Download HIV_AIDS_2008

HIV and AIDS
Human Immunodeficiency Virus (HIV) is
the virus that causes Acquired
Immunodeficiency Syndrome (AIDS).
Human Immunodeficiency
Virus (HIV)
• enters the human body through direct contact of bodily
fluids (blood, saliva, semen)
• infects and replicates in immune cells, macrophages and
helper T cells
• Loss of helper T cells prevents B cell activation
• Activated B cells - needed for antibody production
Secondary infections can be fatal in people with HIV because
their immune systems cannot respond
AIDS
• AIDS = Acquired Immune Deficiency Syndrome
or Acquired Immunodeficiency Syndrome disease resulting from HIV infection
• When a person has AIDS,their HIV infection is
severely impairing immune system function
General facts:
• Between 30.6-36.1 million people infected with HIV in
2007; infection killed ~2.1 million in 2007
~1-1.2 million infected in USA
• Sub-Saharan Africa,>15% infected with HIV
• 90% of HIV transmission from heterosexual contact
• Male circumcision 50-65% effective at preventing
HIV infection (2005-NIH)
Structure of
the HIV virion
HIV has an RNA genome
Viral RNA is enclosed within a capsid inside of the viral envelope
Glycoproteins on viral envelope bind to cell surface molecules on
human cells
The RNA genome encodes a reverse transcriptase enzyme, a DNA
polymerase that uses RNA as a template
HIV RT synthesizes a DNA copy of the viral RNA
HIV envelope glycoproteins bind to the CD4 and
CCR5 receptors on helper T cells
HIV Virion
CD4
CCR5
(Outside cell)
(Inside cell)
HIV infection cycle
1. Virus binds receptors on host cell membrane and
enters cell. Envelope and capsid are degraded.
2. HIV reverse transcriptase (RT) catalyzes formation
of DNA that is complementary to the viral RNA
3. Double-stranded DNA is made
4. Integration of viral dsDNA into host chromosome
catalyzed by HIV integrase
5. Viral genes are transcribed into a long messenger RNA
6. Viral mRNA is translated into a polyprotein that is
processed (cut up into functional proteins) by HIV protease
7. New HIV virus particles are assembled in the cytoplasm
of the infected cell
8. New viruses bud from the host cell and can infect
another susceptible cell
http://www.cellsalive.com/hiv0.htm
Late in HIV infection
1. HIV mutates rapidly due to mistakes made by
reverse transcriptase (~ 1 in 5,000 bases).
2. HIV variants occur that can bind receptors on other
immune cells and this induces apoptosis.
3. Lack of immune cells severely impairs response to
secondary infections and cancer.
Resistance to AIDS?
• Some individuals are less susceptible to AIDS than others
• Called Long-term non-progressors
• Usually have a mutated CCR5 receptor gene (with a 32-base
pair deletion). The deletion truncates the CCR5 receptor
protein and prevents it from going to the cell surface.
• Long-term non-progressors are infected but remain healthy
Resistance to AIDS
Infection
HIV Virion
CD4
The people who are “immune”
to HIV often have a
truncated CCR5 receptor.
CCR5
Therefore, HIV can’t
make the correct
contacts to enter cell.
Some anti-HIV Drugs
Drug Type
Mechanism
Reverse Transcriptase
Inhibitor
blocks copying of viral RNA
into DNA
Protease Inhibitor
blocks processing of viral
proteins
Entry Inhibitor
blocks ability of HIV to bind,
fuse with and enter a cell
Reverse transcriptase inhibitors Nucleoside analogs
• Faulty DNA building blocks
• Incorporated into HIV DNA during reverse transcription - prevent
further elongation of DNA chain
• First anti-HIV drug: 3-azidothymidine (AZT) - the 3'-azido group
prevents further 5' to 3' phosphodiester linkages
deoxythymidine
3-azidothymidine
HIV Protease Inhibitors
HIV protease processes viral proteins inside of the cell
HIV Protease
Inhibitors prevent
the processing of
HIV proteins and
assembly of new
infectious viruses
1A30
HIV-1 Protease Complexed With A Tripeptide Protease Inhibitor
HIV Entry Inhibitors
First entry-suppressive factors identified were small
proteins called chemokines.
