The evolution of drug resistance is a major complication of human immunodeficiency virus type 1 (HIV-1) chemotherapy. HIV-1 reverse transcriptase (RT) is a major target of antiretroviral therapy and ultimately the target of drug resistance mutations. Previous studies have indicated that drug-resistant HIV-1 RTs can alter HIV-1 mutant frequencies. In this study, we have tested a panel of HIV-1 RT variants for their ability to influence virus mutant frequencies. The RT variants tested included drug-resistant RT variants as well as other variants analyzed in enzyme fidelity studies with the lacZ␣ gene as a mutation target and/or implicated as being important for enzyme fidelity by structural studies. Combinations of mutations that alone had a statistically significant influence on virus mutant frequencies resulted in different mutant frequency phenotypes. Furthermore, when virus replication occurred in the presence of drugs [e.g., 3-azido-3-deoxythymidine, (؊)2/,3-dideoxy-3-thiacytidine, hydroxyurea, thymidine, or thioguanine] with selected RT variants, virus mutant frequencies increased. Similarly, Vpr variants deficient for binding to the uracil DNA glycosylase repair enzyme were observed to influence HIV-1 virus mutant frequencies when tested alone or in combination with RT variants. In summary, these observations indicate that HIV-1 mutant frequencies can significantly change by single amino acid substitutions in RT and that these effects can be altered by additional mutations in RT, by drugs, and/or by expression of Vpr variants. Such altered virus mutant frequencies could impact HIV-1 dynamics and evolution in small population sizes.
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.
Two RNA stem-loop structures in the gag gene have been implicated as representing the primary encapsidation (packaging) signal for bovine leukemia virus (BLV), a member of the Delta retrovirus of the Retroviridae. In this study, we conducted an analysis of these RNA structures, stem loop 1 (SL1) and stem loop 2 (SL2), to determine if both the loop and the stem nucleotide bases are important for RNA encapsidation. We have found that the primary sequence of the unpaired bases located in the loop regions of both SL1 and SL2 are important for efficient RNA encapsidation and virus replication. The primary sequence of the bases that form the stems for both SL1 and SL2 was observed to aid in efficient encapsidation and replication. We also observed that the order of SL1 and SL2 is important for RNA encapsidation and virus replication efficiency. A viral RNA with two copies of either SL1 or SL2 was found to replicate and package RNA as efficiently as a viral RNA with only one copy of SL1 or SL2. This provides evidence that SL1 and SL2 are not functionally equivalent. Sequences from human T cell leukemia virus type 1 (HTLV-1) that are located in the same region of HTLV-1 as the SL1 and SL2 of BLV were used to replace the BLV SL1, SL2, or both in a BLV RNA. These BLV RNAs were still encapsidated and replicated, suggesting that these sequences may function as an encapsidation signal in HTLV-1. The chimeric RNAs did not replicate as well as the parental, indicating that the primary nucleotide sequence along with the secondary and tertiary structure of the RNA plays a role in efficient RNA encapsidation and replication.
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