RANGKUMAN IMMUNOLOGY 7

Immunity to Microbes and Immunodeficiency

Immunity to Microbes
Overview of Immune Responses to Microbes

● Disease
- short lived: host response effective
- Chronic: response not adequate
● Defense against microbes→ mediated by effector mechanism of innate
and adaptive immunity
- Innate: early defense
- Adaptive: lebih kuat dan berkelanjutan → protection pada
paparan ulang
● Many pathogen→ resist innate immunity → protection dependent on
adaptive immunity
● Immune system→ responds in specialized ways to different type of
microbe
● Survival and pathogenicity→ bergantung pada ability to evade or
resist the effector mechanism of immunity
● Latent or persistent→ immune response controls but does not
eliminate. Ex: DNA virus→ herpes and poxvirus, bacteria→ M
tuberculosis (survive in phagocytic vesicles) → become activated when
immune system weakened
● Analysis of immune response → uji klinis infeksi
 Helpful for
- Microbe cannot be cultured
- Not detectable in blood
- Present in tissues that are not accessible
Contoh
- IgM→ recent infection. IgG→ past infection
- Test for skin reaction → assay for T cell responses. Ex: tuberculin
test

Immunity to Extracellular Bacteria

● Extracellular bacteria → bisa replikasi di luar host cells. Ex: di blood, connective tissue, lumen
● Disease → caused by 2 principal mechanism
1. Bacteria induce inflammation → injury in site of infection
2. Bacteria produce toxin → ex:
- endotoxin (LPS in cell wall of gram -) → stimulate production of cytokine
- exotoxin (secreted) → cytotoxic and kill host cell.
a. diphtheria toxin → shut down protein synthesis in infected cells.
b. Cholera toxin→ interferes w ion and water transport
c. tetanus toxin→ inhibit neuromuscular transmission.
d. Anthrax toxin: disrupt biochemical signaling pathway

Innate Immunity to Extracellular Bacteria Adaptive Immunity to Extracellular Bacteria

a. Activation of phagocytes and inflammation → major defense
EB efficiently killed by phagocytes→ karena EB tidak bisa bertahan di
dalam sel
1. tissue-resident DC and macrophage→ activated by microbes→
secrete cytokine → promote leukocyte infiltration
2. Neutrophil and monocyte-derived macrophage→ use receptor
to recognize EB
a. Mannose and scavenger receptor→ promote phagocytosis
b. TLR→ promote microbicidal activities Humoral immunity→ major protective immune response
c. Fc and complement receptor→ promote phagocytosis to EB
b. Complement activation ● Antibody
- bacteria express mannose – mannose binding lectin/ N-acetyl – - polysaccharide→ T-independent → Ex: S,
ficolin → activate complement pathway pneumoniae, neisseria
- Opsonization→ enhance phagocytosis of bacteria - Spleen: production of antibody and
- MAC complex → lyses bacteria. Ex: Neisseria (thin cell walls) phagocytic clearance of opsonized
bacteria→ pada indiv splenectomy ↑ infection
by encapsulated bacteria
Mekanisme antibodi
- Neutralization; high affinity IgG, IgM, IgA
- Opsonization: IgG1 and IgG3
- Complement activation: IgM, IgG1, IgG3
● Protein antigen of EB→ activate CD4+ Thelper
- Produce cytokine

Injurious Effect of Immune Responses to Extracellular Bacteria

● Inflammation and Sepsis

1. Sepsis ● Superantigen → bind to TCR and MHC II (not on
 - Consequence of severe infection by bacteria and fungi peptide binding cleft) → activate many more clones
- Septic shock: most severe and fatal → circulatory collapse of T cells → activate many T cells → large amount
(shock) of cytokine → sepsis-like systemic inflammatory
- Early phase: response syndrome
a. Caused by cytokine (macrophage→ LPS and
peptidoglycan)
b. TNF, IL-6, IL-1→ sitokin utama
c. Early burst of large amounts of cytokine→ cytokine
storm
Late complication of humoral immune response
● Poststreptococcal glomerulonephritis→ antibody-antigen complexes
deposited in kidney glomeruli

Immune Evasion by Extracellular Bacteria

 ● Bacteria w polysaccharide-rich capsules→ resist phagocytosis
● Sialic acid in capsules→ inhibit complement activation by alternative
pathway
● Variation of surface antigen
- Gonococci and E. coli→ pili→ major antigen: protein pilin → pilin
genes undergo extensive gene conversion → evade attack by
pilin-specific antibodies
- chemical alteration in surface oligosaccharides→ sialylation
- Rilis surface antigen→ buat membrane blebs→ antibodies
dibuang dari tubuh mikroba

Immunity to Intracellular Bacteria

Innate Immunity to Intracellular Bacteria Adaptive Immunity to Intracellular Bacteria

● Mainly by phagocytes and NK cells ● Mainly by Cell-mediated Immunity

Phagocyte ● HIV→ deficient in cell-mediated immunity→
● Phagocyte→ early: neutrophil, late: macrophage→ ingest these extremely susceptible to IB
microbes → but IB resistant to degradation within phagocytes ● 2 tipe reaksi sel T
● Reseptor a. CD4+Th1→ activate phagocytes (CD40L and
- TLR and NLR → recognize product of bacteria → activation of IFN-y) → secrete IFN-y (produce NO, ROS),
phagocytes TNF (recruit other leukocyte)
- CDS (cystosolic DNA receptor) --> STING pathway→ IFN type 1 b. CD8+T cells→ eliminating microbes that
responses escape phagocytes (ex: Listeria creates holes
NK cell in phagosomal membrane→ bacteria escape
● Intracellular bacteria→ activate NK by induce expression of NK into cytosol)
cell-activating ligand + stimulate production IL-12 dan IL-15 (NK
cell-activating cytokines)
● NK cell→ produce IFN-y → activate phagocytes →killing of
phagocytosed bacteria

Injurious Effect

● Macrophage activating→ DTH (delayed type hypersensitivity) → injury

● IB→ resisten pada phagocyte→ bertahan lama→ chronic T cell and
macrophage activation → formation granuloma surrounding microbe
(histologic hallmark for IB infection)--> prevent spread of microbe →
severe functional impairment bcs of tissue necrosis and fibrosis

Immune Evasion by Intracellular Bacteria

 ● Inhibit phagolysosome fusion
● Escaping into the cytosol
● Directly inactivating microbicidal substances. Such as ROS

Immunity to Fungi

Innate Immunity

● Major: phagocytes and the complement system

Phagocyte
- Recognize by: TLR & dectin and mannose receptor
- Neutrophil→ extracellular fungi
- Neutropenia→ disseminated fungal infection
- Neutrophil→ fungicidal substances→ ROS and lysosomal enzymes
Complement
- Complement activation → defense fungi that enter the bloodstream.
Ex: candida
- Fungi→ activate alternative/ lectin complement pathway
- Complement→ opsonize fungi → but not form MAC (bcs fungi have
thick walls)

