HIV and multidrug resistance

Emini, Emilio A.; Graham, Donald J.; Gotlib, Leah; Condra, Jon H.; Byrnes, V W

doi:10.1038/364679b0

Cited by 47 publications

(22 citation statements)

References 7 publications

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“…V106A causes Ͼ30-fold resistance to nevirapine, intermediate resistance to delavirdine, and low-level resistance to efavirenz (18,38,95,108,220,284,290,418). L100I causes intermediate resistance to efavirenz and delavirdine and low-level resistance to nevirapine (37, 38,108,290,403,418).…”

Section: Nnrti Mutations Between Codons 98 and 108mentioning

confidence: 99%

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

2002

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There are 16 approved human immunodeficiency virus type 1 (HIV-1) drugs belonging to three mechanistic classes: protease inhibitors, nucleoside and nucleotide reverse transcriptase (RT) inhibitors, and nonnucleoside RT inhibitors. HIV-1 resistance to these drugs is caused by mutations in the protease and RT enzymes, the molecular targets of these drugs. Drug resistance mutations arise most often in treated individuals, resulting from selective drug pressure in the presence of incompletely suppressed virus replication. HIV-1 isolates with drug resistance mutations, however, may also be transmitted to newly infected individuals. Three expert panels have recommended that HIV-1 protease and RT susceptibility testing should be used to help select HIV drug therapy. Although genotypic testing is more complex than typical antimicrobial susceptibility tests, there is a rich literature supporting the prognostic value of HIV-1 protease and RT mutations. This review describes the genetic mechanisms of HIV-1 drug resistance and summarizes published data linking individual RT and protease mutations to in vitro and in vivo resistance to the currently available HIV drugs

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Section: Nnrti Mutations Between Codons 98 and 108mentioning

confidence: 99%

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

2002

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“…One concern is that HIV-1 may develop multidrug resistance. Indeed, recombinant viruses containing multiple mutations introduced by site-directed mutagenesis show resistance to multiple drugs in vitro (14). However, the emergence of multidrug resistance of HIV-1 in patients receiving combination chemotherapy remains to be studied.…”

mentioning

confidence: 99%

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

Shirasaka

Kavlick

Ueno

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

356

283

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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.

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“…Theoretically this should prevent the development of multi-drug resistance (Chow et al, 1993). It appears, however, that multi-drug-resistant variants can still be selected during such combination therapy (Emini et al, 1993;Larder et al, 1993). Divergent therapy, the more conventional approach for combination regimens, uses antiviral agents that have different mechanisms of action, do not share cross-resistance, and have different dose-limiting toxicities.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Inhibition of Human Immunodeficiency Virus Type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28574) in Combination with Inhibitors of the Virus-Encoded Reverse Transcriptase and Proteinase

Taylor

Brennan

Bridges

et al. 1995

Antivir Chem Chemother

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SummaryThe anti-human immunodeficie~yvirus type 1 (HIV-1) activity of the a-glucosidase 1~nhibitor 6-0-butanoylcastanospermine (MOL 28574) was assessed in combination with the 2',3'-dideoxynucleoside analogues zidovudine (AZT), didanosine (ddl) and zalcitabine (ddC). MOL 28574 was also evaluated in combination with the non-nucleoside reverse transcriptase (RT) inhibitor nevi rapine and the HIV proteinase inhibitor saquinavir (Ro-31-8959). Orug interactions were examined by the isobologram technique and by calculating combination indices (CJ.s). In all cases synergistic inhibition of HIV-1 replication was observed. In three-drug combinations, a marked synergistic antiviral effect was also observed, with Col. values in the range 0.35-0.44 for MOL 28574 in combination with AZT and nevirapine, and in the range 0.34-0.67 for MOL 28574 in combination with AZT and saquinavir. Moreover, the combination of MOL 28574 with other drugs did not produce detrimental effects on cell division. MOL 28574 is currently in clinical trials and may have an important role in combination chemotherapy for HIV infections.

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HIV and multidrug resistance

Cited by 47 publications

References 7 publications

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

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

Synergistic Inhibition of Human Immunodeficiency Virus Type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28574) in Combination with Inhibitors of the Virus-Encoded Reverse Transcriptase and Proteinase

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