Download HIV Drugs and the HIV Lifecycle

HIV Drugs and the HIV Lifecycle
by Liz Highleyman
July 2003
The Basics
HIV drugs cannot cure HIV but they can prevent the virus from
replicating (reproducing or making copies of itself). When HIV cannot
reproduce, it cannot infect new cells in your body. So basically, all HIV
drugs work by interrupting HIV’s lifecycle to stop it from reproducing,
and thereby to “stop it in its tracks.”
HIV’s lifecycle is complex, and different classes of HIV drugs target
different stages or steps. There are currently four approved classes of
HIV drugs:
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Entry inhibitors
Nucleoside and nucleotide reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
The HIV Lifecycle in Brief
Once HIV is in the body, it targets and infects a certain type of white
blood cell called a CD4 cell. HIV then takes over or “hijacks” these cells
and turns them into virus factories that can produce thousands of viral
copies. The steps HIV goes through to complete this process are as
follows:
1. Entry
HIV enters a cell by binding (or attaching) itself to specific
points, called receptors, on the cell’s surface. Once HIV gets
inside a cell, it releases its own genetic material and enzymes.
2. Reverse Transcription
HIV’s genetic material comes in a form known as RNA. The RNA
contains the “instructions" that will reprogram the CD4 cell’s
machinery to produce more viruses. In order to be effective,
HIV’s RNA must be converted into DNA. This conversion process
depends on an HIV enzyme called reverse transcriptase. (You’ll
notice that the words “reverse transcriptase” are part of many
HIV drug names.)
3. Integration
Next, the newly copied DNA is inserted into the genetic material
of the CD4 cell. This is done with the help of another HIV
enzyme called integrase.
4. Cleavage
Once the virus has become part of (is integrated into) the CD4
cell, it can start making new HIV proteins. New HIV proteins are
produced in the form of long chains. These chains have to be cut
up into smaller pieces, and then reassembled (or put back
together in a certain way) in order to become new HIV virus.
This cutting process depends on a third HIV enzyme called
protease.
5. Assembly and Budding
Finally, the cut-up pieces are put together to form new virus
particles, which then “bud” back out of the original CD4 cell. This
new virus goes on to target and infect other cells.
Types of HIV Drugs
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Entry Inhibitors
These drugs stop (inhibit) HIV from entering a host cell. If HIV
can’t get in, it can’t replicate and make new viruses. There are
different types of entry inhibitors including chemokine blockers
and fusion inhibitors. Entry inhibitors are the newest HIV drug
class. There is currently just one fusion inhibitor available,
Fuzeon (enfuvirtide, or T-20), but researchers are studying
many others.
Reverse Transcriptase Inhibitors
These drugs interfere with the reverse transcriptase enzyme in
order to prevent HIV from replicating. Reverse transcriptase
inhibitors are the oldest class of HIV drugs. There are three
different types of drugs in this class:
1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs).
Approved NRTIs include Retrovir (zidovudine or AZT),
Videx (didanosine or ddI), Hivid (zalcitabine or ddC), Zerit
(stavudine or d4T), Epivir (lamivudine or 3TC), Ziagen
(abacavir), Combivir (Retrovir plus Epivir), Trizivir
(Retrovir plus Epivir plus Ziagen), Emtriva (emtricitabine
or FTC), Epzicom (Epivir plus Ziagen),Truvada (Emtriva
plus Viread), and Atripla (Sustiva plus Emtriva and Viread).
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2. Nucleotide Reverse Transcriptase Inhibitors. There is
only one approved nucleotide drug, Viread (tenofovir).
3. Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs). The approved NNRTIs are Viramune
(nevirapine), Rescriptor (delavirdine), Sustiva (efavirenz),
and Atripla (Sustiva plus Emtriva and Viread).
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Integrase Inhibitors
These drugs interfere with HIV’s integrase enzyme. They prevent
HIV from inserting its own genetic material into the host cell, so
HIV cannot make new viruses. Currently there are no approved
integrase inhibitor drugs, but several experimental ones are
being studied.
Protease Inhibitors (PIs)
These drugs interfere with the action of HIV’s protease enzyme.
Protease works as a scissor to cut up newly created protein
chains into smaller pieces. These smaller pieces are then used to
build new viruses. There are several approved protease
inhibitors, including Agenerase (amprenavir), Crixivan
(indinavir), Fortovase (saquinavir sgc), Invirase (saquinavir
hgc), Viracept (nelfinavir), Norvir (ritonavir), Kaletra, which is
actually a blend of lopinavir and ritonavir, Reyataz (atazanavir),
Lexiva (fosamprenavir calcium), and Prezista (darunavir, TMC114).
Assembly and Budding Inhibitors
These experimental HIV drugs are designed to interfere with the
final steps of putting together new virus particles (assembly).
They also prevent the so-called budding of the new viruses out
of the CD4 cell. There are no drugs of this type yet, but several
candidates are in early studies.
Combining Drug Classes
Doctors often combine drugs from different classes in order to attack
HIV at more than one point in its lifecycle. This is because HIV can
mutate, or change forms, which makes it resistant to specific drugs.
(This can cause your HIV drugs to quit working as well, or to “lose
efficacy.”)
If you take only one drug (monotherapy) or take a few drugs that all
belong to one class of drugs, it is very easy for HIV to mutate around
that one drug or class. However, HIV has a much harder time
mutating in the presence of multiple drugs or drug classes.
What does this mean to you? It means that combination therapy with
drugs that interfere with HIV at different stages of its lifecycle can
prevent most of the production of new HIV. This means slower disease
progression and longer life for HIV+ people.
The Bottom Line
Currently four different classes of HIV drugs target three different
stages of HIV’s lifecycle. Attacking HIV on multiple fronts by combining
drugs from different classes is the best way to slow or stop HIV
replication. It is also the best way to prevent the development of drug
resistance. New classes of HIV drugs—and new drugs in the classes
already available—will provide more treatment options for HIV+ people
in the future.