactivate Toxic substances, in food or from pathogens
- Prevent access of pathogens to the human gut
- Interact with epithelium to trigger development of secondary lymphoid tissue (GALT)
5
Q
GALT (gut associated lymphoid tissue)
A
- Inductive compartment: directly beneath the mucosal epithelium. Where interactions between antigen and lymphocytes induces adaptive immune responses
- Effector compartment: the underlying connective tissues; where the effector cells reside.
6
Q
Waldeyer’s ring
A
The tonsils and adenoids form a ring of lymphoid tissues around the entrance to the gut and airways
Palatine tonsils
Adenoids
Lingual tonsils
7
Q
Villi
A
The small intestine is the major site of nutrient absorption, and its surface is deeply folded into fingerlike projections
8
Q
Peyer’s patches
A
Secondary lymphoid organs of the small intestine
9
Q
The difference between systematic and mucosal immune systems?
A
- Instead of being reactive like systemic immunity, the mucosal immune response is proactive, constantly making adaptive immune responses against the gut microbiota. The healthy gut tissues are populated with memory, and effector T and B cells that stand guard, and poised to respond immediately to any invader from the gut lumen
- Sparing the use of inflammation. Because the inflammatory response inevitably causes damage to the tissue. In mucosal tissues, particularly in the gut, inflammation, is more likely to exacerbate infection, rather than clear it up. Inflammation of the gut is the cause of a variety, chronic human diseases.
10
Q
How does the gut prevent inflammation in mucosal tissues?
A
Use Treg cells to turn off inflammatory T cells. IL-10 is a cytokine secreted by Treg cells that suppresses inflammation by preventing the synthesis of inflammatory cytokines.
11
Q
Crohn’s disease
A
Rare individuals lack a functional IL-10 receptor and is mediated by inflammatory Th1 and Th17 T cells
12
Q
How does intestinal epithelial cells contribute to innate immune responses in the gut?
A
- Through TLRs, NOD1, NOD2 on cell surface or in intracellular versicles
- TLRs, NOD1, NOD2 can activate NFkB and cytokines productions
13
Q
What are the differences between intestinal macrophages and regular macrophages?
A
Intestinal macrophages eliminated pathogens without creating a state of inflammation
Although intestinal macrophages express MHC II, they do not have B7 co-stimulators and can not make IL-1, IL-10, Il-12 etc cytokines necessary to activate and differentiate naïve T cells
14
Q
The source of intestinal macrophages?
A
- Intestinal macrophages only live for a few months and needs to be constantly replenished
- Their population is replenished through the recruitment of monocytes from the blood
- These blood monocytes, then differentiated into intestinal macrophages
- Role of TGF-beta: When the monocytes arrive at the intestines, they have all the inflammatory properties associated with macrophages. Under the influence of TFG-beta, these monocytes differentiate into intestinal macrophages that have no inflammatory capacity
- This attenuated state is achieved by preventing the expression of a subset of Fc receptors for IgA, IgG, CR3, CR4, IL-2, IL-3 receptors and LFA-1 —-> to prevent activation of NFkB (a major regulator of the inflammatory response)
15
Q
M cells (microfold cells)
A
M cells are specialized to transport a micro organisms to gut associated lymphoid tissues
16
Q
Oral tolerance
A
Soluble proteins and other macro molecules enter the body from your mouth do not a stimulate immune response.
Healthy humans do not make antibodies against the numerous degradation products of food that leave the stomach and pass through the intestines. This state is called oral tolerance.
17
Q
How is oral tolerance formed?
A
In healthy gut, potential antigens from food are transported through M cells and are taken up by a subset of dendritic cells to lymph nodes.
In lymph nodes, the dendritic cells present these antigens to antigen specific T cells and drive their differentiation into a Treg cells expressing the transcription factor FoxP3. Treg cells actively suppress the immune response to food antigens.
18
Q
Which Isotype antibody controls the commensal microorganism?
