M228: Biology of HIV

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M228 Biology of HIV

• Dr. Beth D. Jamieson
• 310-206-8217
• jamieson_at_mednet.ucla.edu

• Reading material Course Reader Material
• 1080 Broxton Ave.
• 1081 Westwood Blvd.
• [phone]

• Website http//cyto.mednet.ucla.edu/biohiv

• Lectures available at www.bruincast.ucla.edu
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• For problems, call [phone] or (310)
  794-9232

• Office Hours TBA

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You cant understand HIV pathogenesis without
understanding basic immunology
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You cant understand HIV pathogenesis without
understanding basic immunology
WHY?
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Innate immunity

-

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Cells of the Innate Immune System

• Mast Cells release of histamines, hormones,
  chemokines. Important in inflammation and
  allergies.
• Neutrophils phagocytosis
• Basophils histamines
• Eosinophils - toxic proteins and free radicals
• Macrophages phagocytosis antigen presenting
  cells (APC)
• Dendritic Cells - phagocytosis APC
• Natural Killer Cells lysis of altered cells
• gd T-cells and iNKT- border between innate and
  adaptive immunity

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Cells Use Surface Proteins to Communicate

• CD Cluster Designation (CD4, CD8, CD3)
• MHC Major Histocompatibility Complex
• encoded by chromosome 6 in humans. Approx. 140
  genes, 70 of these are involved in immune
  responses.
• HLA Human Leukocyte Antigens. Is the name of
  the MHC in humans interchangeable.

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Cells Use Surface Proteins to Communicate

• Antigen Receptors Allows cells to bind antigens
  with some specificity.

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Antigen Presenting Cells

• These specialized cells internalize antigen by
• phagocytosis or endocytosis and then express
• parts of the antigen on the cell surface. These
• cells are distinguished by two properties
• Express class II MHC molecules (Helps in
• in presentation of antigen)
• Provide co-stimulatory signals necessary for
• activation of T-cells.

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Acquired Immunity
Is adaptive and displays four characteristic
attributes

• Antigen specific
• Diversity
• Immunologic Memory
• Self/nonself recognition

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Adaptive Immunity

• Involves two major types of cells
• Lymphocytes
• Tcells
• B cells
• Antigen presenting cells (APC)
• Macrophages
• B cells
• Dendritic cells

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Lymphocytes

• B-cells
• Produce antibodies and can present antigens.
• Are identified by the markers CD19 and CD20.

• T-cells
• Cytotoxic T cells kill infected cells.
• Are identified by the surface marker CD8.
• Helper T cells (Th) provide help for
• Cytotoxic T cells and B cells.
• Are identified by the surface marker CD4.

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Effector functions
Are induced following physical contact with
non-self

• B cells secrete their antigen receptors
• antibodies.
• CD4 T-cells secrete cytokines and
• chemokines.
• CD8 T-cells seek and kill cells that express
• nonself and also secrete cytokines
• and chemokines.

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cyto cell, kine indicating
movement-intercellular messengers of the immune
system regulate intensity and duration of immune
responses by stimulating or inhibiting the
activation, proliferation, and/or differentiation
of various cells regulating the secretion of
antibodies or other cytokines -a.k.a.
lymphokines (secreted by lcytes), monokines
(secreted by mo), interleukins (between white
blood cells now up to IL-22).
Cytokine
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Chemokine
Small cyotokines that contain four cysteine
residues. They are chemotactic, they induce
movement of cells.
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APC
Antigen ag
CD4 T-cell
Y
Y
CD8 T-cell
B-cell
Cytokines And Interferon
Y
Y
Y
Y
Death signals Perforin Granzyme etc.
Y
Y
Lysis
Clearance, Neutralization
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Cell mediated immune responses
Humoral responses
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Lymphocytes cont.


CD4 T cells bind antigen with MHC class II CD8
T cells bind antigen with MHC class I
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Immune responses are most efficient in tissue
parenchyma.
Lymph nodes and the spleen provide architectural
support for cell-to-cell interactions, and serve
as filters for fluids draining other tissues.
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Thymus
Spleen
Bone Marrow
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Antigen Specificity
Is determined by interactions between
cellular receptors (T-cell receptor and B-cell
receptor complex), antigen and human leukocyte
antigens (HLA).
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Human Leukocyte Antigens
Are encoded by the major histocompatibility
complex (MHC) on chromosome 6 in humans. Class
I antigens are found on all nucleated cells.
A,B,C CD8 T cells recognize Class I
antigens Class II antigens are primarily on
antigen presenting cells (macrophages, dendritic
cells and B cells). DR, DP, DQ CD4 T cells
recognize Class II antigens.
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Processing and presentation of antigens
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Diversity
of the adaptive immune response is due to
the diversity of the T-cell and B-cell receptor
complexes.
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Signal joint (sj) and coding joint (cj) TREC
production from the a/d locus
Va
Vd
dRec
Dd
Jd
Cd
Ja
Ca
yJa
Douek et al. Nature 1998
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MHC peptide binding
T-cell recognition sequences
Anchor
Anchor
Anchor sequences bind to the MHC.
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Peptide sequences effect MHC binding and TCR
recognition
Binds MHC AndTCR
Loss or decrease In MHC binding
Loss or decrease in TCR binding
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Antibody antigen recognition
Y
Antibodies recognize either linear epitopes
or epitopes in secondary structures. A change is
the amino acid sequence or secondary structure
can eliminate or diminish the antibody binding.
Y
No binding
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Activation of T-cells requires signaling through
the TCR and co-stimulatory molecules
CD8086
CD4
CD4
CD28
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B-cell
T-cell TCR complex
MHC class II
Ag processed For MHC presentation
TCR and CD4 Engagement of MHC and ag
CD28 Engagement of CD80/86
Upregulation Of CD80/86
CD40 engagement of CD40
Upregulation of CD40
MHC class II
TCR complex
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Memory
Is established through the clonal expansion
of activated T or B cells
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Self/nonself recognition
Is achieved through the interaction of
antigen receptors, HLA, and antigen. Responses
to this complex are controlled through A process
of education.
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Tolerance
The inability to react with self.
Autoimmunity
The state in which tolerance to
self is lost.
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Take Home Points

• There are two arms of the immune system
• The immune system is designed to protect us from
  pathogens like HIV
• HIV primarily infects cells of the immune system
• Know the major functions of each major lymphocyte
  type
• Understand how the body responds to an antigen