A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors

Zhang, Zhijun; Xu, W.; Koh, Yung-hyo; Shim, Jae Hoon; Girardet, Jean‐Luc; Yeh, Li‐Tain; Hamatake, Robert; Hong, Zhi

doi:10.1128/aac.01032-06

Cited by 57 publications

(44 citation statements)

References 13 publications

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“…2). However, the T369I mutation was previously identified as a novel mutation in the RT connection domain in patient-derived viruses with reduced NNRTI and AZT susceptibility (28) and in viruses selected in vitro against the novel NNRTI VRX-480773 (89). The T165K mutation, on the other hand, was previously reported to emerge in vitro during the selection of viruses resistant to the novel NNRTI MK-4965 (38).…”

Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Resistance or Cross-Resistance to Nonnucleoside Reverse Transcriptase Inhibitors Currently under Development as Microbicides

Selhorst

Vázquez

Terrazas-Aranda

et al. 2011

Antimicrob Agents Chemother

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Microbicides based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect women from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when these microbicides are used by undiagnosed HIV-positive women, they could potentially select for viral resistance, which may compromise subsequent therapeutic options. Second, NNRTI-based microbicides that are inactive against NNRTI-resistant strains might promote the selective transmission of these viruses. In order to address these concerns, drug resistance was selected in vitro by the serial passage of three viral isolates from subtypes B and C and CRF02_AG (a circulating recombinant form) in activated peripheral blood mononuclear cells (PBMCs) under conditions of increasing concentrations of three NNRTIs (i.e., TMC120, UC781, and MIV-160) that are currently being developed as candidate microbicides. TMC120 and MIV-160 displayed a high genetic barrier to resistance development, whereas resistance to UC781 emerged rapidly, similarly to efavirenz and nevirapine. Phenotypically, the selected viruses appeared to be highly cross-resistant to current first-line therapeutic NNRTIs (i.e., delavirdine, nevirapine, and efavirenz), although they retained some susceptibility to the more recently developed NNRTIs lersivirine and etravirine. The ability of UC781, TMC120, and MIV-160 to inhibit the in vitro-selected NNRTI-resistant viruses was also limited, although residual activity could be observed for the candidate microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT recombinant NNRTI-resistant viruses (i.e., TMC120-resistant VI829, EFV-resistant VI829, MIV-160-resistant VI829, and EFV-resistant MP568) showed impairments in replicative fitness. Overall, these in vitro analyses demonstrate that due to potential cross-resistance, the large-scale introduction of single-NNRTI-based microbicides should be considered with caution.

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Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Resistance or Cross-Resistance to Nonnucleoside Reverse Transcriptase Inhibitors Currently under Development as Microbicides

Selhorst

Vázquez

Terrazas-Aranda

et al. 2011

Antimicrob Agents Chemother

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“…The following 17 CDMs were identified from scientific literature searches and analyzed in the present study: L283I (5, 13), E312Q (25), G333D (9, 21), G333E (9, 21), G335C (13, 25), G335D (13,25), N348I (9, 10, 12, 25, 37), A360I (25), A360T (13,25), A360V (9,25), V365I (25), T369I (10,38), A371V (4), A376S (25,27), I393L (13), E399D (10,31), and E399G (8).…”

Section: Lists Of Mutationsmentioning

confidence: 99%

Connection Domain Mutations in HIV-1 Reverse Transcriptase Do Not Impact Etravirine Susceptibility and Virologic Responses to Etravirine-Containing Regimens