A
Dimeric IgA antibody or penthameric IgM
19
Q
Does activation of naïve lymphocytes in one mucosal tissue committing them to defending all mucosal tissues?
A
Yes, see pic
20
Q
What are the effector lymphocytes guard healthy mucosal tissue in the absence of infection?
A
- Most are T cells
- Some Plasma cells secreting either penthameric IgM or dimeric IgA
21
Q
Selective IgA deficiency?
A
Cause: defective isotype switching from IgM to IgA
People lacking IgA are able to survive and reproduce, and were generally healthy.
Reason for this: increase the secretion of penthameric IgM compensate for the absence of IgA; (2) Transport of IgG from lamina proprietary to the gut mucosa by FcRn (3) Modern developed world hygiene, nutrition and vaccination
Chronic lung disease is more frequent in people with IgA deficiency in industrialized countries suggest the trend toward poorer air quality in the cities
22
Q
Protective immunity
A
Sufficient immunological memory to prevent second exposure to the same virus from becoming a disease causing infection is called protective immunity
23
Q
What confers protective immunity?
A
Long-lived plasma cells
Memory CD4 T cells
Memory CD8 T cells
24
Q
Cell with immunological memory
A
Long-lived plasma cells
Memory CD4 and CD8 T cells
25
How does the immune system prevent reinfection?
The antibodies are secreted by plasma cells, residing in the bone marrow or in the tissue beneath a mucosal surface, and are sustained at high levels for several months after the infection has been cleared to prevent reinfection
26
What are the short-lived plasma cells
Most plasma cells made in primary response are short-lived effector cells; their purpose is to proliferate as quickly as possible and secret as much antibodies as possible. The stress and the speed of this activity causes the cellular damage and genomic mutation, characteristics that are undesirable in a memory B cell.
Short-lived B cells die by apoptosis: When immune complexes of specific antibody and pathogen antigens bind to FcrRIIB1 on the plasma-cell surface and induce apoptosis of the plasma cells
27
What are long-lived plasma cells
Produced under conditions that do not induce the cellular damage or genomic mutation
They make the most effective antibodies and are sheltered and nurtured in the bone marrow
28
What sustains the survival of long-lived plasma cells
They are sheltered and nurtured in the bone marrow; and sustained by interactions with bone marrow stromal cells and by the IL-6 the stromal sells the secrete.
29
The differences between memory B cells, Naive B cells and plasma cells
They are distinguished by the expression of their B cell receptors:
Naive B cells: have surface IgM as their BCR and makes the primary B-cell responses
Memory B cells: emerged from primary immune response and have experience of a pathogen;
have surface IgG, IgA or IgE but does NOT have IgM as its BCR after Isotype switching
Plasma cells: Does NOT express a cell surface form of immunoglobulin
30
FcγRIIB1
Inhibitory receptor expressed by naive B cells (IgM B cells)
Its inhibitory pathway:
Through interactions with an IgG coated pathogen
(1) IgM — antigen
(2) FcγRIIB1 — Fc region of IgG bound to the pathogen
Results: inhibitory signals to Naive / IgM B cells that prevents it’s activation and condemns it to die by apoptosis
31
Does memory B cells express FcγRIIB1?
Yes it does
32
Fetal hemolytic anemia and how to prevent?
Mom: RhD- while Dad: RhD+
Can be prevented using the immune complex-mediated inhibition of naive B cells
33
Does plasma cell divide?
No.
Although the long lived plasma cells do not divide, they are metabolically very active.
They maintain their infrastructure in a process called autophagy — a mechanism by which cellular components are degraded by lysosomal degradation and then renewed.
34
Why is the suppression of naive B cells activation that occurs during the secondary immune response disadvantageous in confronting highly mutable pathogens?
Influenza viruses change its epitopes on yearly basis and a persons immunity erodes with time.
Because the activation of naïve influenza specific B cells is prevented, new clones of influenza specific B cells cannot be brought into play until the time is reached when none of the antibodies made in the primary response is able to recognize that the current strain of the influenza.
