Combination of Drugs and Drug-Resistant Reverse Transcriptase Results in a Multiplicative Increase of Human Immunodeficiency Virus Type 1 Mutant Frequencies

Abstract

Replication of drug-resistant human immunodeficiency virus type 1 (HIV-1) in the presence of drug can lead to the failure of antiretroviral drug treatment. Drug failure is associated with the accumulation of drug resistance mutations. Previous studies have shown that 3-azido-3-deoxythymidine (AZT), (؊)2,3-dideoxy-3-thiacytidine (3TC), and AZT-resistant HIV-1 reverse transcriptase (RT) can increase the virus in vivo mutation rate. In this study, the combined effects of drug-resistant RT and antiretroviral drugs on the HIV-1 mutant frequency were determined. In most cases, a multiplicative effect was observed with AZT-resistant or AZT/3TC dually resistant RT and several drugs (i.e., AZT, 3TC, hydroxyurea, and thymidine) and led to increases in the odds of recovering virus mutants to over 20 times that of the HIV-1 mutant frequency in the absence of drug or drug-resistance mutations. This observation indicates that HIV-1 can mutate at a significantly higher rate when drug-resistant virus replicates in the presence of drug. These increased mutant frequencies could have important implications for HIV-1 population dynamics and drug therapy regimens.

Influence of Reverse Transcriptase Variants, Drugs, and Vpr on Human Immunodeficiency Virus Type 1 Mutant Frequencies

“…Previous studies have indicated that both RT variants and drugs could increase virus mutant frequencies (42,43). Several of the RT variants identified in Table 1 were found to significantly decrease virus mutant frequencies.…”

“…Previous studies have shown that some drug-resistant RT enzymes can influence virus mutant frequencies and the virus mutation rate (42,43). In particular, two zidovudine (AZT)-resistant enzymes with multiple mutations, i.e., M41L/T215Y and M41L/D67N/K70R/T215Y, were found to increase the mutation rate by factors of 3.3 and 4.3, respectively (42).…”

“…The virus mutant frequency of the HIV-1 vector containing the lacZ␣ peptide gene with Y115A RT in the presence of AZT was 18 times higher than that observed when wt RT was used in virus replication in the absence of drug. The increase in virus mutant frequency follows a multiplicative model (43). When Y115A RT was used with W54R * Vpr in the presence of 0.4 M AZT, the virus mutant frequency was 25 times higher than during replication with wt RT, wt Vpr, and no drug ( Table 6).…”

Cross-Clade Inhibition of Recombinant Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus SIVcpz Reverse Transcriptases by RNA Pseudoknot Aptamers

“…The HIV-1 enzymes are, in general, slightly more active than their HIV-2 counterparts (14,27,49,56), which has been proposed to contribute to the greater virulence of the HIV-1 strains than of the HIV-2 strains (19,44). Many of the same factors that drive rapid viral evolution and diversification of the M group (7,8,17,40,43) have also contributed to the rapid appearance of drug resistance mutations in the RT and protease (PR) genes.…”

A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity

“…The polymerase of one isolate of 3TC-resistant virus contains a mutation, M184V, which is thought to result in reduced incorporation of chain-terminating nucleotide analogs (7). The M184V reverse transcriptase may display altered fidelity of DNA synthesis, though there is some controversy as to whether fidelity is increased or decreased (7)(8)(9)(10)(11). Could variants of RNA viruses with increased replicative fidelity display resistance to ribavirin?…”