Adaptive Immunity to Fungi Immune Evasion by Fungi

● Peran penting: Th17 ● Little is known

1. Fungi→ recognize by CLR (C- type lectin receptor) and TLR ● Virulent strain of C. neoformans→ inhibit
2. Stimulate DCs and macrophage to produce cytokine→ promote production of cytokine (TNF and IL-12 by
Th17 development (IL-1, IL-6, IL23) macrophage) and ↑ IL-10→ inhibit macrophage
● Th1-mediated cellular immunity→ against intracellular fungi infection activation
 -Histoplasma capsulatum (facultative intracellular) → lives in
macrophage
● Th2→ ineffective at clearing fungi and may cause harm
- Aspergillus infection of airways→ Th2 reaction→ reaksi alergi →
bronchopulmonary aspergillosis
 Immunity to Viruses

Innate Immunity to Viruses

● Associated with production of IFN type 1 by infected cells,

plasmacytoid DCs, and macrophages
● Pathways trigger IFN production :
a. recognition of viral RNA by endosomal TLRs → activation of
cytoplasmic RIG-like receptors
b. recognition of viral DNA by endosomal TLRs → activation of
STING pathway
c. activation of protein kinases → activate IRF transcription
factors → stimulate IFN gene transcription → inhibit viral
replication in both infected and uninfected cells & production
of restriction factors
NK cells kill virus-infected cells early in the course of infection
before adaptive immune responses have developed
● viral infection inhibits class I MHC expression on infected cells
+ induces expression of additional activating ligands → NK cell
inhibitory receptor is not engaged & activating receptor trigger
responses of NK cells

Adaptive Immunity to Viruses

Mediated by :
● CTLs → killing infected cells
● Antibodies → block virus binding and entry

Antibodies
● Effective only during the extracellular stage
● Antiviral antibodies bind to viral envelope / capsid antigens →
neutralizing antibodies → prevent virus attachment and entry
into host cells
● Antibodies opsonize viral particles → promote clearance by
phagocytes
CTLs
● Most virus-specific CTLs are CD8+ T cells that recognize
cytosolic, viral peptides presented by class I MHC molecules
● Programmed cell death
● Activation of nucleases within infected cells → degrade viral
genomes
● Cytokines (IFN-γ) → activates phagocytes

There are some conditions in adaptive immune response : ● CTLs caused tissue injury
● Latent infections → viral DNA exist in cell (host immune e.g. Hepatitis B virus, lymphocytic choriomeningitis virus (LCMV)
response controls but does not eliminate the infection) →
recurrent infection during immunocompromised
e.g. shingles – latent varicella, cold sores – latent HSV

Immune Evasion by Viruses

Antigenic Variation Inhibit the ability to induce antiviral state

e.g. SARS-CoV, MERS-CoV, and SARS-CoV-2
● Affected most commonly surface glycoproteins
● Principal mechanisms : point mutations & reassortment of ● shut off the host type I IFN response
RNA genomes (in RNA viruses) → antigenic drift and antigenic ● modify viral RNA (by adding 7-methyl guanosine cap & 2’O-methy
shift group to the ribose in the next nucleotide) → prevents recognition
a. Antigenic drift → mutations in the genes that encode by RIG-I and MDA-5
surface proteins, then the variation occurs
b. Antigenic shift → reassortment of viral genes results in
major changes in antigenic structure which creates distinct
viruses
Inhibition of MCH class I

● Viruses make a variety of proteins that

block different steps in antigen
processing, transport, and presentation
→ blocks the assembly and expression
of class I MHC → cannot be recognized
or killed by CD8+ CTLs.

Inactivation of CTL Cause “exhaustion” of CTL

e.g. Poxviruses
● encode molecules secreted by infected ● chronic viral infections → persistent
cells → bind to several cytokines (IFN-γ, antigen stimulation → upregulation of
TNF, IL-1, IL-18, and chemokines) → may PD-1 transcription factor
function as competitive antagonists of
the cytokines
e.g. Epstein-Barr virus Inactivation of immunocompetent cells
● production of IL-10 like protein → e.g HIV → infecting and eliminating CD4+ T
inhibits activation of macrophages & cells
DCs → suppress cell-mediated
immunity
 Immunity to Parasites
Parasitic infection refers to infection with animal parasites such as protozoa, helminth, and ectoparasites (e.g ticks and mites)

Innate Immunity to Parasites

● Principal to protozoa → phagocytosis

● Some protozoa express surface molecules that are recognized by TLRs and activate phagocytes
e.g. Plasmodium species, Toxoplasma gondii, and Cryptosporidium species express glycolipids → activate TLR2 and TLR4

● Principal to helminths → eosinophils, alternative pathway of complement

Adaptive Immunity to Parasites

● Principal to protozoa that survive within macrophages →

cell-mediated immunity (macrophage activation by Th1
cell–derived cytokines)

● Principal to helminthic infections → mediated by the activation

of Th2 cells
● Helminths → naive CD4+ T cells to Th2 cells → secrete :
a. IL-4 → production of IgE → binds to the Fcε receptor of mast
cells
b. IL-5 → activates eosinophils
 Immune Evasion by Parasites

● Parasites evade by reducing immunogenicity & inhibiting host Protozoan conceal themselves from the immune system
immune responses ● either by living inside host cells or developing cysts

Change surface antigens during life cycle in vertebrate hosts

● stage-specific change in antigen expression → mature tissue
stages produce antigens different from the infective stages
● e.g. infective sporozoite stage of Plasmodium is antigenically
distinct from merozoites that reside in the host and responsible
for chronic infection, Trypanosoma brucei and Trypanosoma
rhodesiense
Parasites inhibit host immune responses by multiple mechanisms
● T cell anergy (severe schistosomiasis & filarial infections)
● lymphatic filariasis in lymph nodes → deficient immunity
● Leishmania → stimulate the development of Tregs → suppress the
immune response
● Production of immune suppressive cytokines

Become resistant to immune effector mechanisms during

residence in vertebrate hosts
● e.g. schistosome larvae (develop a tegument) → resistant to
complement and CTLs
 Strategies for Vaccine Development

● Fundamental principle → administer a killed or attenuated
form of an infectious agent, or a component of a microbe, that
does not cause disease but elicits an immune response that
provides protection against infection
● Vaccines most effective if the infectious agent does not
establish latency, undergo antigenic variation, interfere with
host immune response, and limited to human hosts
● Most vaccines in use today work by inducing humoral immunity →
the best vaccines are stimulate development of long-lived plasma
cells that produce high-affinity antibodies and memory B cells
● There are major challenges in developing effective vaccines → the
immunologic correlates of protection are often poorly defined and
fundamental questions about how to maximally stimulate durable
memory, effective T cells, and long-lived plasma cells remain
unresolved

Attenuated and Inactivated Bacterial and Viral Vaccines

● Some of the earliest (first generation) and most effective

● Advantage → elicit many of innate and adaptive immune responses (both humoral and cell-mediated) → the ideal way of inducing
protective immunity
● The attenuated or killed bacterial vaccines currently in use generally induce limited protection and are effective for only short periods
● Live, attenuated viral vaccines are usually more effective → polio, measles, yellow fever
● Viral vaccines often induce long-lasting specific immunity
● The major concern is safety → vaccine-induced disease