35
Catabolic metabolism
its also called starvation metabolism.
It involves mitochondrial oxidative phosphorylation, fatty acid oxidation, autophagy and mitophagy.
36
Anabolism
Anabolism is the process by which living organisms build complex molecules from simpler ones, usually requiring an input of energy. During anabolic metabolism, smaller molecules such as amino acids, fatty acids, and simple sugars are combined to form more complex molecules such as proteins, lipids, and carbohydrates.
Anabolic metabolism is the opposite of catabolic metabolism, as it involves the synthesis of larger molecules from smaller ones, rather than the breakdown of larger molecules into smaller ones. Anabolic reactions often require energy, which is typically obtained from ATP (adenosine triphosphate), which is produced during catabolic reactions.
37
Metabolic reprogramming of T cells
After being activated by pathogens, T cells begins its activation and start to divide and changes its metabolism from catabolism to anabolism
This reprogramming process is orchestrated by mTORC1, a protein kinase complex in the cytoplasm
38
Asymmetric division of T cells
Mitosis occurs while the antigen activated T cells remain attached to the dendritic cell. After the first of cell division, one of the two daughter cells, it becomes a physically closer to the dendritic cell then the other. In the course of mitosis, most of cellular components and continents are divided equally between the two daughter cells, expect for mTORC1, which is preferentially inherited by the daughter cell closest to the dendritic cell and give rise to effector T cells. The distal daughter cell is likely the precursor of a memory cell.
39
Three types of memory T cells
Central memory T cells (Tcm cells):
1. Express L-selectin & CCR7 —> enables entering secondary lymphoid organs like naive T cells to surveys antigens presented there by dendritic cells
2. Limited capacity for effector function.
3. Low threshold for activation, and a high capacity to produce IL-2 to proliferate and differentiate into effector T cells
Effector Memory T cells (Tem cells)
1. No L-selectin & CCR7 —> cannot go into secondary lymphoid tissues. Instead they express CCR 4, 5, 6 and CXCR3 and gain access to non-lymphoid tissues, especially inflated tissues and mucosal tissues
2. They respond to an infection at its origin and much faster than memory T cells
Resident memory T cells (most numerous type):
1. These pathogen-specific memory T cells are incorporated as sentries placed throughout the repaired tissue. These memory T cells never returned to the circulation, but stay to protected the origin of primary infection
2. It reduces the time taken to initiate a secondary immune response against a subsequent infection by the same pathogen.
40
Differences btw Naive, Effector, Memory T cells
They are differentiated by the proteins they express:
1. Memory T and effector T cells does not depend on CD28-mediated co-stimulation
2. Threshold for activation: mediated by the different binding affinity of CD45RO (expressed by Effector/Memory T cells) vs CD45RA (expressed by Naive T cells). CD45RO has better interaction with TCR.
CD45, tyrosine phosphatase involved in signaling from the T cell receptor.
41
Primary and secondary immune responses
Primary immune response:
1. Phase 1: innate immunity
2. Phase 2: adaptive immunity
Purpose: (1) clears infection (2) temporary strength the defense to prevent reinfection (3) establishes a long lasting immunological memory of the pathogen
Secondary immune response:
Close coordination between innate and adaptive immunity
42
Three reasons that smallpox is the only infectious disease to be eradicated by vaccination
1. Smallpox evolves slowly, and has the conserved antigenic Epitopes, the immunity acquired as an infant remains effective throughout life
2. The vaccine is a live virus that establishes an infection at the injection site in the skin, the tissue where natural smallpox infections occur. Thus the immune response stipulated by vaccine mimics smallpox infection and produces immunological memory that is effective against the smallpox.
