Summary Elective course Infectious Diseases pre-master Health Sciences block 5
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Course
Infectieziekten (AP_470905)
Institution
Vrije Universiteit Amsterdam (VU)
Book
Microbiology
Here are the summaries of the infectious diseases elective course of the pre-master Health Sciences at the VU. With the total summaries, you will get a good grade for the infectious diseases exam.
Keuzevak Infectieziekten pre-master Health Sciences blok 7
Keuzevak Infectieziekten pre-master Health Sciences blok 6
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Health Sciences pre-master
Infectieziekten (AP_470905)
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Chapter 17 (414-420): Failures of the Immune Response
Acquired Immune Deficiency Syndrome
AIDS is caused by infection with the human immunodeficiency virus (HIV).
HIV is an enveloped retrovirus that is transmitted through sexual contact or
by contact with infected body fluids. Retroviruses contain the enzyme
reverse transcriptase, which allows it to copy its RNA genome into a DNA
copy that can then integrate into a host chromosome. There are two major
forms of virus: HIV-1 is the predominant form seen throughout the world,
HIV-2 is the form seen mostly in Africa. HIV debilitates the immune
response by attacking cells of the immune system.
Cellular targets of HIV
HIV uses a complex of two glycoproteins, gp120 and gp41, in the viral envelope to bind to the
CD4 molecule on helper T-cells, dendritic cells and macrophages. For infection to be
successful, HIV must also bind to co-receptors. As with CD4, they are normal cellular
proteins. One is the chemokine receptor CXCR4, which binds to the chemokine CXCL12.
Binding by HIV causes virally infected cells to form syncytia (giant cells), which enable the
virus to spread. Some variants of HIV use co-receptor CCR5, which binds to chemokines
CCL3, CCL4 and CCL5. Several other co-receptors have been found in places such as the brain
and thymus, but are not yet characterized. People who have mutations in the genes that
code for these receptors are less susceptible to infection with HIV.
Modes of HIV transmission
HIV is transmitted through sexual contact and via blood and body fluids.
The efficiency of transfer is based on the concentration of viral particles in
the fluid. The highest viral loads are found in peripheral blood monocytes,
blood plasma and cerebrospinal fluid. Semen and genital secretions are
also sources of the virus.
Other sexually transmitted diseases can contribute to HIV transmission,
probably because infected and ulcerated genital tissue permits direct
access of the virus to the blood. Although sexual activity is still the leading
mode of transmission, IV drug abuse is the next most common form.
Children are also at risk because the virus can be transmitted across the
placental barrier and can be found in breast milk (although transmission
rates through breastfeeding are low).
Except for direct access through an injection, needlestick injury or blood transfusion, HIV
enters the lamina propria when the mucosal epithelial cell layer is broken. Infection relies on
sufficient viral numbers, and infected cells are the richest source of the virus. Spread of virus
from infected cells to uninfected cells can be observed in tissue culture. Cells of the mucosal
immune system, including M cells in the bowel and dendritic antigen-presenting cells in the
vagina and cervical epithelium, are prime targets for initial infection because they function to
pick up and process antigens. It has been shown that dendritic cells can bind to the HIV-1
1
, envelope proteins with high affinity and hold them stable for several days until susceptible
T-cells come along and are infected. In sexually active males, cells lining the penis can
become infected by contact with viruses from infected macrophages or Langerhans cells in
the cervix or intestinal mucosa of an infected partner.
HIV genome
HIV has an RNA genome, because it is a retrovirus the RNA must be copied to DNA by reverse
transcriptase, which is carried in HIV virions. The DNA copy is integrated into the host DNA
using the viral enzyme integrase to form a provirus. The HIV genome comprises only nine
genes flanked by long terminal repeat sequences (LTR’S), which are required for the virus to
integrate into the host chromosome. Once the provirus has been integrated into a host
chromosome, host cell machinery is used to replicate the virus. It is important to note that
reverse transcriptase has no proofreading ability, therefore many mutations occur. These
mutations help HIV develop rapid resistance to antiviral drugs and escape therapy.
Dynamics of HIV replication in infected patients
The minimum rate of release into the blood based on one cycle of infection per infected cell
per day is 10^10 virions. When this high rate is coupled with the high mutation rate, it can be
predicted that every possible mutation at every position in the viral genome can occur
numerous times each day. It is estimated that the genetic diversity of HIV produced in a
single infected person is greater than all the diversity that would be seen in a worldwide
epidemic of influenza.
Course of infection
The pathology of HIV infection consists of three phases: acute phase, asymptomatic phase
and symptomatic phase with the development of AIDS.
1. Acute phase:
Begins in the first few days after initial infection. During this time the virus is produced in
large quantities by infected lymphocytes in the lymph nodes, resulting in lymphadenopathy
and flu-like symptoms. This initial viremia is greatly reduced by 10 weeks after initial contact.
The decrease is most probably a result of the action of CD8 T-cells, which kill infected targets.
Support for this hypothesis is demonstrated by the increase in number of CD8 T-cells seen
during this period. The CD4 T-cell target population, which is initially decreased, rebounds by
the end of this phase to near-normal numbers. During this phase, the viral population is
homogeneous, indicating that little mutation is occurring.
2. Asymptomatic phase:
Usually begins three to four months after the initial infection. By this point, the viremia is
very low, with only occasional small bursts of virus being released. Many of the infected cells
have been killed by CD8 T-cells. However, memory T-cells and dormant macrophages that
contain HIV provirus serve as reservoirs for infection. While its genome is in the provirus
form, HIV is latent and does not make any new virions. The degree of active viremia seen
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