Purified Antigen (Subunit) Vaccines

● Composed of antigens purified from microbes / inactivated ● Purified protein vaccines stimulate helper T cells and antibody
toxins and usually administered with an adjuvant → responses, but they do not generate potent CTLs → exogenous
prevention of diseases caused by bacterial toxins proteins (and peptides) usually enter the class II MHC pathway of
● Diphtheria and tetanus are two infections whose antigen presentation → vaccines are not recognized efficiently by
life-threatening consequences have been largely controlled class I MHC–restricted CD8+ T cells (except in the special situation
because of immunization of children with toxoid preparations of cross-presentation)
● Vaccines composed of bacterial polysaccharide antigens are
used against Pneumococcus and Haemophilus influenzae
● Polysaccharides (T-independent antigens) → tend to elicit
low-affinity antibody responses
● High-affinity generated by coupling to proteins to form
conjugate vaccines → elicit helper T cells to simulate germinal
center reactions, which would not occur with simple
polysaccharide vaccines
e.g. H. influenzae, pneumococcal, and meningococcal vaccines
 Synthetic Antigen Vaccines

● A goal of vaccine research has been to identify the most
immunogenic microbial antigens or epitopes, to synthesize
these in the laboratory, and to use the synthetic antigens as
vaccines.
● It is possible to deduce the protein sequences of microbial antigens
from nucleotide sequence data and to prepare large quantities of
proteins by recombinant DNA
● Vaccines made of recombinant DNA–derived antigens are now in
use for hepatitis B virus and HPV

Live Viral Vaccines Involving Recombinant Viruses

● Introduce genes encoding microbial antigens into a
noncytopathic virus → virus serves as a source of the antigen in
an inoculated individual
● Advantage of viral vectors : like other live viruses, induce the
full complement of immune responses, including strong CTL
responses
● A potential problem with recombinant viruses is that the viruses
may infect host cells, and even though they are not pathogenic,
they may produce antigens that stimulate CTL responses that kill
the infected host cells

DNA Vaccines mRNA Vaccines

● Inoculation of a plasmid containing complementary DNA
(cDNA) encoding a protein antigen leads to humoral and
cell-mediated immune responses to the antigen
● Bacterial plasmids are rich in unmethylated CpG nucleotides
→ recognized by TLR9 in DCs and other cells → could be
effective even when administered without adjuvants
● Uses messenger RNA (mRNA) encoding microbial antigens
● The main advantages : can be rapidly developed, the ability to
bypass the need for the large-scale manufacture and purification of
protein antigens, the ability to combine mRNAs encoding many
different protein antigens from a pathogen into a single vaccine

Adjuvants and Immunomodulators

● The initiation of T cell–dependent immune responses against
protein antigens requires adjuvants → elicit innate immune
responses → increased expression of costimulators and
cytokines, such as IL-12, that stimulate T cell growth and
differentiation
● Heat-killed bacteria are powerful adjuvants that are commonly
used in experimental animals
● Approved for patients :
a. Aluminum hydroxide gel (promote mostly B cell responses)
b. Bacterial product, monophosphoryl lipid A, alone or with
aluminum salt
c. Lipid formulation called squalene (activate phagocytes)
d. CG-rich oligonucleotides (CpG DNA) (for hepatitis B vaccines)
→ activating TLR9 → elicit potent innate immune reactions

Passive Immunization

● Most commonly used for rapid treatment of potentially fatal

diseases caused by toxins, such as tetanus, and for protection
from rabies, hepatitis, and SARS-CoV-2
● Convalescent plasma has been used in cases of Ebola and
COVID-19.
● Recombinant monoclonal neutralizing antibodies are now
utilized as a therapy for COVID-19
● Short-lived
● Does not induce memory
 Primary and Acquired Immunodeficiencies
● The primary immunodeficiencies are genetic defects that ● Secondary, or acquired, immunodeficiencies are not inherited
result in an increased susceptibility to infection that is diseases but develop as a consequence of malnutrition, disseminated
frequently manifested in infancy and early childhood but cancer, treatment with immunosuppressive drugs, or infection of cells
is sometimes first clinically detected later in life of the immune system

Overview of Immunodeficiency Diseases

● The principal consequence of immunodeficiency is

increased susceptibility to infection → opportunistic
microorganism
● Deficient humoral immunity → infection by encapsulated,
pus-forming bacteria and some viruses
● Defects in cell-mediated immunity → infection by viruses,
other intracellular microbes / reactivation of latent
infections
● Patients with immunodeficiencies are also susceptible to
certain types of cancer
 Primary (Congenital) Immunodeficiencies

● Primary immunodeficiencies → monogenic disease, caused
by germline mutations in genes
● Earliest → X-linked recessive disease, majority → autosomal
recessive
● Often seen in consanguineous families (same mutation
inherited from both parents)
● Other cases in nonconsanguineous → one defective allele of
a specific gene from parent A, and different defective
mutation in the same gene from parent B → compound
heterozygotes
● Some primary immunodeficiency from autosomal dominant,
include gain-of-function mutations & loss-of function
mutations (impaired function but not complete loss of
protein)
Example:
❖ Activating mutations in PIK3CD (encodes hyperactive PI3
kinase δ (gain-of-function)
❖ Mutation in CTLA4 → haploinsufficiency
(loss-of-function)
● Expression, clinical manifestation from same mutation may
be variable
❖ Contributed by phenotypic variability → coinheritance of
modifier genes, environmental factos, epigenetic
modifications
● Diagnosis of primary immunodeficiencies made from:
measurement of serum Ig levels, flow cytometry of immune
cells, assessment of neutrophil function in vitro
● In the US → required for newborns to be screened → looking
for DNA that is deleted during TCR gene rearrangement →
failure to detect these DNA: absence of T cell development
❖ Early diagnosis → early correction of defect by
hematopoietic stem cell transplantation
● Defects in one mechanism → individuals susceptible to only
some infections
● Certain immunodeficiencies → associated with autoimmunity
❖ Mutation → changes in regulatory mechanism, or
❖ Persistent infection → tissue injury → activation of
autoreactive lymphocytes

Defects in Innate Immunity

● Innate immunity → first line of defense → congenital disorders leads to recurrent infections
● Includes: NK cell deficiencies, defects in TLR signaling & in IL-12/IFN-y pathway
● Phagocyte defects → infections of the skin & respiratory tract with bacteria & fungi, e.g. Aspergillus & Candida; deep-seated
abscess & oral stomatitis
● TLR & type 1 IFN signaling defects → recurrent pyogenic infections, severe viral infections
● IL-12 & IFN-y pathway defects→ intracellular pathogens (mycobacterial)

Defective Microbicidal Activity of Phagocytes: Chronic Granulomatous Disease (CGD)

● ⅔ (mostly) → X-linked recessive, remainder autosomal
recessive
● CGD cause by mutations in phagocyte oxidase (PHOX)
enzyme complex
❖ X linked form → mutation in gene encoding 91-kD α
subunit of cytochrome b558/PHOX-91
= defective production of superoxide anion (ROS
species), major microbicidal mechanism of phagocytes,
esp neutrophils → failure to kill phagocytosed microbes
● CGD → recurrent infections with fungi & bacteria, e.g.
Staphylococcus
● Leading cause of death → invasive Aspergillus infections
● Organism produce catalase (destroys the hydrogen peroxide
produced by host cells) → in CGD, neutrophils cannot
accommodate this situation → chronic cell-mediated immune
response → T cell-mediated macrophage activation →
granulomas from activated macrophages
● Cytokine IFN-y → ↑ transcription of gene encoding PHOX-91
→ ↑ production of superoxide → therapy to CGD

