AZT-resistant HIV-1 reverse transcriptase

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

Human Immunodeficiency Virus (HIV) specifically attacks CD4 Helper T cells 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 subunits: 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.