|
|  |
written by Douglas Mayers, M.D.
published on HIVresistanceWeb: February1, 1998
HIV-1 has developed two basic mechanisms to escape pressure from the
immune system: an error-prone reverse transcriptase enzyme and viral
recombination. The virus also uses these escape mechanisms to evade the selection pressure exerted by drugs, by evolving drug-resistant
variants.
HIV-1 reverse transcriptase makes roughly one mistake (mutation) during each round of viral replication. This results in the formation of many closely related variants of HIV-1 (quasispecies)
during virus replication which has been well described. As infection
progresses, a patient will harbor all possible one-base mutants and many possible two-base mutants due to this mechanism. This is the basis for the rapid loss of antiviral activity with monotherapy with 3TC or the nonnucleoside reverse transcriptase inhibitors, such as
nevirapine or delaviridine.
In order to limit viral escape by this mechasnism, combination drug regimens used today target two different viral enzymes: reverse transcriptase and HIV protease. This approach to therapy requires the development of multiple base mutations in two distinct genes for viral escape to occur. Genetic recombination of two viral quasispecies, however, offers the possibility that HIV-1 could stitch together a variant resistant to reverse transcriptase inhibitors with a variant resistant to protease inhibitors leading to the rapid production of a multidrug resistant virus.
Examples of this mechanism have been described from both in vitro studies and in individual patients. As combination therapies are
developed which include drugs directed at novel targets in HIV-1, such as the integrase enzyme or the tat protein, recombination will
increasingly offer an alternative mechanism for the virus to escape drug pressure. This clear and readable review by Burke and colleagues concisely discusses the potential implications of viral recombination in antiviral therapy and vaccine development.
|
|
