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Current Disease Treatment

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Engineered Human Cells: STOP HIV



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Introduction

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In spite of a great improvement in understanding HIV and AIDS that science has made in the last years we still do not have the ultimate cure for AIDS. One of the problems in AIDS treatment is also the price of the therapeutics; only a small amount of infected population can afford the expensive treatment. The biggest problem in developing the cure is HIV itself. Because it can mutate easily, it can escape or hide itself from deadly actions of therapeutics.

HIV (human immunodeficieny virus) is a retrovirus which means that it has its genome in a form of single stranded RNA. It has a typical gag/pol/env genome organization; gag genes (group specific antigen) codes for structural proteins, env for proteins that build viral envelope, pol genes are responsible for viral reproduction (they contain genes for reverse transcriptase, integrase and HIV protease).
HIV envelope consists of lipids and viral glicoproteins gp120 and gp41, which are crucial for binding of HIV to host cell membrane and for entering to the cell. There are also other glicoproteins that guarantee firmness and protective function of viral envelope. Gp120 binds to receptors on host cell surface (CD4), additional co-receptors like chemokine receptors are also needed for successful entry of HIV. Mutations in co-receptor genes can cause immunity – if HIV cannot enter host cells infection then development of AIDS is not possible.
Typical enzyme for retroviruses is reverse transcriptase, which transcripts viral RNA into DNA. Only DNA can integrate into host cell genome – this is the crucial step in expressing viral proteins that are needed for assembly of new viral particles. Gag and gag/pol genes of HIV are expressed as a polyprotein; until this polyprotein is cut into functional units, it expresses no biological function. The cutting is done by HIV protease; parts of polyprotein then represent functional enzymes and structural proteins.
Transcription of viral RNA into DNA and processing of the viral polyprotein are two most important steps in HIV cycle. That also means that reverse transcriptase and HIV protease are obvious targets for HIV therapeutics – inhibitors of reverse transcriptase and HIV protease.


Current disease treatment

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One of the first AIDS therapeutics were nucleotide or nucleoside analogues (NRTI – nucleoside-analogue reverse transcriptase inhibitors) – pseudosubstrates, that are integrated into viral DNA instead of nucleosides during reverse transcription and thus block the transcription. Next step were non-nucleoside inhibitors (NNRTI) that could inhibit reverse transcriptase by binding into alosteric site of the enzyme.
Combination of therapeutics listed above is now accompanied by a family of HIV protease inhibitors. In most cases inhibitors are very much similar to the protease substrates - the only difference is that because they cannot be cut they block active site by binding into it.

Weakness of all therapeutics mentioned above is that they are very sensitive to HIV mutations – HIV can easily mutate and thus become resistant to certain drug. Combination of drugs is used to minimize HIV's potential to develop resistance to every drug in the mixture. Some of the drugs induce mutations that have negative influence on virulence; drugs like that can be used in spite of developed resistance.
We still do not have a cure for AIDS that would be insensitive to HIV mutations. Our project presents several new ways of potential AIDS therapeutics; all are mostly independent of HIV mutations. We have set up few ambushes; if HIV manages to avoid them we presume that it would not be able to infect the cell anyway.


Classes of antiretroviral drugs

Antiretroviral drugs are mostly inhibitors of different stages in HIV life cycle. They are targeted at different enzymes or events that are typical for HIV infection – entry of virus to the cell, reverse transcriptase, protease... They are divided into seven main classes:


Cell backgrounds:

Type of inhibitor Action/target Role in current AIDS treatment
HIV protease inhibitors They are very much alike; they all mimic cut sites in protein chains. Their difference compared to 'normal' protein recognition sites is their increased stability – when HIV protease binds to what should be cut site, inhibitor blocks its active site and thus block enzymatic activity. Without viral polyprotein being cut virus is not able to form new viral particles. There are around ten FDA approved drugs that are protease inhibitors (Sequinavir, Indinavir, Nelfinavir...).
Reverse transcriptase inhibitors They inhibit viral reverse transcriptase – if RNA is not transcribed in DNA, HIV is not able to replicate itself. There are two main types – nucleoside/nucleotide analogue reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Zidovudine was first FDA approved antiretroviral drug for AIDS treatment. There are numerous other drugs of different types.
Integrase inhibitors By inhibiting viral integrase transcribed DNA cannot integrate into host cell genome. None has been approved but there are a few undergoing testing.
Fusion inhibitors They bind to gp41 and prevent fusion with cell membrane. Enfurvitide is used with patients with multi-drug resistant HIV strains.
Entry inhibitors They compete for binding sites in gp120 receptors – when inhibitor is bound gp120 cannot bind to receptor and co-receptor and HIV entry is blocked. Fuzeon is the only FDA approved.
Other inhibitors Some of the inhibitors are targeted at blocking the conversion of polyprotein into mature capsid protein, others are a combination of different types if inhibitors (Portmanteau inhibitors).




It is much harder to discover a useful drug than finding the idea behind it. It is not enough for inhibitors to just bind to its target; they have to have high affinity for specific target (and not for other similar enzymes in the cell), it has to be resistant to other anti-HIV therapeutics and compatible with other drugs that are used against opportunistic infections. It has to be stable enough to maintain constant concentration level in the body, resistance should not evolve quickly...

HAART

Current AIDS treatment is based on HAART – highly active antiretroviral therapy. It is a mixture of at least three different antiretroviral drugs; by disturbing viral replication cycle at different stages it is much harder for HIV to mutate and become drug-resistant. Synergistic enhancers are added; they are drugs that are either inappropriate for monotherapy or are enhancers of metabolism of other antiretroviral drugs.
Although HAART can provide longer and better life for patients with AIDS it is not the ultimate cure. It cannot totally exile HIV from patient's body because it cannot excise latent viral DNA that is integrated into host genome.

There are two more problems with HAART – it's side effects and cost. We can try to minimize the side effect but we will probably never find a cure for AIDS that would be completely harmless. Because HAART must be taken continuously it's price makes it impossible to use widely in areas with the highest percentage of infected population. Ideally, vaccination could limit AIDS epidemic because vaccines usually cost less than drugs for continuous treatment and could be affordable for developing countries. After many years of intense research we still do not have a vaccine for HIV and because of its high mutation rate HIV is a difficult target.


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