Leukocyte Adhesion Deficiencies

● A group of autosomal recessive disorders → defects in
leukocyte & endothelial adhesion molecules
● Failure of leukocyte (particularly neutrophil) recruitment to
site of infection = severe periodontitis, recurrent bacterial
infections, inability to make pus
Leukocyte adhesion deficiency type 1 (LAD-1)
● Cause: defect in adhesion-dependent functions of
leukocytes (adherence to endothelium, neutrophils
aggregation & chemotaxis, phagocytosis, cytotoxicity by
neutrophils, NK cells, T lymphocytes)
● Defect: mutation in CD18 gene → absent/reduced
 expression of β2 integrins (leukocyte function-associated
antigen 1, LFA-1/CD11aCD18; MAC-1/CD11bCD18;
p150,95/CD11cCD18) → for adhesion of leukocytes to other
cells, binding of T lymphocytes to APCs
● Manifestation:
❖ Recurrent bacterial & fungal infection
❖ Impaired wound healing
❖ Delayed umbilical cord separation (normally occurs
because inflammation and neutrophil infiltration)
❖ Leukocytosis

Leukocyte adhesion deficiency type 2 (LAD-2)

● Cause: defective attachment of leukocytes to endothelium,

absence of leukocyte rolling → defective recruitment
● Defect:
❖ Mutation in guanosine diphosphate (GDP)-fucose
transporter (responsible of fucose transport into Golgi)
→ absence of sialyl Lewis X (carbohydrate ligand on
leukocytes, required for binding to E-selectin & P-selectin
on cytokine-activated endothelium)
● Manifestation:
❖ Recurrent infections
❖ Leukocytosis
❖ Development abnormalities (nonimmunological
manifestations related to defective fucose metabolism →
“congenital disorder of glycosylations”) (CDG)
*abnormality in fucosylation → contributes to Bombay blood
 group phenotype
❖ Lack of fucosylated H glycan that forms the core of A, B,
O blood group antigens

Leukocyte adhesion deficiency type 3 (LAD-3)

● Cause: defect in adhesion-dependent functions of

leukocytes, platelet aggregation
● Defect:
❖ inside-out signaling pathway that mediates
chemokine-induced integrin activation → required for
leukocytes-endothelium binding & platelet aggregation;
❖ mutations in gene KINDLIN-3 (protein that binds to
cytoplasmic tail of integrin → involved in signaling)
● Manifestation:
❖ Repeated bacterial infections
❖ Delayed umbilical cord separation
❖ Bleeding disorder, life-threatening (defective platelet
aggregation

Defects in NK Cells and Phagocytes

Autosomal dominant mutations Subject: Gene encoding GATA2 transcription factor (key roles in hematopoietic development)
→ diminished precursor populations in bone marrow
Impact: loss of NK, ↓ monocytes, DC, B cells

Autosomal recessive mutations Subject: DNA Helicase MCM4 (minichromosome maintenance complex component 4)
 Impact: loss of NK (subset CD56), adrenal insufficiency & growth retardation

Subject: CD16 (FCyRIIIA) → Fc receptor that mediates antibody-dependent cell-mediated

cytotoxicity
Impact: loss of NK function = severe infections from viruses, mainly herpesvirus & papillomavirus

Chediak-Higashi syndrome

Subject: Gene encoding protein LYST → regulates intracellular trafficking of lysosomes

Manifestation: formation of giant lysosomes in neutrophils, monocytes, and lymphocytes;
defect in chemotaxis & phagocytosis, impaired NK function (abnormality in cytoplasmic granules)
Impact:
❖ Defective phagosome-lyososome fusion in neutrophils & macrophages = reduced
resistance to infection
❖ Defective melanosome formation in melanocytes = albinism
❖ Lyososmal abnormalities in nervous system cells = nerve defects & platelets = bleeding
disorders
❖ Recurrent infections by pyogenic bacteria
❖ Infiltration of various organ by nonneoplastic lymphocytes
❖ Leukopenia

Inherited Defects in TLR Pathways, NF-kB Signaling, and Type 1 IFNs

● TLR mutation → herpes simplex encephalitis Mutations in MyD88 & IRAK4 → severe invasive bacterial
● Almost all virus → generate double-stranded RNA (dsRNA) infections in early life, esp. pneumococcal pneumonia
transcript, recognized by TLR3
● Major signaling pathway for TLRs & IL-1 receptor → involves
MyD88 adaptor & IRAK-4 and IRAK-1 kinases → result in
 NF-kB dependent induction of inflammatory cytokines
● TLR signaling → use TRIF adaptor protein & TBK1
(serine-threonine kinase, functions in downstream of TRIF to
activate IRF3 & NF-kB)
● TLR 3, 7, 8, 9 in endosome → recognize nucleic acids →
require UNC93B protein (endoplasmic reticulum membrane
protein, deliver newly synthesized TLRs to endosome)
● Signaling downstream of endosomal TLRs → synthesis &
secretion of type 1 IFN → activate STAT1 (signal transducer &
activator of transcription 1) transcription factor
Autosomal recessive mutations in TRIF, autosomal dominant
mutations in TRAF3 E3 ligase, autosomal dominant mutations
in TBK1 → susceptibility to herpes simplex encephalitis
Homozygous mutations in UNC93B → reduced type 1 IFN →
susceptibility to herpes simplex enxephalitis
Loss-of function STAT1 mutations → severe viral infections

Point mutations in IKKy (inhibitor of kB kinase y)/NEMO (NF-kB

essential modulator) → X-linked recessive disease → anhidrotic
ectodermal dysplasia with immunodeficiency (EDA-ID)
→abnormal differentiation of ectoderm-derived structure,
impaired immune function → infections from encapsulated
pyogenic bacteria & intracellular bacterial such as mycobacteria,
viruses, fungi e.g. P. jiroveci

Defects in the IL-12/IFN-y Pathway

● IL-12 secreted by DCs & macrophages, IL-12R signaling → synthesis of IFN-y by helper T cells, cytotoxic T cells, NK cells
● Mutations in genes encoding IL-12p40, IL-12Rβ1 chain, IFN-y receptor, and mutations in STAT1 & IKKy/NEMO → susceptibility
to environmental Mycobacterium species (atypical mycobacteria): Mycobacterium avium, M. kansasii, M. fortuitum
● Disorder → Mendelian susceptibility to mycobacterial (MSMD) → severe disease caused by weakly virulent mycobacteria, as
well as other intracellular pathogens such as Salmonella

Defects in Splenic Development

● Autosomal dominant “isolated congenital asplenia”
Caused by:
❖ Heterozygous missense mutations in NBX2.5 (encodes transcription factor)
❖ Genes controlling left-right laterality
● Suffer from severe infections with encapsulated bacteria, esp Streptococcus pneumoniae
 Severe Combined Immunodeficiency
● Immunodeficiency that affect both humoral & cell-mediated immunity
● Usually results from impaired T lymphocyte → defective cell mediated immunity, with or without defects in B cell maturation
● Severe infections include pneumonia, meningitis, bacteremia
● Most dangerous organism in SCID → P. jiroveci = severe pneumonia
● Chickenpox (varicella) → usually only in skin & mucous membrane, in SCID could affect lungs, liver, brain
● CMV may be easily transmitted from mothers with SCID to their offspring → fatal pneumonia in newborn
● Children with SCID:
❖ GI infections caused by rotavirus, CMV, protozoa Cryptosporidium & Giardia lamblia = persistent diarrhea, malabsorption
❖ Develop infections from live-attenuated vaccine (chickenpox, measles, mumps, rubella, rotavirus)
● 50% autosomal recessive, rest are X-linked

