virus that targets cells in the immune system. Over time, the immune system begins to fail
which is called immunodeficiency, and this increases the risk of infections and tumors
that a healthy immune system would usually be able to fend off. These complications are
referred to as AIDS, or acquired immunodeficiency syndrome. Now there are two distinct types of HIVHIV-1
and HIV-2.
HIV-1 is the more commonly associated with AIDS in the US and worldwide, HIV-2 is
more rare, and typically restricted to areas in western Africa and southern Asia. HIV-2
is so uncommon that HIV almost always refers to HIV-1. Alright HIV targets CD4+
cells, meaning cells that have this specific molecule called CD4 on their membrane. Macrophages,
T-helper cells, and dendritic cells are all involved in the immune response and all have
CD4 molecules; therefore they can be targeted by HIV.
The CD4 molecule helps these cells
attach to and communicate with other immune cells, which is particularly important when
the cells are launching attacks against foreign pathogens. So this little molecule is pretty
important for our immune system, but its also extremely important for HIV. HIV targets
and attaches to the CD4 molecule via a protein called gp120 found on its envelope. HIV then
again uses gp120 to attach to another receptor, called a co-receptor.
HIV needs to bind to
both the CD4 molecule and a coreceptor to get inside the cell. The most common co-receptors
that HIV uses are the CXCR4 co-receptor, which is found mainly on T-cells, or the CCR5 co-receptor
which is found on T-cells, macrophages, monocytes, and dendritic cells. These coreceptors are so important that some
people with homogeneous genetic mutations in their CCR5 actually have resistance or
immunity to HIV, since HIV cant attach and get into the cell. In fact, even heterozygous
mutations which lead to fewer co-receptors on the cells, can make it harder for the virus
to spread, and results in a slower disease progression.
For those without this mutation though, once
HIV binds to CD4 and either CCR5 or CXCR4, it gains access to the cell. HIV is a single-stranded,
positive-sense, enveloped RNA retrovirus, meaning that it injects its single strand
of RNA into the T-helper cell. The retro part of retrovirus isnt referring to its
style, but refers to it needing to use an enzyme called reverse transcriptase to transcribe
a complementary double-stranded piece of proviral DNA. Proviral just means that its ready
to be integrated into the hosts DNA, so it enters the T-helper cells nucleus and
pops itself into the cells DNA, ready to be transcribed into new viruses, pretty sneaky,
huh? Well heres the actual sneaky partwhen the immune cells become activated, they start
transcribing and translating proteins needed for the immune response.
Ironically, this
means that whenever the immune cell is exposed to something that causes it to start up an
immune response, like any infection, the immune cell ends up inadvertently transcribing and
translating new HIV viruses, which bud off from the cell membrane to infect more cells.
Very sneaky indeed! One thing to know is that HIV is notorious
for making errors when it replicates and that during an infection it can mutate to create
slightly different strains of viruses. These viruses are all still considered HIV
but behave slightly differently from each other and target different cells in the host,
in fact that host cell preference is called viral tropism. So lets start with HIV entering
the body through sexual intercourse which is how it typically spreads from person to
person. At this early point, during what we call acute infection, the R5 strain of HIV,
which bind to the CCR5 coreceptor will get into macrophages, dendritic cells, and T cells.
Usually dendritic cells hanging out in the epithelial or mucosal tissue where the virus
entered the body, capture the virus and migrate to the lymph nodes, where a lot of immune
cells live, and the R5 strain of HIV essentially has a field day, infecting T-helper cells,
macrophages, and more dendritic cells, which leads to a big spike in HIV replication and
the amount of virus found in the patients blood.
Patients typically experience flu-like
or mononucleosis-like symptoms during the acute infection. In response, the immune system
mounts a counterattack, and starts to control the amount of viral replication, and the amount
of virus in the blood declines to lower but still detectable levels by 12 weeksat which
point the patient enters the chronic or clinically-latent phase, which can last between 2 and 10 years.
