Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance

Wensing, Annemarie M. J.; Maarseveen, Noortje M van; Nijhuis, Monique

doi:10.1016/j.antiviral.2009.10.003

Cited by 297 publications

(272 citation statements)

References 152 publications

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“…European guidelines now recommend that if adherence is questionable, as is often seen in teenagers, a PI‐based regimen should be initiated because of its higher genetic barrier to resistance 3, 20. Many of the participants with perinatal HIV infection on PI‐based regimens in our study would have been on lopinavir/r regimens, which are unpopular among adolescents as they require twice‐daily administration, but now both darunavir and atazanavir are available to adolescents in once‐daily formulations and have better tolerability.…”

Section: Discussionmentioning

confidence: 99%

Higher rates of triple‐class virological failure in perinatally HIV‐infected teenagers compared with heterosexually infected young adults in Europe

et al. 2016

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ObjectivesThe aim of the study was to determine the time to, and risk factors for, triple‐class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection.MethodsWe analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15–29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV‐1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI.ResultsThe median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4–111) vs. 8 (IQR 2–38) weeks, respectively], and highest in perinatally infected participants aged 10–14 years [49 (IQR 9–267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0−12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9−5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10–14 years when starting ART (27.7%; 95% CI 13.2−42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10–14 years, African origin, pre‐ART AIDS, NNRTI‐based initial regimens, higher pre‐ART viral load and lower pre‐ART CD4.ConclusionsThe results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

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Section: Discussionmentioning

confidence: 99%

Higher rates of triple‐class virological failure in perinatally HIV‐infected teenagers compared with heterosexually infected young adults in Europe

et al. 2016

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“…The chimeric FIV/HIV system demonstrated that HIV-1 PR inhibitors with broad-spectrum properties, such as LPV, DRV, and TL-3, can be distinguished using comparative studies of WT and chimeric FIVs, both in vitro and ex vivo. DRV and LPV are new FDA-approved HIV-1 PR inhibitors that are effective against WT HIV-1 and many drug-resistant HIV-1 mutants, and they have high genetic barriers (i.e., they require many mutations for drug resistance to develop) (3,33,53). Conversely, RTV, an older HIV-1 PR inhibitor, was not very potent against the 6s-98S/H PRs; it also displays a lower genetic barrier and is not as effective against many of the common drug-resistant mutants found in HIV-1 PR.…”

Section: Discussionmentioning

confidence: 99%

“…There are currently nine FDA-approved PR inhibitors for the treatment of patients infected with human immunodeficiency virus type 1 (HIV-1): saquinavir (SQV), indinavir (IDV), nefinavir (NFV), amprenavir (APV), atazanavir (ATV), ritonavir (RTV), lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). In combination with reverse transcriptase (RT) inhibitors, multidrug therapy has dramatically reduced the mortality rate and improved the quality of life for infected patients (2,27,44,53). In spite of the success of drug development and chemotherapy, however, the continuous selection and emergence of viral variants resistant to these inhibitors and the generation of cross-resistant mutants remain major challenges to drug development.…”

mentioning

confidence: 99%

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

Lin¹,

Torbett

Elder³

2010

J Virol

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Feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1) proteases (PRs)share only 23% amino acid identity and exhibit distinct specificities yet have very similar 3-dimensional structures. Chimeric PRs in which HIV residues were substituted in structurally equivalent positions in FIV PR were prepared in order to study the molecular basis of PR specificity. Previous in vitro analyses showed that such substitutions dramatically altered the inhibitor specificity of mutant PRs but changed the rate and specificity of Gag cleavage so that chimeric FIVs were not infectious. Chimeric PRs encoding combinations of the I37V, N55M, M56I, V59I, L97T, I98P, Q99V, and P100N mutations were cloned into FIV Gag-Pol, and those constructs that best approximated the temporal cleavage pattern generated by wild-type FIV PR, while maintaining HIV-like inhibitor specificity, were selected. Two mutations, M56I and L97T, were intolerant to change and caused inefficient cleavage at NC-p2. However, a mutant PR with six substitutions (I37V, N55M, V59I, I98P, Q99V, and P100N) was selected and placed in the context of full-length FIV-34TF10. This virus, termed YCL6, had low-level infectivity ex vivo, and after passage, progeny that exhibited a higher growth rate emerged. The residue at the position of one of the six mutations, I98P, further mutated on passage to either P98H or P98S. Both PRs were sensitive to the HIV-1 PR inhibitors lopinavir (LPV) and darunavir (DRV), as well as to the broad-based inhibitor TL-3, with 50% inhibitory concentrations (IC 50 ) of 30 to 40 nM, consistent with ex vivo results obtained using mutant FIVs. The chimeras offer an infectivity system with which to screen compounds for potential as broad-based PR inhibitors, define structural parameters that dictate specificity, and investigate pathways for drug resistance development.

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“…aspartyl protease | protease mechanism | transition-state structure | drug design H uman immunodeficiency virus-1 (HIV-1) protease is an essential enzyme for the HIV-1 viral life cycle and is the target of nine drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV/AIDS (1). HIV-1 protease inhibitors are administered as part of a drug combination in a treatment termed highly active antiretroviral therapy (HAART), which has become the most effective therapeutic strategy since the discovery of the virus.…”

mentioning

confidence: 99%

“…Nevertheless, mutations in viral enzymes that reduce drug affinity but not catalytic activity continue to breed resistance to HAART. Several mutations in HIV-1 protease have been identified, and resistance to all nine FDAapproved drugs has been reported (1,2). Accordingly, attempts to improve inhibitor quality continue with a common goal of increasing the specificity and affinity of enzyme-drug interactions.…”

mentioning

confidence: 99%

Transition states of native and drug-resistant HIV-1 protease are the same

Kipp¹,

Hirschi²,

Wakata³

et al. 2012

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

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HIV-1 protease is an important target for the treatment of HIV/ AIDS. However, drug resistance is a persistent problem and new inhibitors are needed. An approach toward understanding enzyme chemistry, the basis of drug resistance, and the design of powerful inhibitors is to establish the structure of enzymatic transition states. Enzymatic transition structures can be established by matching experimental kinetic isotope effects (KIEs) with theoretical predictions. However, the HIV-1 protease transition state has not been previously resolved using these methods. We have measured primary 14 at the carbonyl carbon, proton transfer to the amide nitrogen leaving group, and C-N bond cleavage. A transition structure consistent with the KIE values involves proton transfer from the active site Asp-125 (1.32 Å) with partial hydrogen bond formation to the accepting nitrogen (1.20 Å) and partial bond loss from the carbonyl carbon to the amide leaving group (1.52 Å). The KIEs measured for the native and I84V enzyme indicate nearly identical transition states, implying that a true transition-state analogue should be effective against both enzymes.aspartyl protease | protease mechanism | transition-state structure | drug design

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Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance

Cited by 297 publications

References 152 publications

Higher rates of triple‐class virological failure in perinatally HIV‐infected teenagers compared with heterosexually infected young adults in Europe

Higher rates of triple‐class virological failure in perinatally HIV‐infected teenagers compared with heterosexually infected young adults in Europe

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

Transition states of native and drug-resistant HIV-1 protease are the same

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