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HIV-1 Reverse Transcriptase

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HIV has a genome made up of RNA instead of DNA. RNA cannot be integrated into the genome of the host, hence it must be made into DNA. HIV realeases enzymes, one of which, is the HIV-1 Reverse Transcriptase. It facilitates the reverse transcription of RNA into DNA.

HIV-1 RT0001

Reverse Transcriptase is defined by its structure. It looks like a hand. The blue region is dubbed the "finger" region. The red is considered the "palm". Here, the polymerase active site is located. The green is called the "thumb". The yellow part is the "connection", and the teal part is the "RNAse H" active site. The thumb is flexible, and it has two conformations. It's either closed or open. Only the closed position allows transcription of RNA.

ActionsEdit

Reverse Transcriptase has 2 active sites, the Ribonuclease H and Polymerase active site. At the polymerase, single stranded RNA is transcribed into an RNA-DNA double helix using host cell nucleotides. This double helix arrives at the Ribonuclease H active sate where the RNA is cleaved into nucleotides. The DNA goes back to the polymerase to be completed into a DNA version of the viral genome.

StructureEdit

Reverse Transcriptase is a heterodimer, because its subunits are different. The grey subunit is the P51 subunit and the colored subunit is the P66 subunit. The P66 subunit has a green thumb region, a blue finger region, a red palm region, and a yellow arm region. The cyan region is the RNAse domain. The P66 subunit resembles a hand, like most DNA polymerases of eukaryotic cells. It even has the active site of eukaryotic polymerases, but it is a RNA dependent DNA polymerase, It is flexible, another similarity to DNA polymerases, the thumb and finger region can touch each other, and then return to its normal position. When the fingers and thumb touch, it is the closed position. Not touching, they are in the open position.

InhibitorsEdit

A well known drug used to inhibit the Polymerase active site non-competitively is Nevirapine. It is a NNRTI ( Non Nucleoside Reverse Transcriptase Inhibitors ), that binds to a hydrophobic binding site located in the palm region. All NNRTI's bind to the site, locking the thumb in the open position stopping reverse transcription. Reverse Transcriptase only is able to transcribe in the closed position, when the finger and thumb are touching.. Some mutations may lead to resistance of these drugs. Other inhibitors were also made. They are called NRTI's (Nucleoside Reverse Transcriptase Inhibitors) because they inhibit the Polymerase active site, using the nucleosides on the RNA. NRTI's have a structure on the bottom part resembles a corresponding nucleoside to the nucleoside they will target. The top part of NRTI's have 'arms' that block makes an impact with the polymerase active site. This rips the RNA and stops other host DNA nucleotides from coming in, and causes terminations in the RNA-DNA double helix. Other inhibitors such as KP-1461 is an effective inhibitor. They trick Reverse Transcriptase into using it as a nucleotide, Its comformation allows it to become mismatched base pairs. This causes too many mutations and leads to viral decay and possible viral extinction of the host.

Responsibility for ResistanceEdit

HIV sometimes develops drug resistance mutants. One crucial step to be a mutant is that Reverse Transcriptase has no proofreading activity. Wrong nucleotides may be used to make the RNA DNA double helix. This happens up to 5 nucleotides wrong. When the RNA is broken down, the DNA double helix is made. Up to 5 mutations may be incorporated in the DNA. Mutations in the sequence that codes for the enzymes, results in the making of mutant enzymes. The amino acids are changed in the enzymes. For example, the Protease enzyme activity is normally blocked by anti-retrovirals. However some mutations may lead to resistance to one or many drugs. Resistance to many drugs is called cross resistance. Many mutations may lead to resistance to all drugs given in the therapy. However, some drugs are made with highly improved mechanisms to overcome the mutations in the enzymes. Tipranavir, Lopinavir, Atazanavir are very effective Protease Inhibitors.

Gallery Edit

HIV-1 RT Step 3

Then, the RNA is broken down by the Ribonuclease H active site, marked in teal. This results in the release of a single DNA strand which contains multiple errors.

HIV-1 RT Step 1

In the first step of reverse transcription, the viral RNA enters into the polymerase active site, marked in red.

HIV-1 RT Step 2

Then, using host nucleotides, a RNA-DNA double helix is formed. Reverse Transcriptase has a high error rate, and incorrect nucleotides may become incorporated into the helix. Since Reverse Transcriptase has no proofreading activity, the nucleotide sequence is not repaired, and mutations accumulate. Incorrect nucleotides are marked in yellow.

HIV-1 RT Step 4

Then, the single stranded DNA moves to the polymerase active site, where it is completed. Note that since no errors are fixed, the mutations accumulate, and wrong nucleotides are exchanged.

HIV-1 RT Step 5

The DNA is completed, and contains mutations. These mutations result in mutant HIV virions, and resistance to some anti-retroviral drugs. These mutations are almost certain to induce resistance if they are located in the sequence that codes for the viral enzymes.

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