No association found between the detection of either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus and chronic fatigue syndrome in a blinded, multi-site, prospective study by the establishment and use of the SolveCFS BioBank.

Background: In 2009, a retrospective study reported the detection of xenotropic murine leukemia virus-related virus (XMRV) in clinical isolates derived from individuals with chronic fatigue syndrome or myalgic encephalomyelitis (CFS). While many efforts to confirm this observation failed, one report detected polytropic murine leukemia virus (pMLV), instead of XMRV. In both studies, Polymerase Chain Reaction (PCR)-based methods were employed which could provide the basis for the development of a practical diagnostic tool.

Pyridopyrimidinone inhibitors of HIV-1 RNase H.

Using a structure based pharmacophore design, a weak inhibitor of RNase H, identified from a small library of two metal binding HIV-1 integrase inhibitors, was optimized for potency and physicochemical properties. This manuscript describes the SAR and in vivo DMPK for the pyridopyrimidinone class of inhibitors.

Inhibition of the ribonuclease H activity of HIV-1 reverse transcriptase by GSK5750 correlates with slow enzyme-inhibitor dissociation.

Compounds that efficiently inhibit the ribonuclease (RNase) H activity of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have yet to be developed. Here, we demonstrate that GSK5750, a 1-hydroxy-pyridopyrimidinone analog, binds to the enzyme with an equilibrium dissociation constant (K(d)) of ~400 nM. Inhibition of HIV-1 RNase H is specific, as DNA synthesis is not affected.

Sensitivity of phenotypic susceptibility analyses for nonthymidine nucleoside analogues conferred by K65R or M184V in mixtures with wild-type HIV-1.

Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy.Consistent with this notion were (1) the presence of low level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus.

Differential impact of thymidine analogue mutations on emtricitabine and lamivudine susceptibility.

The impact of drug resistance-associated mutations on subsequent antiretroviral therapy is an important consideration in managing treatment-experienced, HIV-1-infected patients. Lamivudine (3TC) and emtricitabine (FTC) are structurally related nucleoside reverse transcriptase inhibitors (NRTIs) approved for use in HIV-1-infected individuals. To evaluate whether susceptibility differences exist between lamivudine and emtricitabine, the phenotypic impact of common NRTI resistance-associated mutations was compared in HIV-1 from patient samples with paired FTC and 3TC susceptibility results.

Nucleoside and nucleotide analogue reverse transcriptase inhibitors: a clinical review of antiretroviral resistance.

Although advances in highly active antiretroviral therapy (HAART) have made long-term suppression of HIV an achievable goal of therapy, a substantial proportion of first-line regimens will eventually fail. Successful longterm treatment requires consideration of downstream treatment options at the time of initiating or changing regimens. An understanding of the patterns and interactions of resistance mutations, and the appropriate use of genotypic and phenotypic testing is an important component of successful drug sequencing.