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Human Immunodeficiency Virus

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  1. Sep 22, 2014 #1
    Hi,
    Today our teacher taught us about AIDS, and she said that it has no cure, because every time the genetic material of the virus replicates, it undergoes mutations, and a new type of virus is formed. Because of this, a lot of viruses are formed, each with a different genotype. That is why antivirals are also not effective in this case.
    When she taught us about its life cycle, she said that it incorporates its genetic material into the genome of the host cell (say, macrophage), using the integrase enzyme, and, when the host cell replicates its DNA, genetic material of the virus also get replicated, along with it.

    My question is,
    Whenever our body's DNA replicates, some repair enzymes, like DNA polymerase II and III, are involved. Don't they work over the viral DNA? If they do, then what causes errors?
    I mean, they are there to detect copy-error mistakes and correct them, don't they do the same over the viral genome?
     
  2. jcsd
  3. Sep 22, 2014 #2

    Ygggdrasil

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    There are two separate issues here: 1) the relatively high mutation rate of HIV, and 2) integration of the viral genome into the host cell genome, establishing a latent reservoir.

    The high mutation rate makes it difficult to treat HIV because the high mutation rate enables fast evolution, allowing resistance to antiretroviral drugs to arise quickly. However, modern anti-HIV treatments get around this problem by using a combination of drugs targeting different viral enzymes. Whereas resistance to one drug can arise from a small number of mutations, resistance to multiple drugs would require many specific mutations to arise simultaneously, which is unlikely even for HIV. Thus, modern combination therapies can get around the problem of drug resistance and are able to stop viral replication very effectively, to the point that patients on combination therapy have no detectable virus in their blood (and, thus, cannot transmit the virus).

    If these patients have no detectable virus, then why aren't they cured? As you mentioned, the problem is that the virus integrates its genome into a subset of the host's cells. Because antiretroviral drugs target viral proteins involved in replication (e.g. reverse transcriptase and protease), they affect only actively replicating viruses and do not affect any virus that lies latent in infected cells. So even when antiretroviral drugs eliminate all circulating virus, once drug treatment stops, the virus will eventually re-emerge from the latent reservoir of host cells harboring the integrated virus, re-establishing an active infection. Thus, the main impediment to a cure is this latent reservoir. Researchers are still studying which type of cells make up this reservoir, and whether there might be drugs that can kick the virus out of the reservoir. Crazier ideas include using gene editing technologies to disrupt the integrated viral genomes (see for example, http://www.the-scientist.com/?articles.view/articleNo/40531/title/Genome-Editing-Cuts-Out-HIV/ which refers to this study: http://www.pnas.org/content/111/31/11461).

    Now to specifically address your question, mutations arise during the process of reverse transcription, when the viral RNA is converted into DNA prior to integration. After the DNA is integrated into the host cell, it can replicate via using the normal, high-fidelity DNA replication system in the cells. Although our cellular DNA polymerases are capable of sensing and correcting errors, these only work to correct errors introduced by DNA polymerase. If mutations arise during reverse transcription, DNA polymerase will faithfully copy these mutations into further generations.
     
  4. Sep 22, 2014 #3
    That is not entirely true. It does not happen every time at replication.
    There is a rate for mutation, with viruses having one of the highest for base pair per generation in comparison to other DNA replications of other organisms. With the virus making millions, billions, trillions of copies, with the mutation rate of DNA replication, a base pair mutation will most surely be found in the next generation. Some of the mutations will make the virus anti-viral resistant, other mutations will not.

    In general, the mutation rate in unicellular https://www.physicsforums.com/wiki/Eukaryotes [Broken] and https://www.physicsforums.com/wiki/Bacteria [Broken] is roughly 0.003 mutations per genome per generation.[4] The highest per base pair per generation mutation rates are found in viruses, which can have either RNA or DNA genomes. DNA viruses have mutation rates between 10−6 to 10−8 mutations per base per generation, and RNA viruses have mutation rates between 10−3 to 10−5 per base per generation.[4] Human mitochondrial DNA has been estimated to have mutation rates of ~3× or ~2.7×10−5 per base per 20 year generation (depending on the method of estimation);[5] these rates are considered to be significantly higher than rates of human genomic mutation at ~2.5×10−8 per base per generation.[6] Using data available from whole genome sequencing, the human genome mutation rate is similarly estimated to be ~1.1×10−8 per site per generation.

    http://en.wikipedia.org/wiki/Mutation_rate
     
    Last edited by a moderator: May 7, 2017
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