Measuring Enzymatic HIV-1 Susceptibility to Two Reverse Transcriptase Inhibitors as a Rapid and Simple Approach to HIV-1 Drug-Resistance Testing

Simple and cost-effective approaches for HIV drug-resistance testing are highly desirable for managing increasingly expanding HIV-1 infected populations who initiate antiretroviral therapy (ART), particularly in resource-limited settings. Non-nucleoside reverse trancriptase inhibitor (NNRTI)-based regimens with an NRTI backbone containing lamivudine (3TC) or emtricitabine (FTC) are preferred first ART regimens. Failure with these drug combinations typically involves the selection of NNRTI- and/or 3TC/FTC- resistant viruses. Therefore, the availability of simple assays to measure both types of drug resistance is critical. We have developed a high throughput screening test for assessing enzymatic resistance of the HIV-1 RT in plasma to 3TC/FTC and NNRTIs. The test uses the sensitive “Amp-RT” assay with a newly-developed real-time PCR format to screen biochemically for drug resistance in single reactions containing either 3TC-triphosphate (3TC-TP) or nevirapine (NVP). Assay cut-offs were defined based on testing a large panel of subtype B and non-subtype B clinical samples with known genotypic profiles. Enzymatic 3TC resistance correlated well with the presence of M184I/V, and reduced NVP susceptibility was strongly associated with the presence of K103N, Y181C/I, Y188L, and G190A/Q. The sensitivity and specificity for detecting resistance were 97.0% and 96.0% in samples with M184V, and 97.4% and 96.2% for samples with NNRTI mutations, respectively. We further demonstrate the utility of an HIV capture method in plasma by using magnetic beads coated with CD44 antibody that eliminates the need for ultracentifugation. Thus our results support the use of this simple approach for distinguishing WT from NNRTI- or 3TC/FTC-resistant viruses in clinical samples. This enzymatic testing is subtype-independent and can assist in the clinical management of diverse populations particularly in resource-limited settings

Prevalence of Transmitted Drug Resistance and Impact of Transmitted Resistance on Treatment Success in the German HIV-1 Seroconverter Cohort

BACKGROUND: The aim of this study is to analyse the prevalence of transmitted drug resistance, TDR, and the impact of TDR on treatment success in the German HIV-1 Seroconverter Cohort. METHODS: Genotypic resistance analysis was performed in treatment-naïve study patients whose sample was available 1,312/1,564 (83.9% October 2008). A genotypic resistance result was obtained for 1,276/1,312 (97.3%). The resistance associated mutations were identified according to the surveillance drug resistance mutations list recommended for drug-naïve patients. Treatment success was determined as viral suppression below 500 copies/ml. RESULTS: Prevalence of TDR was stable at a high level between 1996 and 2007 in the German HIV-1 Seroconverter Cohort (N = 158/1,276; 12.4%; CI(wilson) 10.7-14.3; p(for trend) = 0.25). NRTI resistance was predominant (7.5%) but decreased significantly over time (CI(Wilson): 6.2-9.1, p(for trend) = 0.02). NNRTI resistance tended to increase over time (NNRTI: 3.5%; CI(Wilson): 2.6-4.6; p(for trend)= 0.07), whereas PI resistance remained stable (PI: 3.0%; CI(Wilson): 2.1-4.0; p(for trend) = 0.24). Resistance to all drug classes was frequently caused by singleton resistance mutations (NRTI 55.6%, PI 68.4%, NNRTI 99.1%). The majority of NRTI-resistant strains (79.8%) carried resistance-associated mutations selected by the thymidine analogues zidovudine and stavudine. Preferably 2NRTI/1PIr combinations were prescribed as first line regimen in patients with resistant HIV as well as in patients with susceptible strains (susceptible 45.3%; 173/382 vs. resistant 65.5%; 40/61). The majority of patients in both groups were treated successfully within the first year after ART-initiation (susceptible: 89.9%; 62/69; resistant: 7/9; 77.8%). CONCLUSION: Overall prevalence of TDR remained stable at a high level but trends of resistance against drug classes differed over time. The significant decrease of NRTI-resistance in patients newly infected with HIV might be related to the introduction of novel antiretroviral drugs and a wider use of genotypic resistance analysis prior to treatment initiation

Minority HIV-1 Drug Resistance Mutations Are Present in Antiretroviral Treatment–Naïve Populations and Associate with Reduced Treatment Efficacy

Using real-time PCR to detect HIV resistance mutations present at low levels, Jeffrey Johnson and colleagues investigate prevalence and clinical implications of minority transmitted mutations

Search for B0→π0π0B^{0}\to \pi^{0}\pi^{0} Decay

We have searched for the charmless hadronic decay of B0 mesons into two neutral pions. Using 9.13fb^-1 taken at the Upsilon(4S) with the CLEO detector, we obtain an improved upper limit for the branching fraction BR(B0-->pi0pi0) < 5.7*10^-6 at the 90% confidence level.Comment: pages postscript, also available through http://w4.lns.cornell.edu/public/CLN