X-Linked SCID

● Caused by mutations in gene encoding common y (yc) chain for cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21)
● Inability of lymphopoietic cytokine IL-7 → impaired maturation of T & NK cells
● Failure of IL-15 → impaired NK cell development
● Heterozygous females → phenotypically normal carriers, males inherit abnormal X chromosome manifest this disease

ADA Deficiency & Other Forms of SCID Caused by Defects in Nucleotide Metabolism

● Most common of autosomal recessive SCID → deficiency in
adenosine deaminase (ADA) enzyme
● ADA function → salvage pathway of purine synthesis,
catalyzes deamination of: adenosine → inosine &
2’-deoxyadenosine → 2’deoxyinosine
● Deficiency of ADA → accumulation of deoxydenosine and its
precursors, S-adenosylhomocysteine & deoxyadenosine
● Rarer autosomal recessive form → deficiency of purine
nucleoside phosphorylase (PNP), catalyze the conversion of:
inosine → hypoxanthine & guanosine → guanine
● Deficiency of PNP → accumulation of deoxyguanosine &
deoxyguanosine triphosphate → toxic effect to immature
lymphocytes (mainly T cells)
● Manifestation → neurologic deterioration, autoimmune
 triphosphate (dATP) → toxic effect → inhibition of DNA
synthesis
● Developing lymphocytes → less efficient in degrading dATP
→ more sensitive
● Manifestation → deafness, costochondral abnormalities, liver
damage, behavioral problems, reduced number of B & T cells
hemolytic anemia
● Severe form of SCID → “reticular dysgenesis”
❖ Cause: defect in development of lymphoid & myeloid
progenitors
❖ Defect: mutation in adenylate kinase 2 (AK2) gene
(regulation the level of adenosine diphosphate) →
increased apoptosis of lymphoid & myeloid precursors
❖ Manifestations: absence of T & B lymphocytes, most
myeloid cells

Autosomal Recessive Mutations in Cytokine Signaling Components

● Clinically identical to X-linked SCID

● Mutations affecting IL-17 receptor α chain or the JAK3 kinase (IL-17 associated with γc chain → signaling) → defect in T cell
development
● IL-15 not affected → normal NK cell

Severe Combined Immunodeficiency Caused by Defects in V(D)J Recombination & Pre-TCR Checkpoint Signaling

● Absence of V(D)J recombination → failure to express pre-TCR
& pre-B cell receptor
● Mutations in:
❖ RAG1/RAG2 genes → encode protein mediate cleavage
step during recombination
❖ ARTEMIS gene → encode nuclease, resolve coding-end
hairpins during V(D)J recombination
❖ Gene encoding catalytic subunit of the DNA-dependent
protein kinase (DNA-PK), DNA ligase 4 → proteins
❖ CD3 δ or ε chain or in the CD3-associated ζ chain
❖ Gene encoding T cell receptor α chain (TCRα) constant
region → defect in αβ T cell development → chronic
varicella zoster, EBV infections, autoimmunity & atopy
because absence of regulatory T cells (eosinophilia,
vitiligo, eczema, alopecia areata, etc)
❖ Autosomal recessive mutations in LCK (encodes tyrosine
kinase for pre-TCR & TCR signaling)
❖ Hypomorphic mutations (partially reduce function) in
 involved in double-stranded break repair/nonhomologous
end-joining of DNA
❖ Gene encoding CD45 phosphatase (positive regulator of
SRC family kinases, such as FYN, LCK, LYN)
DiGeorge Syndome and Other Forms of SCID Due to Defective Thymic Epithelial Development
● DiGeorge Syndrome → defective development of the thymus
& parathyroid glands (structure from third and fourth
pharyngeal pouches)
Manifestation: immunodeficiency because
hypoplasia/agenesis of timus → deficient T cell maturation →
absence peripheral blood T lymphocytes, abnormal calcium
homeostasis, tetany, abnormal development of the great
vessels, facial deformities
Mutations in: deletion in the chromosomal region 22q11,
mutation in gene encoding transcription factor T-Box1 (TBX1)
Susceptible to: mycobacterial, viral, fungal infections
Treatment: fetal thymic/bone marrow transplantation →
usually not necessary because tends to improve with age
Bare Lymphocyte Syndrome and Other Defects in T Cell Positive Selection
● Generation of single-positive CD4+ & CD8+ → depends on
positive selection & lineage commitment
● Bare lymphocyte syndrome → autosomal recessive disease
of deficiency of MHC class II → express little or no HLA-DP,
DQ, DR on B lymphocytes, macrophages, and DCs
Cause: mutations in genes encoding proteins that regulate
RAG genes/ARTEMIS → “Omenn syndrome” → reduced
generation of T & B cells
● Causing autosomal recessive forms of SCID
● Autosomal recessive FOXN1 (transcription factor of
Forkhead family, required for development of thymic anlage
& ectodermal structure) mutations → SCID, alopecia, nail
dystrophy
● Mutation in CORONIN1A (encodes protein that regulates
actin cytoskeleton) → defective egress of mature T cell from
the thymus
● Homozygous mutations in MST1 gene (encodes
serine/threonine protein kinase) → failure of T cells to
emigrate from the thymus, loss of native T cells in the
circulation → recurrent bacterial & viral infections, some
develop EBV-driven lymphomas & epidermodysplasia
verruciformis (HPV-infected warts & skin carcinoma)
● Autosomal recessive class I MHC deficiencies → decreased
CD8+ T cell
Cause: mutations in TAP-1 or TAP-2 genes → encore the
subunits of the TAP (transports peptides from the cytosol
into the ER → loaded into MHC class I)
TAP deficiency → peptides cannot be bound with MHC →
 class II MHC gene transcription
For example → mutations on transcription factor RFX5, CIITA
→ defective positive selection of T cells → reduction of mature
CD4+ T cells
Treatment: hematopoietic stem cell transplantation
SCID Caused by Defective T Cell Activation
● Mutation: gene encoding ORAI1 (component of CRAC,
calcium release-activated calcium channel)
Antigen receptor signaling → activation of γ isoform of
phospholipase C (PLCγ) & inositol triphosphate
(IP3)-dependent release of calcium ions → replenished by
CRAC channels → influx of extracellular calcium → this
process crucial for lymphocyte activation
MHC degraded → level of MHC class I reduced
Manifestation: necrotizing granulomatous skin lesions,
respiratory tract bacterial infections
● Another deficiency of class I MHC → mutations in TAPASIN
protein (required for loading the peptides to MHC class I)
● ZAP70 deficiency → defect in lineage commitment →
reduced CD8+, but normal numbers of CD4+ T cells
● Similar phenotype in mutations of STIM1 → encodes ER
protein (senses the depletion of calcium stores) →
contributes to opening of CRAC channel
● Manifestation → not exhibit defect in T cell development,
but their T cells cannot be properly activated
Antibodies Deficiencies: Defects in B Cell Development and Activation

