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TORTORA • FUNKE
• CASE
Microbiology
AN INTRODUCTION
B.E Pruitt & Jane J. Stein
Chapter 19, part B
Disorders Associated with the
Immune System
Acquired Immunodeficiency
Syndrome (AIDS)
• 1981
In U.S., cluster of Pneumocystis and
Kaposi's sarcoma in young
homosexual
men discovered. The men
showed
loss of immune
function.
• 1983
Discovery of virus causing loss of
immune function.
Acquired Immunodeficiency Syndrome (AIDS)
Figure 19.12a
The Origin of AIDS
• Crossed the species barrier into humans in Africa
between 1884 and 1924
• Patient who died in 1959 in Congo is the oldest
known case
• Spread in Africa as a result of urbanization
• Spread worldwide through modern transportation and
unsafe sexual practices
• Norwegian sailor who died in 1976 is the first known
case in Western world
HIV
HIV Infection
Glycoprotein spike:
gp120
gp41
transmembrane
glycoprotein
Envelope
Reverse
transcriptase
enzyme
Envelope
RNA
Core with protein coat
Capsid
Structure of HIV and infection of a CD4+
T cell. The gp120 glycoprotein spike on the
membrane attaches to a receptor on the CD4+
cell. The gp41 transmembrane glycoprotein
probably facilitates fusion by attaching to a
proposed fusion receptor on the CD4+ cell.
HIV Infection
Capsid
Reverse
transcriptase
DNA
Virus
Two identical + stands of RNA
1 Retrovirus penetrates
host cell.
Host
cell
DNA of one of the host
cell’s chromosomes
5 Mature
retrovirus
leaves host
cell, acquiring
an envelope as
it buds out.
Reverse
transcriptase
Viral RNA
Identical
strands of
RNA
2 Virion penetrates
cell and its DNA is
uncoated
4 Transcription of the
Viral proteins
RNA
provirus may also occur,
producing RNA for new
retrovirus genomes and
RNA that codes for the
retrovirus capsid and
envelope proteins.
Provirus
3 The new viral DNA is
tranported into the host cell’s
nucleus and integrated as a
provirus. The provirus may
divide indefinitely with the
host cell DNA.
Figure 13.19
Figure 19.13.1 HIV structure and attachment to receptors on target T cell.
CCR5 or
CXCR4
coreceptor
CD4
receptor
gp41
gp120
CD4+ T cell
Attachment. The gp120 spike attaches
to a receptor and to a CCR5 or CXCR4
coreceptor on the cell.
Figure 19.13.2 HIV structure and attachment to receptors on target T cell.
Viral envelope
Fusion. The gp41 participates in
fusion of the HIV with the cell.
Figure 19.13.3 HIV structure and attachment to receptors on target T cell.
Envelope
remains
behind
Entry. Following fusion with the cell, an entry
pore is created. After entry, the viral envelope
remains behind and the HIV uncoats,
releasing the RNA core (see Figure 19.14b)
for directing synthesis of the new viruses.
Figure 19.14b Latent and active HIV infection in CD4+ T cells.
Provirus
Viral
RNA
mRNA
Core with
viral RNA
Progeny
HIV
Envelope
Virus beginning to bud from T cell
(b) Active infection. The provirus is activated, allowing it to control the synthesis of new
viruses, which bud from the host cell. Final assembly takes place at the cell membrane, taking
up the viral envelope proteins as the virus buds from the cell.
Figure 19.15b Latent and active HIV infection in macrophages and dendritic cells.
Proviru
s
mRNA
Viral RNA
Core with viral
RNA
Activated macrophage. New viruses are
produced from provirus. Completed virions
are either released or persist in the
macrophage within vacuoles.
Figure 19.15a Latent and active HIV infection in macrophages and dendritic cells.
Provirus
Macrophage
Chromosomal
DNA
Vacuole
Insert Fig 19.15a
HIV
Latently infected macrophage. HIV can persist
either as a provirus or as a complete virion in
vacuoles.
Clades (Subtypes) of HIV
• HIV-1
• M (main)
• B (North and South America, Europe)
• C (India, eastern and southern Africa)
• E (southeast Asia)
• O (outlier)
• N (non-M or non-O)
The Stages of HIV Infection
• Phase 1: asymptomatic or chronic lymphadenopathy
• Phase 2: symptomatic; early indications of immune
failure
• Phase 3: AIDS indicator conditions
Figure 19.16 The Progression of HIV Infection.
Understanding how the HIV infection progresses in a host is
integral to understanding the diagnosis, transmission, and
prevention of this pandemic. Although there is no cure, see
information below on drug treatments.
Symptomatic; early
Indications of immune failure
AIDS indicator conditions
1200
12
1100
11
About 2 months following
initial infection, the population
of HIV in the blood peaks at
about 10 million per ml.
1000
900
10
9
CD4+ cell population declines steadily.
Huge but indefinite numbers of HIV, 8
Population of CD4+
many in latent or proviral form, are
7
T cells plunges during
consistently present
acute phase of HIV
in lymphoid tissue. At least 100 billion
6
infection, then recovers as
HIV are generated each
Immune response appears.
day for years, mostly by infected
5
T cells.
+
Clinical AIDS: CD4
Seroconversion: Detectable antibodies
T cell population 4
against HIV appear. Immune response
drops to 200 cells /μl.3
causes rapid decline in HIV population.