Search for Zgamma events with large missing transverse energy in ppbar collisions at sqrt(s)=1.96 TeV

We present the first search for supersymmetry (SUSY) in Zgamma final states with large missing transverse energy using data corresponding to an integrated luminosity of 6.2 fb-1 collected with the D0 experiment in ppbar collisions at sqrt(s)=1.96 TeV. This signature is predicted in gauge-mediated SUSY-breaking models, where the lightest neutralino is the next-to-lightest supersymmetric particle (NLSP) and is produced in pairs, possibly through decay from heavier supersymmetric particles. The NLSP can decay either to a Z boson or a photon and an associated gravitino that escapes detection. We exclude this model at the 95% C.L. for SUSY breaking scales of Lambda < 87 TeV, corresponding to neutralino masses of < 151 GeV.Comment: submitted to Phys. Rev. Let

Measurement of Leptonic Asymmetries and Top Quark Polarization in ttbar Production

We present measurements of lepton (l) angular distributions in ttbar -> W+ b W- b -> l+ nu b l- nubar bbar decays produced in ppbar collisions at a center-of-mass energy of sqrt(s)=1.96TeV, where l is an electron or muon. Using data corresponding to an integrated luminosity of 5.4fb^-1, collected with the D0 detector at the Fermilab Collider, we find that the angular distributions of l- relative to anti-protons and l+ relative to protons are in agreement with each other. Combining the two distributions and correcting for detector acceptance we obtain the forward-backward asymmetry A^l_FB = (5.8 +- 5.1(stat) +- 1.3(syst))%, compared to the standard model prediction of A^l_FB (predicted) = (4.7 +- 0.1)%. This result is further combined with the measurement based on the analysis of the l+jets final state to obtain A^l_FB = (11.8 +- 3.2)%. Furthermore, we present a first study of the top-quark polarization.Comment: submitted versio

A search for charged massive long-lived particles

We report on a search for charged massive long-lived particles (CMLLPs), based on 5.2 fb$^{-1}$ of integrated luminosity collected with the D0 detector at the Fermilab Tevatron $p\bar{p}$ collider. We search for events in which one or more particles are reconstructed as muons but have speed and ionization energy loss $(dE/dx)$ inconsistent with muons produced in beam collisions. CMLLPs are predicted in several theories of physics beyond the standard model. We exclude pair-produced long-lived gaugino-like charginos below 267 GeV and higgsino-like charginos below 217 GeV at 95% C.L., as well as long-lived scalar top quarks with mass below 285 GeV.Comment: submitted to Phys. Rev. Letter

Zgamma production and limits on anomalous ZZgamma and Zgammagamma couplings in ppbar collisions at sqrt(s)=1.96 TeV

We present a measurement of ppbar->Zgamma->ll+gamma (l = e, mu) production with a data sample corresponding to an integrated luminosity of 6.2 fb^{-1} collected by the D0 detector at the Fermilab Tevatron ppbar Collider. The results of the electron and muon channels are combined, and we measure the total production cross section and the differential cross section dsigma/dp_T^gamma, where p_T^gamma is the momentum of the photon in the plane transverse to the beamline. The results obtained are consistent with the standard model predictions from next-to-leading order calculations. We use the transverse momentum spectrum of the photon to place limits on anomalous ZZgamma and Zgammagamma couplings

Search for the Higgs boson in lepton, tau and jets final states

We present a search for the standard model Higgs boson in final states with an electron or muon and a hadronically decaying tau lepton in association with two or more jets using 9.7 fb^{-1} of Run II Fermilab Tevatron Collider data collected with the D0 detector. The analysis is sensitive to Higgs boson production via gluon fusion, associated vector boson production, and vector boson fusion, followed by the Higgs boson decay to tau lepton pairs or to W boson pairs. The ratios of 95% C.L. upper limits on the cross section times branching ratio to those predicted by the standard model are obtained for orthogonal subsamples that are enriched in either H -> tau tau decays or H -> WW decays, and for the combination of these subsample limits. The observed and expected limit ratios for the combined subsamples at a Higgs boson mass of 125 GeV are 11.3 and 9.0 respectively

Search for a Narrow ttbar Resonance in ppbar Collisions at sqrt{s}=1.96 TeV

We report a search for a narrow ttbar resonance that decays into a lepton+jets final state based on an integrated luminosity of 5.3/fb of proton-antiproton collisions at sqrt{s}=1.96 TeV collected by the D0 Collaboration at the Fermilab Tevatron Collider. We set upper limits on the production cross section of such a resonance multiplied by its branching fraction to ttbar which we compare to predictions for a leptophobic topcolor Z' boson. We exclude such a resonance at the 95% confidence level for masses below 835 GeV.Comment: 7 pages, 3 figures, submitted to Physical Review Letter