X-Linked Agammaglobulinemia: An X-Linked Pre-BCR Signaling Defect

● Also called Bruton’s agammaglobulinemia ● Common immunodeficiency

● Mutations/deletions: in gene encoding enzyme called Bruton ● BTK → involved in signals from pre-BCR, associates with
tyrosine kinase (BTK) → failure of B cells to mature beyond survival & differentiation of pre-B cell
pre-B cell stage in bone marrow ● Treatment → periodic injections of IgG from donors
● Characterized by: absence of antibodies in the blood →
undetectable serum Ig, reduced/absent B cells in peripheral
blood & lymphoid tissues, no germinal centers, no plasma cells
in tissue
Selective Immunoglobulin Isotype Deficiencies
● Most common → selective IgA deficiencies
❖ Many of patients are normal, other have occasional
respiratory infections & diarrhea, rarely severe recurrent
infections
❖ Heterogenous
❖ Defect in IgA class switching
❖ Cause → mutations in TACI (transmembrane activator and
calcium modulator and cyclophilin ligand interactor) gene,
one of receptors for BAFF (B-cell activating factor) & APRIL
(a proliferation-inducing ligand)
Defects in B Cell Differentiation: Common Variable Immunodeficiencies (CVID)
● Group of heterogeneous disorders → reduced levels of serum
Ig → impaired antibody response
● Most common immunodeficiency in adolescents & young
adults
● Diagnosis → exclusion, made based on very low serum IgG
levels, decreased IgM and/or IgA, poor antibody response to
vaccine
● Manifestation → major infection: H. influenzae & S.
● Autosomal recessive forms → mutant in genes encoding the
µ (IgM) heavy chain, λ5 surrogate light chain, Igα (signaling
component of pre-BCR and BCR), p85α subunit of PI3
kinase, BLNK (adaptor protein downstream of pre-BCR &
BCR)
● Selective IgG subclass deficiencies
❖ Total serum IgG levels normal but concentration of
subclasses are not
❖ Most common → IgG3
❖ Recurrent bacterial infections in some individuals
❖ Cause → homozygous deletions of constant region (Cγ)
genes → abnormal B cell differentiation
● Mature B lymphocytes present, but memory B cells reduced
in blood & plasma → abnormal B cell differentiation
● Mutations:
❖ TACI
❖ PIK3CD (gene encoding the catalytic subunit of PI3
Kinase δ → hyperactivation of T cells, block of B cell
development)
❖ Loss-of-function mutations of CTLA-4 → ↓ Treg, block of
 pneumoniae; autoimmune: pernicious anemia, hemolytic B
anemia, IBD, RA; tumors: lymphoma ❖ ICOS (Inducible T cell costimulator) → ↓ Tfh
● Mostly sporadic ❖ CD19 gene → signaling of CR2(CD21) coreceptor
● Monogenic forms → mainly autosomal dominant inheritance complex, essential for B cell activation by complement

Defects in T Cell-Dependent B Cell Activation: Hyper-IgM Syndrome

● X-linked hyper IgM Syndrome ● Small subset → autosomal recessive

Caused by → mutations in the gene encoding T cell effector
molecule CD40L (CD154) → B cells do not undergo heavy
chain isotope switching
Manifestation → defective switching of B cells to IgG & IgA
isotype, major antibodies: IgM, impaired production of
high-affinity antibodies, defects in cell-mediated immunity
Disease → susceptibility to intracellular fungi such as P.
jiroveci
● Abscence of AID → defect in switching & hypermutation
❖ Defects may be in CD40/enzyme activation-induced
deaminase (AID), involved in isotype switching & affinity
maturation
❖ Mutations in the gene encoding uracil N-glycosylase
(UNG), enzyme which removes U residues from Ig genes
during class witching & somatic mutation
❖ Hypomorphic NEMO mutations → EDA-ID disorder →
hyper-IgM state
Abscence of UNG → defect in isotype switching only
AID & UNG → do not compromise cell mediated immunity

Defects in T Lymphocyte Activation and Function

Defects in TCR Signal Transduction

● Mutations in genes encoding T cell proteins

Examples:
❖ Impaired TCR complex expression or function caused by mutations in CD3 ε or γ genes
❖ Defective TCR-mediated signaling caused by mutations in ZAP70
❖ Mutations affecting CD3 complex, LCK
 Hyper Ig-E Syndromes

● Also known as Job syndrome ❖ In autosomal recessive: mutation in gene DOCK8

● Cause:
❖ In autosomal dominant: heterozygous dominant-negative
mutations affecting STAT3 (transcription factor for IL-6,
IL-10, IL-17, IL-21, IL-22)
Diminished acute-phase IL-6 downstream
Defective innate immunity
Defective Th-17 responses
Defective inhibitory responses by IL-10
(guanine nucleotide exchange factor) → ↓ T cells, B cells,
NK cells, defect in lymphocytes signaling & cytoskeletal
rearrangements
*DOCK8 → participates in actin polymerization &
maintenance of STAT3
● Manifestation: eczema, eosinophilia, recurrent pulmonary
infections, staphylococcal & fungal skin abcess
● Defective JAK-STAT signaling → ↑ Tfh cells → ↑ IL-4 & L-13
→ drive IgE response

X-Linked Lymphoproliferative Disease (XLP)

● XLP → inability to eliminate EBV → mononucleosis, ● Manifestation: ↓ NK & T cell activation

development of B cell lymphoma
● Cause: mutations in gene encoding SLAM (signaling
lymphocyte activation molecule)-associated protein (SAP),
involves in activation of NK cells, T & B lymphocytes
● SAP → links the membrane proteins SLAM & 2B4 to SRC
family kinase FYN
● SAP → required for Tfh cell → inability to make germinal
centers & high affinity antibodies
● Other variation → mutation in gene encoding XIAP (X-linked
inhibitor of apoptosis) → ↑ apoptosis of T & NK cells

X-Linked Immunodeficiency-Magnesium Defects-EBV Infection-Neoplasia Syndrome

● MAGT1 → transporter of magnesium intracellular → activation ● Treatment → magnesium diet supplements

of PLCγ1 → calcium signaling in T & NK Cell activation ● B cells → have high PLCγ2 → not affected
● Mutations in X chromosome encoding MAGT1 (magnesium
transporter protein 1) → defect in NK cells, CTL, CD4+ T cell
 lymphopenia

Defective CTL & NK Cell Function: Familial Hemophagocytic Lymphohistiocytosis (HLH)

● Familial HLH → defective function of NK & CTL in killing infected cell → viral infection not held in check → compensatory
excessive macrophage activity (macrophage activation syndrome)
● Cause: mutations in genes encoding granule exocytosis
● Mutations:
❖ RAB27A → involved in vesicular fusion
❖ MUNC13-4 → participates in granule exocytosis
❖ Gene for component AP3 protein → disrupt intracellular transport
● Compensatory → excessive IFN-y-mediated macrophage → hemophagocytosis & lymphadenopathy
● Treatment → antibody to IFN-y

Multisystem Disorders With Immunodeficiency

Wiskott-Aldrich Syndrome

Definition Manifestation Mutation

X-linked disease characterized
by Eczema, thrombocytopenia,
susceptibility to bacterial
infections
● Initial stage → ● Gene encodes cytoplasmic ● In autosomal recessive form
lymphocyte numbers are protein, WASP → caused by mutations in
normal (Wiskott-Aldrich gene encoding WIP
● Principal defect → syndrome protein) → (WASP-interacting protein)
inability to produce expressed on → binds to WASP and
antibodies in T bone-marrow derived cells stabilizes it
cell-independent ● WASP interacts with
polysaccharide antigens → adaptor molecules
susceptibility to downstream of antigen
 encapsulated bacteria
● Lymphocytes & platelets
smaller than normal
receptor (GRB2), ARP2/3
complex (actin
polymerization), G
proteins of RHO family
(actin cytoskeletal
rearrangement) →
defective formation of
immune synapses,
impaired mobility of
leukocytes