3. Smallpox only infects in the human species, there are no reservoirs of the virus in other animals. Once the chain of transmission among humans was broken, the virus cannot survive
43
Killed / inactivated virus
No replication ability such as influenza and rabies vaccines
44
Live-attenuated virus vaccine
A mutant form of live virus that grows poorly in human cells and is no longer pathogenic to humans
Usually elicit a better protective immunity than that by killed virus vaccines. Most of the viral vaccines today are live-attenuated vaccine. Because the attenuated vaccine has a limited capacity to infect cells and replicate and thereby mimics a real infection.
45
How to attenuate a pathogenic human virus?
To attenuator of pathogenic human virus, it is growing in cells from another animal species. Such conditions is select for variants that grow faster in the non-human cells which makes them less fit for growth in human cells.
46
Subunit vaccines
Made from the most antigenic components of a pathogen, such as HBV vacccines; first vaccines to be made using recombinant DNA technology. Making the vaccine in this way did not involve viral particles, and avoided any contact with them.
47
Rotavirus
Wheel shaped and major cause of severe childhood diarrhea
48
Conjugate vaccines
For vaccines that contains bacterial polysaccharides but not bacterial proteins, the vaccine cannot activate helper CD4 Th cells (recall T cells can only recognize peptides) and could only stimulate a TI B-cell response that gave rise to low affinity IgM, with no potential for somatic hypermutation, isotype switching or memory B cells.
This deficiency led to the concept of a conjugate vaccine, in which different epitopes recognized by B cells and T cells synthetically linked together.
49
Adjuvant vaccines
Means “helper”
It is needed to activate innate immunity. Protein subunits and conjugates cannot activate innate immunity because they are not recognized by TLR or other receptors of the innate immunity.
To make these protein vaccines effective, another component ie adjuvant is included in the vaccine. The adjuvant activates innate immunity necessary to activate an adaptive immune response against the protein antigens of the vaccine.
50
Why does influenza vaccine not as effective?
Influenza is an RNA virus, the replication always genome is much more error-prone than the replication of DNA viruses such as smallpox and measles.
51
How do we manufacture influenza vaccine without eggs?
Once a potentially epidemic string of virus was identified and genome sequenced. The sequence would be immediately sent electronically to manufacturers, who then synthesize the virus in one day, using recombinant DNA technology. This synthetic virus would then be grown in large cultures of virus infected cells, purified from the culture fluid, inactivated and equality controlled. This would avoid having to grow the virus before sending it to the manufacturer. It would also avoid the traditional method of growing influenza virus in the eggs of chickens.
52
Reverse vaccinology
A pathogens genome is mined to identify candidate antigens that are then studied it to determine their biology and how they interact with the immune system.
53
Serotype
Pathogens evolve to have different strains. These strains differ in their antigenic macromolecule structures. A good example being streptococcus pneumoniae. The strains differ in the structure of their capsular polysaccharides and compete with each other to infect humans. These different strains are called serotypes Because antibody based serological assays are used to define and detect the differences between them.
54
Outbreaks / epidemics
Seasonal outbreaks, doing which the virus spreads quickly through a local population and then subsides abruptly
55
How many RNA does influenza have?
The genome of influenza virus consists of eight RNA molecules. Replication of the viral genome is error-prone and generates many pointed mutations.
56
What is antigenic drift?
If you are exposed to strain A with a specific antigen and developed antibodies and memory immunities for. But that strain A mutated to strain B with a different antigen due to the error prone replication process. You will need to develop a primary immune response against strain B as the antibodies developed for strain A cannot neutralize strain B.
57
What is antigenic shift?
The strains that are recombinant viruses that derive some of their RNA genome from an avian influenza virus and their remainder from a human influenza virus. If such a recombinant virus jumps back into humans, it has a tremendous competitive advantage, and can cause pandemics.
58
Protozoans?
Protozoa are single-celled microorganisms that belong to the kingdom Protista. They are eukaryotic organisms, meaning they have a nucleus and other organelles within their cells, such as parasites (Trypanosome). Protozoa are found in a variety of aquatic and terrestrial environments, including freshwater, saltwater, and soil.