Gupta¹,

Vingerhoets²,

Fransen³

et al. 2011

Antimicrob Agents Chemother

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Connection domain mutations (CDMs) in HIV-1 reverse transcriptase (RT) alter susceptibility to some nucleoside/nonnucleoside RT inhibitors (NRTIs/NNRTIs). Their effects on susceptibility and virologic responses to etravirine were analyzed. Seventeen CDMs were evaluated: L283I, E312Q, G333D, G333E, G335C, G335D, N348I, A360I, A360T, A360V, V365I, T369I, A371V, A376S, I393L, E399D, and E399G. CDM prevalence and effects on virologic responses were analyzed retrospectively using clinical data. The effects on etravirine susceptibility were assessed in clinical samples and confirmed using site-directed mutants. The most prevalent CDMs (>10%) were A371V, E399D, A376S, N348I, A360T, G333E, and L283I. CDM presence was positively correlated with thymidine analogue-associated mutations, but not with NNRTI resistance-associated mutations (RAMs). The presence or number of CDMs did not significantly reduce etravirine susceptibility, although small reductions were seen in samples with G333D, N348I, A360V, T369I, and A376S. N348I, E399G, and N348I/T369I were associated with reduced etravirine susceptibility when present with K103N, L100I, or Y181C. N348I or T369I was associated with reduced etravirine susceptibility when present with K101P or K103R/ V179D. Virologic responses to an etravirine-containing regimen were slightly diminished when G333D, G335D, or A376S was present, but this was not confirmed in subgroups with higher baseline resistance or without etravirine RAMs. CDMs alone do not confer substantial reductions in etravirine susceptibility but can further reduce etravirine susceptibility in combination with certain NNRTI mutations. Since virologic responses to etravirine were not affected by CDMs, the clinical impacts of these mutations on etravirine susceptibility appear to be minimal.Human immunodeficiency type 1 (HIV-1) reverse transcriptase (RT) is a heterodimer consisting of two subunits, p66 and p51 (18,36). The p66 subunit is composed of three domains. The polymerase domain (amino acids 1 to 318) and active site are situated in the N-terminal region and contain the binding sites for both nucleoside and nonnucleoside RT inhibitors (NRTIs and NNRTIs). The C-terminal region of RT includes the connection domain (amino acids 319 to 426) and the RNase H domain (amino acids 427 to 560) (18,22). The p51 subunit contains identical N-terminal sequences but lacks the C-terminal RNase H domain.Because most known NRTI and NNRTI resistance mutations are clustered around the polymerase active site and the NNRTI binding pocket (17,22,32), routine genotypic analysis of mutations in RT covers the first 300 to 400 N-terminal amino acids. However, recent data have shown that mutations in or near the connection domain of RT are also selected, along with thymidine analogue-associated mutations (TAMs), and can affect both NRTI and NNRTI resistance

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“…There was 36% G190A mutation in that is a no polymorphic mutation selected by NVP and EFV [14,15]. Occurrence mutation of G190A reduces NVP susceptibility more than 50-fold and EFV susceptibility 5 to 10-fold [16,17]. It does not appear to be selected by ETR and RPV to reduce their antiviral activity [18].…”

Section: Discussionmentioning

confidence: 99%

Survey of Antiretroviral Drug Resistance Pattern Among HIV-Infected Patients with Treatment Failure in Iran

Gholami¹

2015

JHVRV

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Antiretroviral Therapy is classified in six classes and acquired great achievements in HIV inhibition, but this advantage can be affected by developing drug resistance. The combinations of antiretroviral (ARV) drugs have been proven as effectiveness key to control the progression of AIDS; however, these benefits may be compromised by drug resistancy. Thus, drug-resistance testing has become an important tool to the management of HIV-infected patients. Viral RNA was extracted from the plasma by using the QIAamp→ Viral RNA kit (Qiagen, Germany) according to the manufacturer's protocol. RT-PCR performed with the one-step PCR kit (Qiagen, Germany) and Nested PCR.

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A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors

Cited by 57 publications

References 13 publications

Human Immunodeficiency Virus Type 1 Resistance or Cross-Resistance to Nonnucleoside Reverse Transcriptase Inhibitors Currently under Development as Microbicides

Human Immunodeficiency Virus Type 1 Resistance or Cross-Resistance to Nonnucleoside Reverse Transcriptase Inhibitors Currently under Development as Microbicides

Connection Domain Mutations in HIV-1 Reverse Transcriptase Do Not Impact Etravirine Susceptibility and Virologic Responses to Etravirine-Containing Regimens

Survey of Antiretroviral Drug Resistance Pattern Among HIV-Infected Patients with Treatment Failure in Iran

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