Ataxia-Telangiectasia

Definition Manifestation Mutation

Autosomal recessive disorder
characterized by abnormal gait
(ataxia), vascular malformations
(telangiectases), neurologic
deficits, increased risk of tumors,
and immunodeficiencies
● Most common humoral ● Gene encodes protein kinase ATM (ataxia-telangiectasia
immune defects → IgA & mutated) → required for dsDNA break repair, relevant to
IgG2 deficiency V(D)J & class switching recombination → reduced levels of
● Thymic hypoplasia → T IgG, IgA, IgE
cell defects ● Clinical → URT & LRT infections, autoimmune
phenomena, increasingly cancers occurence

Therapeutic Approaches for Primary Treatment Disease

Immunodeficiencies Passive immunization with
Two aims: minimize & control infections, replace the gamma globulin
defective/absent components of immune system
Hematopoietic stem cell
transplantation → treatment
X-linked agammaglobulinemia
SCID, Wiskott-Aldrich, bare
lymphocyte, LADs
of choice

Enzyme replacement ADA deficiency

Defective gene replacement ADA deficiency, X-linked SCID

with self-renewing stem cells
 Secondary (Acquired) Immunodeficiencies

● Not genetic, acquired ● Chronic infections → M. tuberculosis, fungi = anergy to many

● Caused by:
❖ Immunosuppression as biologic complication of disease
❖ Iatrogenic immunodeficiencies (complications of therapy)
❖ Infection that target immune cells
● Disease in which immunodeficiency is a frequent complication
→ malnutrition, cancer, infections
● Cancer → bone marrow tumors (metastatic, leukimias arising
in bone marrow) → produce substance that affect
lymphocytes development
● Viruses: HIV, measles, HTLV-1 (human T cell lymphotropic
virus 1) → transforms CD4+ T cells → produces malignant
neoplasm = T cell leukimia/lymphoma (ATL)
antigens
● Iatrogenic immunosuppersion → drug therapies that inactives
lymphocytes or block chemokines
❖ Treatment for inflammatory disease
❖ Prevent rejection of organ allograft
❖ Chemotherapeutic drugs → cytotoxic to proliferating cells,
including mature & developing lymphocytes
● Abscence of spleen: surgical removal, treatment to
hematologic disease such as autoimmune hemolytic anemia,
thrombocytopenia (red cells & platelets destroyed by
phacoytes in spleen) → susceptible to pneumococci &
meningococci bacteria

Human Immunodeficiency Virus & Acquired Immunodeficiency Syndrome

● AIDS → caused by infection with HIV

● HIV can infects activated CD4+ helper T cells, also macrophages & DCs (less efficiently)
● Currently there is no vaccine or permanent cure

An Overview of HIV Virology

 HIV Structure and Genes
● Infectious HIV particle: two identical
strands of RNA packaged within a core of
viral proteins, surrounded by a
phospholipid bilayer envelope derived
from the host cell membrane
● Long terminal repeats (LTRs) at each end
of genome regulate viral gene
expression, viral integration into host
genome, and viral replication
● Gag sequence → encode code structural
proteins
Viral Life Cycle
● HIV infection → begins when envelope
glycoprotein gp120 binds CD4 &
chemokine receptor (coreceptor)
● 2 components of Env → transmembrane
gp41 subunit & external gp120 subunit
→ produced by proteolytic cleavage of
gp160 precursor
● Env complex mediates fusion of virion
envelope with membrane target cell
❖ Gp 120 subunit binding with CD4 →
conformational change → secondary
gp120 binding to chemokine receptor
● Env sequence → encode HIV Envelope
protein, exist as trimer of glycoprotein,
gp120, g41 (inserted in viral lipid bilayer)
● Pol sequence → encode reverse
transcriptase, integrase, viral protease
enzyme
● HIV-1 genome → additional regulatory
genes: tat, rev, vif, nef, vpr, vpu
❖ After virus completes life cycle in infected
cell → free viral particles released from
infected cell → bind to an uninfected cell
❖ Gp120 & gp41 expressed on plasma
membrane of infected cell → mediates
cell-cell fusion with uninfected cell
expressing CD41 & coreceptor
● Coreceptors:
❖ CCR5 & CXCR4 (most important)
❖ Several transmembrane-spanning G
protein-coupled receptor (e.g.
leukotriene B4 receptor)
 (CCR5/CXCR4 as coreceptor) →
conformational change in gp41 →
gp41 refolding into six-helix bundle,
exposes a hydrophobic region (fusion
peptide) → inserts into cell membrane
→ viral membrane fuse with target cell
membrane
● HIV virion enters the cell → viral reproductive cycle begins
❖ Nucleoprotein core of virus disrupted → RNA genome of HIV
reverse-transcripted into dsDNA → viral DNA enter nucleus
❖ Viral integrase enters nucleus → catalyze the DNA
integration
❖ Integrated HIV DNA → provirus
❖ Provirus may remain transcriptionally inactive for years →
latent phase
● Transcription of provirus → regulated by LTR upstream
● LTR: polyadenylation signal sequence, TATA box promotor
sequence, binding site of transcription factors (NF-kB & SP1)
● Initiation of transcription → activation of T cells by antigen &
cytokines → activation of NF-kB → binding to LTR
Example: IL-2, TNF, lymphotoxin → T cell, IFN-y &
granulocyte-macrophage colony-stimulating factor (GM-CSF) →
macrophage
● Rev → promoting export of incompletely spliced late gene RNA
out of the nucleus → initiates switch from early to late expression
● Pol → precursor protein, cleaved to form reverse transcriptase,
● Main target of HIV → CD4+, some strain
with very high affinity with CD4+ could
infect macrophages (M-tropic strains)
● Only 1 viral strain act as disease
transmitter → founder strain (T-tropic
strain) → low affinity of CD4, mostly use
CCR5
● Tat protein → required for HIV gene expression. Without tat
HIV genes could not be transcripted completely because
polymerase complex stop before mRNA completed
● mRNA encoding various HIV protein → derived from single
full-genome-length transcript by differential splicing events
● HIV gene expression:
❖ Early → expressing of regulatory genes
❖ Late → expressing of structural genes, full-length viral
genomes are packaged
● Rev, Tat, Nef → early gene products encoded by fully spliced
mRNA, exported from nucleus & translated into proteins in
cytoplasm
● Env, gag, pol → late genes, encode structural components of
the virus
● Viral protein synthesized in cytoplasm
● Assembly → packaging proviral genome within
nucleoprotein complex → buds from the plasma membrane,
 protease, ribonuclease, integrase enzymes capturing Env & host glycoproteins as part of its envelope
● Gag → encodes protein that cleaved by protease into p24 capsid
protein, p17 matrix protein, p7 nucleocapsid protein, p6 domain, 2
spacer peptides (sp1 & sp2)
● Env → gp160, cleaved by cellular protease in ER to gp120 &
gp41