59
Variable Surface Glycoproteins (VSGs)
The Trypanosome’s surface is formed of a glycoprotein, of which there are numerous variants, each encoded by a different gene. Trypanosome genome contains more than 1000 genes encoding these VSGs
60
What is gene conversion? And how does it cause immune evasion?
Trypanosomes uses gene conversion to change their surface antigens:
For a VSG gene to be expressed, it has to be rearranged into an “expression site”, of which there is only one copy in the trypanosome genome. This requirement means that an individual Trypanosome can express only one VSG at a time. When a Trypanosome first infects a human it will rapidly replicated in the absence of adaptive immunity and almost all of the trypanosomes will Xpress the same dominant VSG. However, a small minority will be mutants formed by gene conversion at the expression site, which replaces the dominant VSG gene with another. So even if you developed antibodies and cleared the first VSG, the second one emerges and the cycle goes on.
61
How does Herpesviruses persist in human hosts?
1. They are large dsDNA viruses.
2. When their linear genome becomes circular and acquires nucleosomes and patterns of DNA methylation just like the host-cell genome. They enter into latent phase which they neither provokes an immune response, nor causes disease.
62
Why do we say the relationship between CMV and humans are symbiotic?
CMV is the largest of human herpesvirus.
CMV is successful, well adapted human-specific pathogens, that infects most of the human population.
Primary CMV infection induces vigorous NK cell and T cell responses that prevent the virus from spreading, but allow it to survive in the latent state. More than half of the US population is infected.
The healthy CMV infected person, has a well tuned balance in which the virus survives without causing harm.
For people with compromised immune systems, CMV can be life-threatening.
CMV is the most common infection in patients receiving a hematopoietic stem cell transplant, and is fatal if not treated with antiviral drugs.
CMV infections also confers the benefits. CMV infection correlates with stronger antibodies responses, specific CD8 T cells with greater sensitivity, and a higher level of interferon gamma in the circulation. They are associated with improved immune responses to other pathogens. Thus CMV has a symbiotic relationship with his human hosts in which is the costs of infection are outweighed by the benefits, unless the host is immunocompromised.
63
Human herpesviruses cause a variety of disease
See pic
64
Superantigens?
Some species of a gram-positive bacteria, notably Streptococcus pyogenes, secrete potent toxins, and can induce a violent disruption of an infected persons immune system. Because these small bacterial protein toxins activates so many different T cell clones they’re called superantigens.
65
Primary vs Secondary immunodeficiency disease?
Primary is caused by defective genes
Secondary is caused by environmental factors, such as immunosuppressive drugs or infections
66
What cells secrete interferon gamma?
1. Secreted by NK cells to activate macrophages
2. Th1 CD4
3. CD8 T cells
67
IFN-gamma receptor deficiency
Both dominant and recessive mutations in the gene for IFNgammaR1 cause the disease.
68
X-linked agammaglobulinemia
Caused by a genetic mutation in the protein tyrosine kinase BTK (Burton’s tyrosine kinase). BTK contributes to intracellular signaling from BCR and is necessary for the development and differentiation of pre-B cells.
Antibody deficiency leads to poor clearing of extra cellular bacteria
69
What diseases can complement defects cause?
Complement defects impair antibody mediated immunity and cause the immune-complex (antibody-antigen complex) disease.
70
What are Serpins?
A large family of serine and cysteine protease inhibitors, including C1 inhibitor, C1INH. By acting as a pseudosubstrate, each serving molecule poisons the active site of a protease molecule.
71
What is the pathophysiological cause of Hereditary Angioedema (HAE)
1. Autosomal dominant disease
2. Caused by deficiency of C1 inhibitor (C1IHN)
C1IHN regulates —> activation of C1r and C1s by binding to their active sites
In HAE patients —> classical pathway overactive due to lack of C1 inhibitor —> really high level of vasoactive C2a —> vasodilation
In HAE patients —> blood-clotting pathways overactive due to lack of C1 inhibitor —> really high level of vasoactive peptide Bradykinin —> Fluid leaking into tissues from the blood
72
Different types of genetic defects affecting phagocytes?
