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Failure of antiretroviral therapy: role of viral and cellular factors.

Effective therapy of human immunodeficiency virus (HIV) infection is mainly based on inhibition of reverse transcriptase by nucleoside analogues such as zidovudine (azidothymidine; AZT), didanosine, and zalcitabine. A major problem associated with long-term AZT therapy is the waning efficacy ('clinical resistance') over time. Clinical isolates of HIV-1 with reduced susceptibility to AZT can be recovered from HIV-infected individuals under prolonged treatment. However, the clinical importance of AZT resistance is uncertain. Other factors such as increased virus burden, increased virulence, and AZT toxicity could contribute, singly or in combination, to the loss of therapeutic benefit. Recent observations based on experimental models and clinical trials suggest that cellular mechanisms ('cellular resistance') may account for clinical resistance to antiviral agents. In vitro experiments demonstrated that in analogy to antitumoral therapy, the acquisition of multidrug resistance, i.e., resistance of cells to multiple, structurally unrelated chemotherapeutic agents, may play a role in the failure of long-term antiretroviral therapy. The 'cellular resistance' may contribute directly to the failure of antiviral therapy by the generation of subtherapeutic levels of antiviral compounds and/or their active forms. Indirectly, such subtherapeutic concentrations of active substances which permit limited replication of virus may represent a selective pressure for emergence and development of a resistant virus population. Hence it is of great importance to investigate the role of cellular factors in 'clinical resistance' to AZT and other anti-HIV agents. More detailed knowledge of cellular interactions and antiviral agents could help to improve or develop new strategies for antiviral therapy regimens.