Pathogenesis of HIV Infection and AIDS

Acute (early) infection Transition From Acute Phase-Chronic Phase

● Infection of activated CD4+ T cell in mucosal lymphoid tissue &
death of many infected CD4+ cells
● Viremia & development of adaptive response
● DCs in epithelia capture the virus → migrate to lymph nodes
→ pass the virus to CD4+ T cells
● DCs express protein with mannose-binding lectin domain
(DC-SIGN), binds with HIV envelope
● Replication in lymph nodes → viremia (large number of hIV
present in blood) → acute HIV syndrome → control by
adaptive response → drop of viremia

Chronic Phase

● Lymph nodes, spleen, GI tract → sites of continuous HIV replication

● Immune system competent at handling infection with opportunistic microbes → clinical latency period
● Destruction of CD4 T cells steadily progresses
● Early in course, host may continue to replace CD4+ T cell → period of years, cycle leads to loss of CD4+ T cells

Mechanisms of Immunodeficiency Caused by HIV

● Major cause of the loss of CD4+ T cells → direct effect of ❖ Gp120 - newly synthesized intracellular CD4 → interfere
infection normal protein processing → block expression of CD4 →
❖ Budding → ↑ plasma membrane permeability, influx of lethal incapable responding to antigen
amounts of calcium/water → apoptosis/osmotic lysis
❖ Viral production → interfere cellular protein → cell death
● Additional mechanism:
❖ Chronic activation of uninfected cells with infection common
in AIDS → apoptotic death
❖ HIV-spesific CTLs → kills infected CD4+
❖ HIV envelope protein antibodies → target infected cells

● Depletion of T cell → functional defects ● DCs → also can be infected, not directly
❖ Decrease in T cell response to antigens injured by HIV but intimate contact with
❖ Nonneutralizing humoral immune naive T cells could infect these cells
response ● FDCs in germinal center of lymph nodes
● Bound HIV on CD4 → can't interact with → trap HIV
MHC & signals→ antigen response ❖ May be a reservoir and infect
inhibited, downregulate function macrophages & CD4+ cells
● Macrophages: resistant to cytophatic ❖ Normal functions are impaired
effects of HIV, may infected from ● Latent virus in Tfh cells in light zone of
phagocytosis of the virus & Fc germinal center → protected from CTLs
receptor-mediated endocytosis →
infected but not killed with HIV →
reservoir

Clinical Features of HIV

Acute phase Chronic phase/clinical latency Final phase/AIDS

● Acute HIV syndrome, period of viremia
with nonspecific symptoms
● Spike of plasma virus, modest reduction
of CD4 T cell counts
● Last for many years, virus
contained within lymphoid tissue
● Loss of CD4 → replenished from
progenitors
● Asymptomatic or minor infection
● Predictors of progression → level
of virus & CD4+ blood counts
● Disease progress → susceptible to
other infections, immune response
to this → stimulate HIV production
● Blood CD4+ T cell count drops <200
cells/mm3
● Viral replication accelerates
● Combination of opportunistic infections,
neoplasms, cachexia (wasting), kidney
failure (neprophathy), CNS (AIDS
encelopathy or HIV-associated
neurocognitive disorder, HAND)

Immune Responses to HIV

Innate Immunity to HIV & Host Restriction Factors

● HIV → sensed by TLR, RIG-1

● Key sensors that recognize viral reverse transcription products early in infection:
❖ IFI16 (interferon inducible protein 16) → bind to HIV-derived cDNA & signals via the STING (stimulator of IFN genes) adaptor,
TBK1 protein kinase, IRF3 & IR7 transcription factors → induces type 1 IFN & host restriction factors: APOBEC3, TRIM5α,
SAMHD1, tetherin
❖ cGAS (cyclic GMP-AMP synthase)

Tetherin APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic

polypeptide like 3)

● Inhibition of budding process → prevents virion release ● Cytidine deaminase that interferes with viral replication
● Antagonized by HIV protein Vpu ● HIV Vif protein target APOBEC3 for ubiquitination &
proteasomal degradation
 TRIM5α
● Interacts with HIV capsid protein causing premature uncoating
of virus & proteasomal degradation of viral reverse
transcriptase, block nuclear translocation of viral complex
Adaptive Immune Responses to HIV
● Provide limited protection
● Immune response may be detrimental to the host (stimulating
uptake of opsonized virus into uninfected cells)
● Initial adaptive response → CTLs specific HIV
❖ Control infection in early phase
❖ Could not produce memory CD8+ because needs effective
CD4+ response
❖ Evolution of virus → lost of original CTL & CD4+ epitope
Mechanisms of Immune Evasion by HIV
● High mutation rate
● Most antigenically variable part of the virus → V3 loop region
of gp120
Treatment and Prevention of AIDS & Vaccine Development
Nucleoside analogues
● Bind to & inhibits viral reverse transcriptase
SAMHD1 (SAM domain & HD domain 1)
● Hydrolyzes & depletes intracellular deoxynucleoside
triphosphate → prevent synthesis of viral DNA by reverse
transcription
● HIV-2 produces Vpx → antagonize depleting activity
● Antibody response → detectable 6-9 weeks postinfection
● Most immunogenic HIV → envelope glycoproteins → high
anti-gp120& gp-40
● Early antibodies → not neutralizing
● Neutralizing antibodies cannot cope with rapidly change
epitope
● 10-15% neutralizing Ig bind to a site on viral protein that
the virus cannot afford to mutate, such as CD4 binding of
gp140
● Epitopes of the virus shielded by HIV-glycan shield
● HIV Nef protein → inhibits expression of MHC Class 1
Nonnucleoside reverse transcriptase
● Directly bind to enzyme & inhibit its function
● Deoxythymidine nucleoside analogues: AZT, deoxycytidine
nucleoside analogues, deoxyadenosine analogues
● Often effective in reducing plasma HIV RNA, do not halt
progression of HIV-induced disease
● Mutated forms of reverse transcriptase → resistant to drugs
● Viral protease inhibitors → block processing of precursor
proteins into mature viral capsid & core proteins
● Used alone → mutant virus resistant → used together with
2 different reverse transcriptase inhibitor (highly active
antiretroviral therapy, HAART or antiretroviral therapy,
ART)

Integrase Inhibitors Entry inhibitors

Fusion inhibitors ● Prevent viral entry, targeting CD4/CCR5

● Target gp41 → prevent fusion of viral envelope with host cell plasma membrane

Pre-exposure prophylaxis (PrEP)

● Reverse transcriptase inhibitors, protect uninfected individuals with high risk

Vaccine

● Complicated by ability of virus to mutate
● Involved infection of macaques with simian immunodeficiency
virus (SIV) → vaccine to SIV has been developed
● Nonvirulent recombinant hybrid virus (part SIV, part HIV) →
attenuated by deletions of viral genome, e.g. nef gene
● Use of live recombinant non-HIV viral vector carrying HIV
genes →structural/regulatory genes of HIV + mammalian DNA
expression vector
● Recombinant subunit vaccine with HIV trimer → purpose
for neutralizing antibodies to gp140 (highly conserved)
● Use of passive immunity of broadly neutralizing antibodies
● Vectored immunoprophylaxis → protein that can mediate
immune synthesized in the host after injection of specific
DNA into skeletal muscle
❖ Ig heavy & light chain genes that encode broadly
neutralizing antibody → cloned into adenovirus vector →
DNA injected