See pic
73
What causes more severe disease? T cell or B cell deficiency?
B cells contributed only to anybody responses
T cells function in all aspects of adaptive immunity
Individuals with T cell deficiencies tend to be susceptible to persistent or recurring infections from a broader range of pathogens than people with B cell deficiencies
74
SCID (severe combined immunodeficiency)
1. Infants with SCID can only survive if their immune system is replaced by hematopoietic stem cell transplantation
2. SCID phenotype can rise from defects in any one of a number of genes Given T cell development and function dependent on numerous proteins
3. Genetic causes:
(1) ADA or PNP deficiency
(2) X-linked severe combined immune deficiency
(3) Wiskott- Aldrich Syndrome
(4) MHC Class I deficiency
(5) MHC Class II deficiency
75
ADA or PNP deficiency
ADA (Adenosine Deaminase) and PNP (purine nucleoside phosphorylase) are enzymes involved in purine degradation. The absence of these enzymes causes nucleotide metabolites to accumulate in all types of human cell, but the effects are particularly toxic to developing T cells. Infants with these deficiencies have a poorly developed thymus., containing fewer lymphocytes.
Autosomal recessive
76
X-linked severed combined immune deficiency
Mutation in the X-chromosome gene encoding the common gamma chain, a signaling component of the cell-surface receptors for IL2, IL4, IL7, IL9 and IL15 cytokines —> no intracellular signal transduction (ie cannot interact with JAK3)
77
Wiskott-Aldrich Syndrome (WAS)
WAS protein contributes to cytoskeleton re-organization that T cells undergo in forming cognate interactions with B cells, macrophages, and other target cells. Which leads to inadequate antibody responses and need IVIG.
78
MHC class ii deficiency
CD4 T cells fail to develop due to the absence of interaction with self MHC class II molecules in the thymus.
79
MHC class I deficiency
A defect in either one of the two proteins forming the TAP peptide transporter impedes peptide binding by HLA class I, leading to an abnormally low level of cell surface HLA class I. Less severe than MHC class II deficiency.
80
Some inherited immunodeficiencies cause a susceptibility to particular pathogens
See pic
81
AIDS (acquired immune deficiency syndrome)
Characterized by massive reduction in the number of circulating CD4 T cells and accompanied by severe infections caused by pathogens that rarely trouble healthy people.
82
HIV (human immunodeficiency virus)
HIV-1 and HIV-2
HIV is an RNA retrovirus, with an RNA nucleoprotein core (the nucleocapsid) surrounded by a lipid envelope derived from the host cell membrane and containing virus-encoded envelope proteins.
83
Retrovirus
A virus can use an RNA genome to direct the synthesis of DNA intermediate and then incorporate into host genome
84
Lentivirus
A group of viruses that cause scowling progressing chronic disease such as HIV
85
Endogenous retroviruses
Around 8% of the human genome is made up of retrovirus-like sequences. They are permanently integrated into human genome and transcripts from endogenous retroviruses, are found in all human tissues. The endogenous retroviruses are part of the human virome. HIV is an exogenous retrovirus.
86
How does HIV hijack the host cellular machinery?
Host cell infected by HIV —> HIV RNA —> cDNA (complementary DNA) by reverse transcriptase (key enzyme) —> cDNA integrated into the genome of the host cell to form a Provirus by viral Integrase (key enzyme)
87
Provirus
HIV sequence integrated into host cell genome
Flanked by long terminal repeats (LTRs)
Proviruses use the transcriptional and the translational machinery of the host cell to make viral proteins and RNA genomes, which assemble into new infectious virions.
88
Human immune systems are better adapted to HIV2 than HIV1
Infections are more common in HIV1. HIV2 has evolved an accommodation with its human host, which allows both host and virus to survive and multiply. In those countries where HIV-2 is endemic, some people become infected with both HIV-1 and HIV-2. A first infection with HIV-2 can reduce the severity of a subsequent infection with HIV-1. This points to HIV-2 can induce immune response that provides protection against the related and more dangerous pathogen HIV-1.
