Human Immunodeficiency Virus Types 1 and 2 Exhibit Comparable Sensitivities to Zidovudine and Other Nucleoside Analog Inhibitors In Vitro

Smith, Robert A.; Gottlieb, Geoffrey S.; Anderson, Donovan J.; Pyrak, Crystal L.; Preston, Bradley D.

doi:10.1128/aac.01004-07

Cited by 33 publications

(34 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the overall sensitivity of HIV-2 to NRTIs, some articles have suggested that HIV-2 may be naturally resistant to certain NRTIs such as zidovudine (ZDV) (41). However, a recent study claimed that HIV-1 and HIV-2 display comparable sensitivities to ZDV and other NRTIs in vitro (48).…”

mentioning

confidence: 99%

Nucleoside and Nucleotide Analogs Select in Culture for Different Patterns of Drug Resistance in Human Immunodeficiency Virus Types 1 and 2

Ntemgwa

Toni

Brenner

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Recent findings suggest bidirectional antagonisms between the K65R mutation and thymidine analogue mutations in human immunodeficiency virus type 1 (HIV-1)-infected, treatment-experienced patients, yet little is known about HIV-2 in this regard. This study addressed the effects of innate polymorphisms in HIV-2 on emergent resistance to nucleoside/nucleotide analogues. Emergent drug resistance profiles in HIV-2 subtypes A (n ‫؍‬ 3) and B (n ‫؍‬ 1) were compared to those of HIV-1 subtypes B and C. Drug resistance was evaluated with cord blood mononuclear cells (CBMCs) and MT2 cells, using selective pressure with tenofovir (TFV), zidovudine (ZDV), stavudine (d4T), didanosine (ddI), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), or various dual-drug combinations. Resistance was evaluated using conventional and ultrasensitive sequencing approaches. In agreement with our previous findings, dual-drug combinations of TFV, ddI, ABC, d4T, ZDV, and 3TC preferentially selected for K65R in HIV-1 subtype C isolates. In HIV-1 subtype B, TFV-3TC and ZDV-3TC selected for M184I and D67N, respectively. In contrast, selections with all four HIV-2 cultures favored the development of M184I in dual-drug combinations that included either 3TC or FTC. Since HIV-2 cultures did not develop K65R, an ultrasensitive allele-specific real-time PCR assay was developed to distinguish the presence of 65R from wild-type K65 after 16 cycles with a discriminatory ability of 0.1% against a population of wild-type virus. These results underscore potential differences in emergent drug resistance pathways in HIV-1 and HIV-2 and show that polymorphisms may influence the development of the resistance pathways that are likely to emerge.

show abstract

mentioning

confidence: 99%

Nucleoside and Nucleotide Analogs Select in Culture for Different Patterns of Drug Resistance in Human Immunodeficiency Virus Types 1 and 2

Ntemgwa

Toni

Brenner

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…We have previously shown that these isolates exhibit comparable susceptibilities to FDAapproved NRTIs in the MAGIC-5A cell line, with EC 50 s that differ by 2-fold or less between the two strains (53). In the present study, we performed a total of 10 independent assay runs in which the sensitivity of HIV-1 NL4-3 and HIV-2 ROD9 to MK-8591 was tested head-to-head (e.g., Fig.…”

mentioning

confidence: 99%

“…A detailed description of the assay protocol has been provided elsewhere (32). Importantly, this methodology directly quantifies antiviral activity in a single round of HIV infection (as opposed to measuring virus-induced cell death or viral protein release following multiple rounds of HIV replication), and the resultant EC 50 s are not affected by strain-specific differences in replication rate, infectivity, cytopathic potential, or cell-to-cell spread (32,53,54). The 50% cytotoxic concentration (CC 50 ) for MK-8591 in MAGIC-5A cells was Ͼ100 nM, as determined using the CellTiter Glo assay (Promega) (32).…”

mentioning

confidence: 99%

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

Smith

Masoum

et al. 2017

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

There is a pressing need to identify more effective antiretroviral drugs for HIV-2 treatment. Here, we show that the investigational compound MK-8591 (4=-ethynyl-2-fluoro-2=-deoxyadenosine [EFdA]) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC 50 ] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC 50 Յ 11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals.

show abstract

“…Both 3TC and ZDV have activity against different subtypes of wild-type HIV-1 and both are also active against HIV-2, although the effectiveness in HIV-2 infected patients is not fully established. [13][14][15] The in vitro 50% effective concentration (EC 50 ) against HIV-1 is approximately 1 μM (230 ng/mL) for 3TC and 0.01 μM (2.7 ng/mL) for ZDV, but several factors influence this value such as the cell-type used for the assay and the subtype of HIV-1 or HIV-2 studied. 8 As one measure of potency in vivo, ZDV monotherapy reduces HIV-RNA in plasma of antiretroviral naïve individuals by about 0.85 log 10 copies/mL whereas 3TC monotherapy reduces plasma HIV-RNA by about 1.5 log 10 copies/mL.…”

Section: Mechanism Of Pharmacologic Actionmentioning

confidence: 99%

Zidovudine and Lamivudine for HIV Infection

Anderson

Rower²

2010

Clinical Medicine Reviews in Therapeutics

View full text Add to dashboard Cite

Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog-reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV-associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine.

show abstract

Human Immunodeficiency Virus Types 1 and 2 Exhibit Comparable Sensitivities to Zidovudine and Other Nucleoside Analog Inhibitors In Vitro

Cited by 33 publications

References 25 publications

Nucleoside and Nucleotide Analogs Select in Culture for Different Patterns of Drug Resistance in Human Immunodeficiency Virus Types 1 and 2

Nucleoside and Nucleotide Analogs Select in Culture for Different Patterns of Drug Resistance in Human Immunodeficiency Virus Types 1 and 2

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

Zidovudine and Lamivudine for HIV Infection

Contact Info

Product

Resources

About