800
700
Insert Fig 19.16
600
500
400
300
200
2
HIV in blood stabilizes at steady rate of 1000 to
10,000 per ml.
100
3 6
mo mo
1
2
3
4
5
6
1
7
Years (for someone not receiving anti-HIV medication)
CD4+ T cell population
HIV population in blood
8
9
Blood plasma HIV/RNA (millions of copies/ml)
CD4+ T cell blood concentration (cells/μl)
Asymptomatic or
chronic lymphadenopathy
10
HIV levels in blood rise as the
immune system breaks down.
HIV progresses as it destroys the T cells essential for the body’s
defenses against infectious disease and cancer.
AIDS is the final stage in this progressive infection.
Some Common Diseases Associated with AIDS
Table 19.5
Diagnostic Methods
• Seroconversion takes up to 3 months
• HIV antibodies detected by ELISA
• HIV antigens detected by Western blotting
• Plasma viral load is determined by PCR or nucleic acid
hybridization
HIV Transmission
• HIV survives 6 hours outside a cell
• HIV survives >1.5 days inside a cell
• Infected body fluids transmit HIV via:
• Sexual contact
• Breast milk
• Transplacental infection of fetus
• Blood-contaminated needles
• Organ transplants
• Artificial insemination
• Blood transfusion
Modes of HIV Transmission
Figure 19.17
Figure 14.4 Reported AIDS cases in the United States.
120,000
Second
250,000
cases
First 250,000 cases
Third
250,000
cases
Fourth
250,000
Cases
100,000
Number of cases
80,000
Expansion of surveillance
case definition
60,000
40,000
Insert Fig 14.4
20,000
0
1979
1983
1987
1991
1995
Year
1999
2003
2007
AIDS Worldwide
• U.S., Canada, western Europe, Australia, northern
Africa, South America
• Injecting drug use, male-to-male sexual contact
• Sub-Saharan Africa
• Heterosexual contact
• Eastern Europe, Middles East, Asia
• Injecting drug use, heterosexual contact
AIDS Worldwide
EASTERN EUROPE &
CENTRAL ASIA
EAST ASIA*
WESTERN EUROPE
NORTH AMERICA
1.5 million
CARIBBEAN
240,000
LATIN AMERICA
1.4 million
770,000
820,000
SOUTH
&
NORTH AFRICA &
SOUTHEAST ASIA*
THE MIDDLE EAST
460,000
SUB-SAHARAN AFRICA
Insert Fig 19.17
4.1 million
AUSTRALIA,
NEW ZEALAND
& OCEANIA
1.4 million
57,000
22.5 million
= 100,000 persons living with HIV/AIDS
are that India now has
*Estimates
about 2.4 million cases; China
is estimated to have less than
1 million cases.
Figure 19.16
Prevention of AIDS
• Use of condoms and sterile needles
• Health-case workers use universal precautions
• Wear gloves, gowns, masks, goggles
• Do not recap needles
• Risk of infection from infected needlestick injury is
0.3%
Vaccines in Clinical
• Whole-cell Salmonella with gp120 gene
• Subunit vaccine using gp120 expressed in
Saccharomyces
• Canarypox virus with HIV capsid protein genes
• Naked DNA consisting of tat (transcription factor) or
gag (capsid protein) genes
Chemotherapy
• Reverse transcriptase inhibitors
• Nucleoside reverse transcriptase inhibitors
• Tenofovir and emtricitabrine
• Non-nucleoside reverse transcriptase inhibitors
• Efavirenz
Chemotherapy
• Protease inhibitors
• Atazanavir, indinavir, and saquinavir
• Cell entry inhibitors
• Block fusion
• Enfuvirtide and maraviroc
• Integrase inhibitors
• Enzyme to form HIV provirus
• Raltegravir
Figure 20.16a The structure and function of the antiviral drug acyclovir.
Guanine
Insert Fig 20.16a
Deoxyguanosine
Acyclovir
Acyclovir structurally resembles the nucleoside deoxyguanosine
Figure 20.16bc The structure and function of the antiviral drug acyclovir.
Phosphate
Nucleoside
Normal
thymidine
kinase
Guanine
nucleotide
DNA polymerase
Incorporated
into DNA
The enzyme thymidine kinase combines phosphates with nucleosides to form nucleotides, which are then
incorporated into DNA.
Phosphate
Thymidine kinase
in virus-infected
cell
DNA polymerase blocked by
false nucleotide. Assembly
of DNA stops.
Acyclovir
(resembles
nucleoside)
False nucleotide
(acyclovir triphosphate)
Acyclovir has no effect on a cell not infected by a virus, that is, with normal thymidine kinase. In a
virally infected cell, the thymidine kinase is altered and converts the acyclovir (which resembles the
nucleoside deoxyguanosine) to a false nucleotide, which blocks DNA synthesis by DNA polymerase.
HAART
• Highly active antiretroviral therapy
• Combinations of nucleoside reverse transcriptase
inhibitors plus
• Non-nucleoside reverse transcriptase inhibitor or
• Protease inhibitor
Highly Active Antiretroviral Therapy (HAART):
Combinations of nucleoside reverse transcriptase inhibitors +
Non-nucleoside reverse transcriptase inhibitor or
Protease inhibitor
Reverse transcriptase inhibitors
Nucleoside reverse transcriptase inhibitors
Tenofovir and emtricitabrine
Non-nucleoside reverse transcriptase inhibitors
Efavirenz