If we also plot the amount of T cells alongside the amount of virus, well see that they
loosely mirror each other, which makes total sense, right? Initially you have a considerable
decline in the acute phase until the immune system mounts its counterattack. After this
point, even though there may not be any clinical signs or symptoms of the virus, the virus
is steadily chipping away at the immune system, and the number of viruses in the blood slowly
increases, while at the same time T cells slowly decrease, losing about 1-2 billion
T cells every day. During this chronic phase, T cell counts usually remain above 500 cells
/ mm3, about the size of the head of a pin, and patients can still fight off other infections
fairly well, although some infections like tuberculosis become more common and severe.
Remember how HIV replication can create mutations?
Well during the chronic phase of HIV infection, its worth pointing out that some patients
develop an X4 strain of HIV which targets the CXCR4 coreceptor, which is essentially
only T-cells. These X4 strains kind of lay low in the lymphoid tissues, and steadily
destroy of CD4 T cells, since about 90% of T cells are found in lymphoid tissue. Not
all patients develop the X4 strain, though, so its not completely clear what the presence
of this strain implies about the disease course. When the bodys T cells drop low enough,
between about 200 and 500 cells / mm3, patients start experiencing symptoms like swollen lymph
nodes, or lymphadenopathy, as well as relatively minor infections like oral hairy leukoplakia,
a hairy-looking white patch on the side of the tongue caused by the same Epstein-Barr
virus that causes mononucleosis, as well as oral candidiasis, a yeast infection in the
mouth.
As more T cells are lost, and the level falls below 200 cells / mm3, the immune system
becomes severely compromised and at this stage the condition has progressed from HIV disease
to AIDS. At this point people experience things like persistent fever, fatigue, weight loss,
and diarrhea. And the HIV count in the blood might increase significantly. At this point, certain conditions start to
develop that are said to be AIDS-defining, such as recurrent bacterial pneumonia, pneumocystis
pneumonia, and fungal infections like candidiasis of the esophagus.
Other conditions include
certain tumors and malignancies like Kaposi sarcoma which causes lesions on the skin and
other soft tissues, and primary lymphoma of the brain. Many people with AIDS die from
infections that a healthy immune system would typically be able to fend off, like pneumocystis,
cytomegalovirus, or mycobacterium avium complex. Male-to-male transmission is the most common
mode of transmission in the US, and male-to-female is the most common mode in resource-limited
settings. Although less common, female-to-male transmissions occur as well since HIV is present
in the vaginal and cervical fluids of infected women.
In fact, over 75% of all cases of HIV
are contracted from sexual intercourse. The next most common means of transmission include
things like intravenous drug abuse and mother-to-child transmission, which can be via the placenta
during delivery, or via breast milk. Other, much less common modes of transmission include
accidental needlesticks, and use of blood products like blood transfusions. As far diagnosis goes, there are a few types
of HIV tests that can be doneantibody tests, antibody/antigen tests, and RNA/DNA tests.
Antibody tests look for antibodies that the bodys made against HIV.
Antigen tests look
for the virus directly, so antibody/antigen tests detect both antibodies to the virus
as well as the virus itself. RNA tests screen for viral RNA, so they also detect the virus
directly, and DNA tests look for copies of the viral RNA (since remember its a retrovirus
so it copies its genetic material into DNA). For screening purposes, the recommended test
is the antibody/antigen test, which is better at identifying early infection. Its also
recommended, if the first test is positive, to follow it with a confirmatory test that
looks for antibody or nucleic acids.
Theres currently no cure for AIDS; treatment
however, can help somebody with AIDS live longer, healthier lives and help reduce the
risk of transmission. The primary method is to use antiretroviral therapy, or ART. ART
isnt a single medicine, but a combination of medicines thats known as an HIV regimen.
These help slow down HIV replication, which gives the immune system a chance to recover
and help fight off other infections more effectively..
No comments:
Post a Comment