Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides.

Abstract

A set of mutations [Ala-62 -> Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain of reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides and has been seen in HIV-1 variants isolated from patients receiving combination chemotherapy with 3'-azido-3'-deoxythymidine (AZT) plus 2',3'-dideoxycytidine (ddC) or 2',3'-dideoxyinosine (ddl). The IC50 values of AZT, ddC, ddI, 2',3'-dideoxyguanosine, and 2',3'-didehydro-3'-deoxythymidine against an infectious clone constructed to include the five mutations were significantly higher than those of a wild-type infectious clone. The Ki value for AZT 5'-triphosphate determined for the virus-associated RT from a posttherapy strain was 35-fold higher than that of RT from a pretherapy strain. Detailed analysis of HIV-1 strains isolated at various times during therapy showed that the Q151M mutation developed first in vivo, at the time when the viremia level suddenly increased, followed by the F116Y and F77L mutations. All five mutations ultimately developed, and the viremia level rose even further. Analyses based on the three-dimensional structure of HIV-1 RT suggest that the positions where at least several of the five mutations occur are located in close proximity to the proposed dNTP-binding site of RT and the first nucleotide position of the single-stranded template.

Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants.

“…An influence of the G190->E substitution with respect to the ddA/ddl-resistant phenotype exerted by the L74--V alteration could also be assumed. V75->I-containing multiple mutant RTs were recently found to be associated with drug-resistance in a few HIV-1 infected patients who underwent NRTI combination therapy with AZT and ddl or AZT and 2',3'-dideoxycytidine (ddC) (27,28 The most likely explanation for the selective advantage of the mutations in codon 74 and codon 75 is an enhanced polymerase activity of the resulting enzymes, as observed with the V75->I/G190->E RT (Table 1). At this point it could be speculated that, i.e., the nature of the enzyme fusion used could affect the activity of certain recombinant RTs relative to wt.…”

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

“…Those mutations that confer moderate (4-to Ͻ50-fold) levels of phenotypic resistance to 3TC reported previously always appeared in the context of a constellation of mutations that confer resistance to multiple nucleoside analogues or as a cross-resistance phenomenon that appears with the emergence of resistance to another nucleoside analogue. This has been the case for the nucleoside multidrug resistance complex of mutations Q151M, F77L, F116Y, A62V, and V75I, although the increase in the level of phenotypic resistance to 3TC in viruses that harbor those mutations is slight (9,20,24,25). In the case of the insertion mutations near position 69 of RT, a notable increase in the frequency of 3TC resistance has been reported together with an increased frequency of phenotypic resistance to other nucleosides (2, 17, 29).…”

Analysis of mutations at positions 115 and 116 in the dNTP binding site of HIV-1 reverse transcriptase

“…Recently, the Tyr-115-Phe mutation, along with the mutations Lys-65-Arg, Leu-74-Val, and Met-184-Val, has been detected in HIV-1 RTs resistant to the carbocyclic nucleoside analog 1592U89 (abacavir) (15,16). The effects of amino acid substitutions at residue 116 have been less well characterized (7,8), although the amino acid substitution Phe-116-Tyr is one of the mutations present in an RT variant resistant to multiple dideoxynucleotides (17)(18)(19). In this study, we have analyzed the effects of mutations Tyr-115-Phe, Tyr-115-Val, and Phe-116-Tyr in the nucleotide-binding pocket on the activity of HIV-1 RT.…”