89
How types of cells does HIV infect and why?
HIV infects CD4 T cells, macrophages, and dendritic cells
Macrophages, dendritic cells and CD4 T cells are vulnerable to HIV infection because they express CD4, which the virus exploits as its cellular receptor.
90
What two receptors are need for HIV to gain access to host cells?
Receptor: CD4 ( macrophages, dendritic cells and CD4 T cells)
Co-receptor: CCR5 or CXCR4
91
How does HIV fuses with host cell?
HIV gains access through its spike proteins: a heterodimer of gp41 and gp120 glycoproteins.
The two proteins are made as a single polypeptide, which is cleaved by a host protease to give gp41 and gp120
The gp120 — CD4 —> virions attaching to cells expressing CD4 —> gp120 — CCR5 or CXCR4 —> gp41 components of the envelope glycoprotein fuses the viral membrane with the host membrane
92
Macrophage-tropic vs Lymphocyte-tropic?
Macrophage-tropic: Uses CCR5 as co-receptor to gain access to host cell; mainly responsible for spread of the infection and its evolution into a global pandemic
Lymphocyte-tropic: Uses CXCR4 as co-receptor to gain access to host cell; causes immunodeficiency disease by targeting CD4 T cells
93
Seroconversion
When an infected person first has detectable levels of an-HIV antibodies is his or her blood serum, that individual is said to have undergone seroconversion.
94
How do some people resist HIV infection?
Genetic deficiency of the CCR5 co-receptor for HIV confers resistance to infection
Homozygous individuals with CCR5-delata32 deletion variant resist HIV infection. They are only in populations of European origin.
Demonstrated by the one cure case of HIV through HSC transplant, the donor has CCR5-32 deletion variant and the recipient is cured of HIV
95
What HLA and KIR polymorphisms influence progression to AIDS
HLA-B*27 and / or HLA-B*57 allotypes slow the HIV progression
KIR-3DL1 is an inhibitory Bw4 receptor of NK cells and T cells
96
The three essential proteins HIV uses to hijack host cellular machinery?
1. Reverse transcriptase (transcribes RNA to cDNA)
2. Integrase (integrate cDNA to host DNA to provirus)
3. Protease (cleaves the precursor proteins to its functional parts of g120 and g 41)
97
ART (anti-retro-viral-therapy) development
1. Retroviruses have high mutation rates because their reverse transcriptase enzymes have no proofreading mechanisms.
2. HIV can resist the immune response and gains resistance to antiviral drugs through repeat mutation
3. Because HIV escapes easily from the action of any one drug, several antiviral drugs are now used in combination therapy. The goal is to destroy the entire population of viruses before any one of them accumulates enough mutations to resist all the drugs.
4. ART typically includes two different types of reverse transcriptase inhibitors with the possible addition of a viral proteases inhibitor.
98
Does ART cure HIV infections?
No, although ART is life changing, it does not cure HIV. ART does not completely restore HIV infected individuals to health, because they have increased risk of bone, cardiovascular, liver, and neurological complications due to chronic activation of the immune system with accompanying intestinal and a systematic inflammation.
Thus in the context of ART, HIV infection becomes a chronic inflammatory disease that originates in the gut and spread to other tissue and organs.
99
What is clinical latency?
Clinical latency is a period of active infection and a renewal of CD4 T cells.
100
CD4 T cells death in HIV infected hosts
1. Direct killing as a consequence of viral infection
2. Increased susceptibility of infected cells to apoptosis
3. Killing by cytotoxic CD8 T cells
101
Broadly neutralizing antibodies and elite neutralizers
Broadly neutralizing antibodies, recognize one of the four epitopes of the HIV-1 envelope glycoprotein. These epitopes are highly conserved and have a biological importance for the virus.
