Transcript Gilead

Gilead -Topics in
Human Pathophysiology
Fall 2009
Drug Safety and Public Health
White Blood Cells
• Granulocytes
– Neutrophils
– Eosinophils
– Basophils
• Agranulocytes
– Monocytes
– Lymphocytes
White Blood Cells
Lymphatic System
• Functions:
– Drains excess tissue fluid (interstitial fluid)
– Transports fats and fat-soluble vitamins absorbed
from digestive system
– Defends against infection
Figure 9.3a
Figure 9.3b
First Line of Defense
• Skin – barrier, sloughs, acidic pH
• Tears- Lubricate and wash eye, contain lysozyme
• Saliva - Lubricates and rinses teeth, contains
lysozyme
• Earwax – waterproof, prevents water (and bacteria)
entry
• Digestive acids – kills pathogens that enter stomach
First Line of Defense
• Mucus – traps pathogens for WBCs to kill, cilia
sweeps
• Vomiting – removes toxins and pathogens from
stomach
• Urination – slightly acidic, cleanses urinary tract
• Defecation – removes bacteria from GI tract
• Resident bacteria – outcompete harmful organisms
Second Line of Defense
(Nonspecific)
•
•
•
•
•
•
Phagocytosis
Inflammatory response
Complement system
Interferons
Natural killer cells
Fever
Figure 9.6a
Phagocytosis
Figure 9.7
Inflammation
Figure 9.8 (1/2)
Complement
Figure 9.8 (2/2)
Interferon
Figure 21.5
Third Line of Defense
(Specific Immunity)
• B lymphocytes
– Mature in bone marrow, responsible for antibody
mediated immunity
– When they recognize a pathogen (antigen) and are
activated, develop into plasma cells and memory
cells
– Plasma cells produce 1000s of antibodies
(immunoglobulins) per second
Figure 9.9
B lymphocytes –
•Recognition
•Activation
•Attack (cloning
and antibody
production)
Antibody functions
Figure 21.14
Third Line of Defense
(Specific Immunity)
• T lymphocytes
– 3 types: helper T cells, cytotoxic T cells,
suppressor T cells
– When recognize a pathogen and are activated,
these attack the pathogen and create a cadre of
memory cells
Figure 9.13
Helper T cells
• Recognize pathogen presented by other WBCs
• Are activated by cytokines by other WBCs
• “Clone”themselves to form active cells and
memory cells
• Release cytokines to activate and stimulate
other WBCs, including B cells and phagocytes
Figure 9.12
Macrophages
act as antigen
presenting
cells
•Helper T cells are
presented with
antigen by
specialized WBCs
•When activated
these helper T
cells clone
themselves into
memory cells and
active cells
Figure 21.17
Cytotoxic T cells
• AKA killer T cells
• Recognize pathogen (antigens) in virally
infected cell or cancer cells
• Activated by cytokines from helper T cells
• “Clone” themselves into attack cells and
memory cells
• Attack by producing proteins that open holes
in infected cells
Figure 21.19
Immunologic Memory
• Memory cells circulate, sometimes for a
lifetime, scanning for that pathogen they
recognize
• A second infection by the same pathogen will
yield a stronger, faster immune response that
prevents illness
Figure 9.15
Figure 21.12
HIV
• A retrovirus that infects host cells
macrophages and helper T cells
• Its RNA is reverse transcribed into DNA, then
inserted into host chromosomes
• Protein synthesis of viral DNA makes
components of new HIV
• The components are assembled into new virus
and released from host
Figure 9.19
Immunobiology – HIV infection
copyright GarlandSciences
• http://www.blink.biz/immunoanimations/ind
ex1.html
Figure 9.20
Reverse transcriptase
required
Protease
required
HIV Transmission
AIDS Progression
• Three phases:
• Phase I – weeks to years
– Virus levels spike briefly
– Flulike symptoms – fever, chills, fatigue, body
aches, swollen lymph nodes
– T cell count may drop then rebound
– Antibodies to HIV in the blood allow diagnosis
Figure 9.21
AIDS Progression
• Phase II – Average length about 10 years
– Virus is replicating and bursting out of helper T cells,
killing them
– T cell count declines, opportunistic infections may
occur
– This phase may be symptomatic or symptom free
– Left untreated 95% of patients will move on to phase
III (AIDS)
– HAART - Highly Active AntiRetroviral Therapy – 3 drug
cocktail with at least 2 classes of antiretrovirals
Figure 9.20
Reverse transcriptase
Inhibitors work here
Protease
inhibitors
work here
Gilead Anti-HIV drugs
AIDS Progression
• Phase III – Full blown AIDS
– T cell count falls below 200/mm3
– Opportunistic infections or cancer associated with
AIDS set in
– Pneumonia, meningitis, tuberculosis, encephalitis,
Kaposi’s sarcoma, non-Hodgkins lymphoma
– Nearly always fatal if untreated
Additional Information
• NRTI mechanism and drug resistance
• http://www.youtube.com/watch?v=qYUnDzD
O-Ic
How HIV Testing Works
From: http://www.clinical-virology.org/graphic/elisa_principle.jpg