593 research outputs found
Beneficial HLA-mediated viral polymorphisms on the transmitted virus additively influence disease progression in HIV-1, subtype C infection
Transmitted viral factors have been shown to affect disease progression but whether infection with viruses carrying beneficial HLA-mediated escape polymorphisms affects disease progression in HLA-mismatched participants remains controversial
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Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure
It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential "transmission signatures", we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection, we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission
Recommendations for a core outcome set for measuring standing balance in adult populations: a consensus-based approach
Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally
First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data
Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of
continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a
fully coherent search, based on matched filtering, which uses the position and rotational parameters
obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto-
noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch
between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have
been developed, allowing a fully coherent search for gravitational waves from known pulsars over a
fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of
11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial
outliers, further studies show no significant evidence for the presence of a gravitational wave signal.
Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of
the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for
the first time. For an additional 3 targets, the median upper limit across the search bands is below the
spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried
out so far
Transmission of HIV-1 CTL escape variants provides HLA - mismatched recipients with a survival advantage.
One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the
genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag
protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with
slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with
rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to
newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted
viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is
associated with lower viral load and higher CD4+ counts
Rapid, complex adaption of transmitted HIV-1 full-length genomes in subtype C-infected individuals with differing disease progression.
CAPRISA 2013.Objective(s): There is limited information on full-length genome sequences and the
early evolution of transmitted HIV-1 subtype C viruses, which constitute the majority of
viruses spread in Africa. The purpose of this study was to characterize the earliest
changes across the genome of subtype C viruses following transmission, to better
understand early control of viremia.
Design: We derived the near full-length genome sequence responsible for clinical
infection from five HIV subtype C-infected individuals with different disease progression
profiles and tracked adaptation to immune responses in the first 6 months
of infection.
Methods: Near full-length genomes were generated by single genome amplification
and direct sequencing. Sequences were analyzed for amino acid mutations associated
with cytotoxic T lymphocyte (CTL) or antibody-mediated immune pressure, and for
reversion.
Results: Fifty-five sequence changes associated with adaptation to the new host were
identified, with 38% attributed to CTL pressure, 35% to antibody pressure, 16% to
reversions and the remainder were unclassified. Mutations in CTL epitopes were most
frequent in the first 5 weeks of infection, with the frequency declining over time with the
decline in viral load. CTL escape predominantly occurred in nef, followed by pol and
env. Shuffling/toggling of mutations was identified in 81% of CTL epitopes, with only
7% reaching fixation within the 6-month period.
Conclusion: There was rapid virus adaptation following transmission, predominantly
driven by CTL pressure, with most changes occurring during high viremia. Rapid escape
and complex escape pathways provide further challenges for vaccine protection
Association of HIV-Specific and Total CD8+ T Memory Phenotypes in Subtype C HIV-1 Infection with Viral Set Point.
Understanding early immunological events during HIV-1 infection that may set the course of disease
progression is important for identifying correlates of viral control. This study explores the association
of differentiation profiles of HIV-specific and total memory CD8+ T cells with viral set point. A
cohort of 47 HIV-1-infected individuals, with differing viral set points at 12 mo, were recruited during
acute infection. We identified that the magnitude of IFN-γ+ T cell responses at 6 mo postinfection
did not associate with viral set point at 12 mo. A subset of 16 individuals was further studied to
characterize CD8+ T cells for expression patterns of markers for memory differentiation, survival
(CD127), senescence (CD57), and negative regulation (programmed death-1). We show that viral
control and the predicted tempo of HIV disease progression in the first year of infection was
associated with a synchronous differentiation of HIV-specific and total CD8+ memory
subpopulations. At 6–9 mo postinfection, those with low viral set points had a significantly higher proportion of early differentiated HIV-specific and total memory CD8+ cells of a central memory (CD45RO+CD27+CCR7+) and intermediate memory (CD45RO−CD27+CCR7−) phenotype. Those with high viral set points possessed significantly larger frequencies of effector memory (CD45RO+CD27−CCR7−) cells. The proportions of memory subsets significantly correlated with CD38+CD8+ T cells. Thus, it is likely that a high Ag burden resulting in generalized immune
activation may drive differentiation of HIV-specific and total memory CD8+ T cells
Structure and recognition of a novel HIV-1 gp120-gp41 interface antibody that caused MPER exposure through viral escape.
CAPRISA, 2017.Abstract available in pdf
Sensitivity of the Advanced LIGO detectors at the beginning of gravitational wave astronomy
The Laser Interferometer Gravitational Wave Observatory (LIGO) consists of two widely separated 4 km laser interferometers designed to detect gravitational waves from distant astrophysical sources in the frequency range from 10 Hz to 10 kHz. The first observation run of the Advanced LIGO detectors started in September 2015 and ended in January 2016. A strain sensitivity of better than 10−23/Hz−−−√ was achieved around 100 Hz. Understanding both the fundamental and the technical noise sources was critical for increasing the astrophysical strain sensitivity. The average distance at which coalescing binary black hole systems with individual masses of 30 M⊙ could be detected above a signal-to-noise ratio (SNR) of 8 was 1.3 Gpc, and the range for binary neutron star inspirals was about 75 Mpc. With respect to the initial detectors, the observable volume of the Universe increased by a factor 69 and 43, respectively. These improvements helped Advanced LIGO to detect the gravitational wave signal from the binary black hole coalescence, known as GW150914
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