Malcolm John

Abstract:

Objective

Long-acting rilpivirine is a candidate for pre-exposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (RT-E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing Human Leukocyte Antigen (HLA)-B*18 where RT-E138X arises as an immune escape mutation. We investigate the global prevalence, B*18-linkage and replicative cost of RT-E138X and its regional implications for rilpivirine PrEP.

Methods

We analysed linked RT-E138X/HLA data from 7772 patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global RT-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in vitro replication as a surrogate of mutation stability following transmission.

Results

RT-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B*18-positive individuals globally (p=3.5x10-20) and in all HIV-1 subtypes except A. RT-E138X and B*18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman’s R=0.75; p=7.6x10-4) and in unlinked HIV/HLA data from 43 countries (Spearman's R=0.34, p=0.02). Notably, RT-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. Sub-Saharan Africa, Southeastern Europe) where B*18 is more common. This, along with the observation that RT-E138X variants do not confer in vitro replicative costs, supports their persistence and ongoing accumulation in circulation over time.

Conclusions

Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional RT-E138X surveillance should be undertaken before use of rilpivirine PrEP.

Abstract:

We report on a measurement of the flavor-specific B0s lifetime and of the D−s lifetime using proton-proton collisions at center-of-mass energies of 7 and 8 TeV, collected by the LHCb experiment and corresponding to 3.0 fb^-1 of integrated luminosity. Approximately 407 000 B0s → D(*)−s μ+νμ decays are partially reconstructed in the K+K−π−μ+ final state. The B0s and D−s natural widths are determined using, as a reference, kinematically similar B0 → D(*)−μ+νμ decays reconstructed in the same final state. The resulting differences between widths of B0s and B0 mesons and of D−s and D− mesons are ΔΓ(B) = −0.0115 ± 0.0053(stat) ± 0.0041(syst) ps^-1 and ΔΓ(D)=1.0131±0.0117(stat)±0.0065(syst) ps^-1, respectively. Combined with the known B0 and D− lifetimes, these yield the flavor-specific B0s lifetime, τfsB0s=1.547±0.013(stat)±0.010(syst)±0.004(τB)  ps and the D−s lifetime, τD−s=0.5064±0.0030(stat)±0.0017(syst)±0.0017(τD)  ps. The last uncertainties originate from the limited knowledge of the B0 and D− lifetimes. The results improve upon current determinations.

Abstract:

Decays of B0 and Bs0 mesons to the charmless baryonic final states pp-h+h′-, where h and h′ each denote a kaon or a pion, are searched for using the LHCb detector. The analysis is based on a sample of proton-proton collision data collected at center-of-mass energies of 7 and 8 TeV, corresponding to an integrated luminosity of 3 fb-1. Four-body charmless baryonic Bs0 decays are observed for the first time. The decays Bs0→pp-K+K-, Bs0→pp-K±πâ", B0→pp-K±πâ" and B0→pp-π+π-A re observed with a significance greater than 5 standard deviations; evidence at 4.1 standard deviations is found for the B0→pp-K+K-decay and an upper limit is set on the branching fraction for Bs0→pp-π+π-. Branching fractions in the kinematic region m(pp-) < 2850 MeV/c2 are measured relative to the B0→J/ψ(→pp-)K∗(892)0 channel.

Abstract:

A highly significant structure is observed in the Λ+cK−π+π+ mass spectrum, where the Λ+c baryon is reconstructed in the decay mode pK−π+. The structure is consistent with originating from a weakly decaying particle, identified as the doubly charmed baryon Ξ++cc. The difference between the masses of the Ξ++cc and Λ+c states is measured to be 1334.94±0.72(stat.)±0.27(syst.)  MeV/c^2, and the Ξ++cc mass is then determined to be 3621.40±0.72(stat.)±0.27(syst.)±0.14(Λ+c)  MeV/c^2, where the last uncertainty is due to the limited knowledge of the Λ+c mass. The state is observed in a sample of proton-proton collision data collected by the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.7  fb^−1, and confirmed in an additional sample of data collected at 8 TeV.