Clinical Significance and Biological Basis of HIV Drug Resistance

Abstract

HIV-1 drug resistance has emerged as a major factor that limits the effectiveness of antiviral drugs in treatment regimens. Many studies have shown that the development and transmission of drug-resistant HIV-1 is largely a consequence of incomplete suppressive antiretroviral regimens; HIV-1 drug resistance can significantly diminish the effectiveness and duration of benefit associated with combination therapy for the treatment of HIV/AIDS (D’Aquila et al., 2003; Lorenzi et al., 1999; Quiros-Roldan et al., 2001; Rousseau et al., 2001; Winters et al., 2000; Yeni et al., 2002). Resistance-conferring mutations in both the HIV-1 reverse transcriptase (RT) and protease (PR) genes may precede the initiation of therapy due to both spontaneous mutagenesis and the spread of resistant viruses by sexual and other means. However, it is also generally believed that multiple drug mutations to any single or combination of antiretroviral agents (ARVs) are required in order to produce clinical resistance to most ARVs and that these are in fact selected following residual viral replication in the presence of incompletely suppressive drug regimens (Balotta et al., 2000; de Jong et al., 1996; Mayers, 1999). In the case of the protease inhibitors (PIs) (Condra, 1998; Deeks, 1999; Molla et al., 1996), and most nucleoside analogue reverse transcriptase inhibitors (NRTIs), the development of progressive high-level phenotypic drug resistance follows the accumulation of primary resistance-conferring mutations in each of the HIV-1 PR and RT genes (Frost et al., 2000; Gotte and Wainberg, 2000; Loveday, 2001). Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have low genetic barriers for the development of drug resistance and, frequently, a single primary drug resistance mutation to any one NNRTI may be sufficient to confer high-level phenotypic drug resistance to this entire class of ARVs (Bacheler et al., 2001; Deeks, 2001). Furthermore, differences have also been reported in regard to the development and evolution of antiretroviral drug resistance between subtype B HIV-1 and several group M non-B subtypes. Non-B subtypes, for example, subtype C HIV-1 variants, are known to possess naturally occurring polymorphisms at several RT and PR codons that are implicated in drug resistance (Holguin and Soriano, 2002; Kantor et al., 2002). In some studies, the presence of these polymorphisms did not significantly reduce susceptibility to ARVs in phenotypic resistance assays or limit the