AZT-resistant HIV-1 reverse transcriptase

Human Immunodeficiency Virus (HIV)Human Immunodeficiency Virus (HIV)

HIV 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 cytosol, 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.

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.

Role of Reverse Transcriptase in HIV ReplicationRole of Reverse Transcriptase in HIV Replication

HIV infects CD4 cells, a type of T Helper cell, within a host's immune system and thus inhibits a host from being able to effectively fight off opportunistic infections. Reverse transcriptase plays a very important role in HIV infection, as it allows the virus to create DNA from its RNA. The creation of DNA allows HIV to incorporate its genetic information into the genome of the host cell. After being incorporated into a host genome, the genetic information from HIV is then replicated each time that the host genome is replicated. This allows HIV to lie dormant in a host before eventually lysing the host cell and releasing many new copies of the virus. The HIV DNA directs that host cell to create and assemble viral particles, thus causing the virus to greatly impact the host immune system.

Reverse transcriptase is essential to the function of HIV. In allowing viral RNA to serve as a template for creating double-stranded DNA, reverse transcriptase greatly contributes to the deadliness of this virus.

Structure of Reverse TranscriptaseStructure of Reverse Transcriptase

Reverse transcriptase is a heterodimer of two related : p66 and p51. These subunits consist of four sub-domains fingers, thumb, palm, and connection, although the positions of the sub-domains relative to each other is different for each subunit.

Inhibition of Reverse Transcriptase ActivityInhibition of Reverse Transcriptase Activity

Approximately half of all anti-HIV drugs target the polymerase activity of reverse transcriptase. Azidothymidine (AZT) is one such medication that affects reverse transcriptase. AZT is classified as a Nucleoside analog Reverse Transcriptase Inhibitor (NRTI), meaning that it is a nucleoside analog which impacts the polymerase activity of the enzyme. AZT is specifically a thymidine analog and AZT-sensitive HIV binds azidothymidine triphosphate (AZTTP) almost as efficiently as DNA thymidine triphosphate (dTTP). When reverse transcriptase binds AZTTP, the polymerase activity is halted. Without completion of polymerase activity, the virus is unable to use its RNA as a template for DNA and incorporate its genetic information into the host genome. Preventing reverse transcriptase from creating viral DNA can greatly impact the progression of the virus by slowing viral replication. This is complicated by the fact that many strains of HIV are able to develop resistance to AZT and other NRTIs.

ReferencesReferences

Sarafianos et al. "Structure and Function of HIV-1 Reverse Transcriptase: Molecular Mechanisms of Polymerization and Inhibition." Journal of Molecular Biology Volume 385, Issue 3. 23 January 2009. 693-713

"Science." AIDS & HIV Information from the AIDS Charity AVERT. Web. 15 Nov. 2010. <http://www.avert.org/>.