HIV Virion
CD4
CCR5
Chemokines are the
normal ligands for the
CCR5 receptor
Chemokine MIP-1b blocks HIV infection
Normal Infection
MIP-1b
HIV Virion
CD4
CD4
Steric Hindrance
CCR5
CCR5
Internalization
Anti-HIV Entry Inhibitor Drugs
FDA approved T20 in 2003 and MVC in 2007
HIV Virion
CD4
X
T20 interacts with glycoproteins on
HIV envelope - blocks HIV from
entering CCR5+ cells
CCR5
MVC interacts with the CCR5 receptor
- blocks HIV from entering CCR5+ cells
Treatment of HIV infection
• Drug therapies have cut the mortality rate from AIDS in
half since 1996.
• Patients take a combination of antiretroviral drugs known
as highly active antiretroviral therapy, or HAART
• Cocktails containing two reverse transcriptase inhibitors
and a protease inhibitor are commonly used
Side effects and cost (>$12,000/year) make staying
on treatments difficult for most people.
FDA approved HIV/AIDS drugs
*
*
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Combivir
lamivudine and zidovudine
Emtriva
emtricitabine, FTC
Epivir
lamivudine, 3TC
Epzicom
abacavir and lamivudine
Hivid
zalcitabine, dideoxycytidine, ddC
Retrovir
zidovudine, azidothymidine, AZT, ZDV
Trizivir
abacavir, zidovudine, and lamivudine
Truvada
tenofovir disoproxil fumarate and emtricitabine
Videx EC
enteric coated didanosine, ddI EC
Videx
didanosine, dideoxyinosine, ddI
Viread
tenofovir disoproxil fumarate, TDF
Zerit
stavudine, d4T
Ziagen
abacavir sulfate, ABC
Protease Inhibitors (PIs)
Agenerase amprenavir, APV
Aptivus
tipranavir, TPV
Crixivan
indinavir, IDV,
Fortovase
saquinavir (no longer marketed)
Invirase
saquinavir mesylate, SQV
Kaletra
lopinavir and ritonavir, LPV/RTV
Lexiva
Fosamprenavir Calcium, FOS-APV
Norvir
ritonavir, RTV
Prezista
darunavir
Reyataz
atazanavir sulfate, ATV
Viracept
nelfinavir mesylate, NFV
Entry Inhibitors
Fuzeon
enfuvirtide, T-20
Selzentry
maraviroc
**
27-Sep-97
2-Jul-03
17-Nov-95
2-Aug-04
19-Jun-92
19-Mar-87
14-Nov-00
2-Aug-04
31-Oct-00
9-Oct-91
26-Oct-01
24-Jun-94
17-Dec-98
15-Apr-99
22-Jun-05
13-Mar-96
7-Nov-97
6-Dec-95
15-Sep-00
20-Oct-03
1-Mar-96
23-Jun-06
20-Jun-03
14-Mar-97
13-Mar-03
6-Aug-07
Mysteries remain
Multidrug resistance:
• After several years on ANY anti-HIV
therapy, the drugs become less effective
• Due to mutations in the target proteins
A 2003 study showed that mutations in HIV
protease decrease the affinity for drugs by
100-1000 fold.
But the affinity for the natural HIV substrate
was only slightly reduced. (Biochemistry, web release
10/30/03)
Mysteries remain:
• HIV virus levels can be dropped below
detectable levels, yet come back in huge
amounts => reservoirs of HIV “hide” from
drugs.
• SIV does not cause disease in African
monkeys. HIV can infect some monkeys, does
not replicate after entering cell.
What do African monkeys have that we need??
TRIM5a protein in monkeys stops HIV and SIV
from replicating soon after it enters the cell
This is why monkeys don’t get HIV
Human TRIM5 doesn’t work as well, so we get
infected
Nature 427 848-853 (2004)
The end
HIV virus particle (virion)
Envelope
gp41
RNA
gp120
Matrix
Capsid
Reverse
Transcriptase
The CCR5 receptor is normally bound by MIP-1b,
a chemokine that stimulates immune cells
MIP-1b
NH2
Extracellular
Surface
CCR5
The HIV fusion process and inhibition by T-20
HIV virus
gp41
gp120
CD4
Human cell
Receptor
Binding
C
gp41
N
CCR5 or CXCR4
T-20 binds
gp41, stops
trimer of hairpin
formation