AZT-resistant HIV-1 reverse transcriptase: Difference between revisions
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{{ | {{STRUCTURE_3kli| PDB=3kli | SIZE=400| SCENE= |right|CAPTION=AZT-resistant HIV-1 reverse transcriptase with P66 (grey) and P51 (green) [[3kli]] }} | ||
[[Human Immunodeficiency Virus ]] is a virus that damages the immune system of those affected by it. When a person is HIV positive, the virus infects the host's Helper T cells by attaching to the CD4 receptor on the host cell and fusing the viral envelope with the host cell membrane. The viral particles are then released into the host cell. Once inside the T cell cytoplasm, the viral enzyme, reverse transcriptase, coverts the virus' single stranded RNA into double stranded DNA. This capability classifies HIV as a retrovirus. The viral [[DNA]] is then incorporated into the host genome using the viral enzyme, integrase. The host genome now contains viral information and each time the host replicates, the viral genetic information is passed on to daughter cells. This makes HIV particularly difficult to treat, as it protects itself by incorporating its genetic information into that of the host. In addition, HIV is able to remain dormant in a host's body for a period of time before it hijacks the host cell and uses the host to create new viral particles. | [[Human Immunodeficiency Virus ]] is a virus that damages the immune system of those affected by it. When a person is HIV positive, the virus infects the host's Helper T cells by attaching to the CD4 receptor on the host cell and fusing the viral envelope with the host cell membrane. The viral particles are then released into the host cell. Once inside the T cell cytoplasm, the viral enzyme, reverse transcriptase, coverts the virus' single stranded RNA into double stranded DNA. This capability classifies HIV as a retrovirus. The viral [[DNA]] is then incorporated into the host genome using the viral enzyme, integrase. The host genome now contains viral information and each time the host replicates, the viral genetic information is passed on to daughter cells. This makes HIV particularly difficult to treat, as it protects itself by incorporating its genetic information into that of the host. In addition, HIV is able to remain dormant in a host's body for a period of time before it hijacks the host cell and uses the host to create new viral particles. | ||
Eventually, HIV infection leads to a weakened immune system, making a host more susceptible to opportunistic infections. The host's damaged immune system makes it more difficult to fight off infections and thus those who are HIV positive are more likely to have serious complications from common infections. This is especially concerning in those who have Acquired Immune Deficiency Syndrome (AIDS). Patients are considered to have AIDS when their CD4 cell count drops below 200 per microliter of blood. This means that their immune systems have been significantly damaged and puts them at great risk for opportunistic infections. | Eventually, HIV infection leads to a weakened immune system, making a host more susceptible to opportunistic infections. The host's damaged immune system makes it more difficult to fight off infections and thus those who are HIV positive are more likely to have serious complications from common infections. This is especially concerning in those who have Acquired Immune Deficiency Syndrome (AIDS). Patients are considered to have AIDS when their CD4 cell count drops below 200 per microliter of blood. This means that their immune systems have been significantly damaged and puts them at great risk for opportunistic infections. | ||
There is currently no cure for HIV/AIDS, but treatments that inhibit the replication of the virus do exist. These treatments, particularly AZT, will be discussed in the "Inhibition of Reverse Transcriptase Activity" section. Researchers are also attempting to create an HIV vaccine, but this is proving difficult because HIV is a retrovirus. The ability to convert single stranded RNA into double stranded [[DNA]] also creates for more opportunity for mutations of the virus to occur. The high frequency of viral mutations creates many challenges for scientists in the quest to create a vaccine. | There is currently no cure for HIV/AIDS, but treatments that inhibit the replication of the virus do exist. These treatments, particularly AZT, will be discussed in the "Inhibition of Reverse Transcriptase Activity" section. Researchers are also attempting to create an HIV vaccine, but this is proving difficult because HIV is a retrovirus. The ability to convert single stranded RNA into double stranded [[DNA]] also creates for more opportunity for mutations of the virus to occur. The high frequency of viral mutations creates many challenges for scientists in the quest to create a vaccine. See also [[Reverse transcriptase]]. | ||
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==Role of Reverse Transcriptase in HIV Replication== | ==Role of Reverse Transcriptase in HIV Replication== | ||
[[Reverse transcriptase]] has two enzymatic activities: [[DNA polymerase]] and RNase H. DNA polymerase is capable of copying either a DNA or an RNA template, while RNase H cleaves RNA that is part of the RNA/DNA duplex. These functions work together to create double-stranded linear DNA from RNA, which can then be incorporated into the host genome | [[Reverse transcriptase]] has two enzymatic activities: [[DNA polymerase]] and RNase H. DNA polymerase is capable of copying either a DNA or an RNA template, while RNase H cleaves RNA that is part of the RNA/DNA duplex. These functions work together to create double-stranded linear DNA from RNA, which can then be incorporated into the host genome | ||
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When polymerase activity begins, reverse transcriptase binds to the nucleic acid substrate. This results in a conformational change in the position of the p66 thumb from a closed conformation to an open conformation. The p66 fingers subdomain then undergoes a conformational change which allows it to close down on the incoming dNTP, helping it to align the 3'-OH of the primer, the alpha-phosphate of the dNTP, and the polymerase active site. This is the rate-limiting step in the polymerization reaction. Following the slow step, phosphodiester bonds are formed between the newly incorporated nucleoside and the primer with the existing pyrophosphate. Eventually the fingers undergo another conformational change so that they can open and release the pyrophosphate from the active site. | When polymerase activity begins, reverse transcriptase binds to the nucleic acid substrate. This results in a conformational change in the position of the p66 thumb from a closed conformation to an open conformation. The p66 fingers subdomain then undergoes a conformational change which allows it to close down on the incoming dNTP, helping it to align the 3'-OH of the primer, the alpha-phosphate of the dNTP, and the polymerase active site. This is the rate-limiting step in the polymerization reaction. Following the slow step, phosphodiester bonds are formed between the newly incorporated nucleoside and the primer with the existing pyrophosphate. Eventually the fingers undergo another conformational change so that they can open and release the pyrophosphate from the active site. | ||
The RNase H activity of [[reverse transcriptase]] is not currently well known. Because so much is known about the activity of polymerase, this is typically the target for | The RNase H activity of [[reverse transcriptase]] is not currently well known. Because so much is known about the activity of polymerase, this is typically the target for reverse transcriptase inhibitors. | ||
[[Image:RT polymerase+nuclease.gif]] | [[Image:RT polymerase+nuclease.gif]] | ||
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[[3kli]] - P66/P51 (mutant)<br /> | [[3kli]] - P66/P51 (mutant)<br /> | ||
[[3kle]], [[3klg]], [[3klh]] – P66/P51 (mutant) + DNA | [[3kle]], [[3klg]], [[3klh]] – P66/P51 (mutant) + DNA | ||
==Additional Information== | |||
For additional information, see [[HIV]]<br/> | |||
==References== | ==References== | ||
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"Science." ''AIDS & HIV Information from the AIDS Charity AVERT.'' Web. 15 Nov. 2010. <http://www.avert.org/>. | "Science." ''AIDS & HIV Information from the AIDS Charity AVERT.'' Web. 15 Nov. 2010. <http://www.avert.org/>. | ||
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