The Body PRO Covers: The 9th Conference on Retroviruses and Opportunistic Infections

New Insights Into Mechanisms of HIV-1 Resistance to Reverse Transcriptase Inhibitors (Plenary Session 22)

February 27, 2002

Dr. Mellors presented a thorough review of the biochemical and structural relationship of resistance to reverse transcriptase (RT). After HIV infects a cell, the viral RNA must be reverse transcribed by the HIV reverse transcriptase to a DNA copy. The resulting HIV DNA is then transported to the nucleus of the cell where it is incorporated into the host cell DNA in order for viral replication to begin anew.

The normal building blocks required for HIV RNA to become DNA are linked together by specific chemical interactions. Nucleoside reverse transcriptase inhibitors (NRTIs) inhibit HIV replication through a process known as chain termination. NRTIs are modified copies of the normal building blocks that do not allow HIV DNA to be assembled. That is, they substitute for the normal building blocks of HIV DNA and interrupt the DNA architecture. There are currently seven U.S. FDA-approved NRTIs.

Resistance to NRTIs has been described for all these agents. Resistance is the result of changes in the amino acid sequence that results from ongoing viral replication in the presence of drug. The reverse transcriptase enzyme that is responsible for making the DNA copy from the viral RNA has a three dimensional structure. The amino acid changes known to confer drug resistance have been mapped to areas within the enzyme involved in the RT's role in viral replication. These amino acid changes result in a structural change of the RT enzyme. This structural change renders the HIV drugs ineffective and therefore viral replication is allowed to continue.

Dr. Mellors presented several examples of how resistance changes affect the activity of HIV drugs. For example, the M184V mutation that confers resistance to 3TC (Lamivudine) changes the RT enzyme structure so that incorporation of 3TC into the growing HIV DNA is markedly reduced. In comparison, mutations that confer resistance to AZT do not affect incorporation, but instead increase the removal of AZT from within the enzyme.

A somewhat different result is achieved with the recently approved drug, tenofovir. Tenofovir has been found to have less cross resistance with other NRTIs and remains active in the presence of multiple mutations in RT. 3TC and AZT have relatively rigid structures and therefore are rendered inactive in an RT enzyme whose structure has been changed by resistant mutations. Tenofovir has a flexible structure that allows it to fit and remain active in a highly resistant RT enzyme that results in inefficient removal of tenofovir, and so it remains active when AZT and 3TC would not. However, there is an accumulative effect which, after four or more AZT-associated mutations are present, results in complete resistance for all NRTIs. If 3TC resistance is present in addition to AZT resistance, AZT resistance can be reversed.

All of these mutations result in a structural change to RT that allows AZT to work again. To further complicate matters, recently identified mutations are now known to confer AZT/3TC co-resistance. Additionally, AZT-associated mutations are also known to confer resistance to d4T and as stated above, all NRTIs. Clinically, we want to avoid development of these mutations by utilizing NRTIs effectively in combination with other HIV drugs. We want to achieve undetectable viral loads and in turn, turn off viral replication, which will prevent the development of these critical mutations. Further, having a better understanding of how these mutations affect the NRTI class will allow for more effective drug discovery and testing.

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