43 research outputs found
SoDA2: a Hidden Markov Model approach for identification of immunoglobulin rearrangements
Motivation: The inference of pre-mutation immunoglobulin (Ig) rearrangements is essential in the study of the antibody repertoires produced in response to infection, in B-cell neoplasms and in autoimmune disease. Often, there are several rearrangements that are nearly equivalent as candidates for a given Ig gene, but have different consequences in an analysis. Our aim in this article is to develop a probabilistic model of the rearrangement process and a Bayesian method for estimating posterior probabilities for the comparison of multiple plausible rearrangements
S021-04 OA. A large-scale analysis of immunoglobulin sequences derived from plasmablasts/plasma cells in acute HIV-1 infection subjects
Background
In acute HIV-1 infection (AHI) there are infectioninduced
polyclonal shifts in blood and bone marrow Bcell
subsets from naïve to memory cells and plasmablasts/
plasma cells (PCs) coupled with decreased numbers of
naive B cells. To study the initial antibody response to
HIV, we have used recombinant technology to create a
database of PC antibody sequences derived from 3 early
stage AHI subjects
P04-45. Characterization of the plasma cell repertoire in acute HIV-1 infection (AHI)
Analysis of immunoglobulin (Ig) VH and VL genes
derived from sorted single B cells is a powerful technology
for definition of Ig repertoires to viral infections. The purpose
of this study was to characterize the Ig repertoire of
plasma cells/plasmablasts (PCs) in subjects early on after
HIV transmission
Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated
Many HIV-1 envelope-reactive antibodies shortly after HIV-1 transmission may arise from crow-reactive memory B cells previously stimulated by non-HIV-1 host or microbial antigen
Envelope Deglycosylation Enhances Antigenicity of HIV-1 gp41 Epitopes for Both Broad Neutralizing Antibodies and Their Unmutated Ancestor Antibodies
The HIV-1 gp41 envelope (Env) membrane proximal external region (MPER) is an important vaccine target that in rare subjects can elicit neutralizing antibodies. One mechanism proposed for rarity of MPER neutralizing antibody generation is lack of reverted unmutated ancestor (putative naive B cell receptor) antibody reactivity with HIV-1 envelope. We have studied the effect of partial deglycosylation under non-denaturing (native) conditions on gp140 Env antigenicity for MPER neutralizing antibodies and their reverted unmutated ancestor antibodies. We found that native deglycosylation of clade B JRFL gp140 as well as group M consensus gp140 Env CON-S selectively increased the reactivity of Env with the broad neutralizing human mAbs, 2F5 and 4E10. Whereas fully glycosylated gp140 Env either did not bind (JRFL), or weakly bound (CON-S), 2F5 and 4E10 reverted unmutated ancestors, natively deglycosylated JRFL and CON-S gp140 Envs did bind well to these putative mimics of naive B cell receptors. These data predict that partially deglycoslated Env would bind better than fully glycosylated Env to gp41-specific naïve B cells with improved immunogenicity. In this regard, immunization of rhesus macaques demonstrated enhanced immunogenicity of the 2F5 MPER epitope on deglyosylated JRFL gp140 compared to glycosylated JRFL gp140. Thus, the lack of 2F5 and 4E10 reverted unmutated ancestor binding to gp140 Env may not always be due to lack of unmutated ancestor antibody reactivity with gp41 peptide epitopes, but rather, may be due to glycan interference of binding of unmutated ancestor antibodies of broad neutralizing mAb to Env gp41
The Role of Viral Introductions in Sustaining Community-Based HIV Epidemics in Rural Uganda: Evidence from Spatial Clustering, Phylogenetics, and Egocentric Transmission Models
Background:It is often assumed that local sexual networks play a dominant role in HIV spread in sub-Saharan Africa. The aim of this study was to determine the extent to which continued HIV transmission in rural communities-home to two-thirds of the African population-is driven by intra-community sexual networks versus viral introductions from outside of communities.Methods and Findings:We analyzed the spatial dynamics of HIV transmission in rural Rakai District, Uganda, using data from a cohort of 14,594 individuals within 46 communities. We applied spatial clustering statistics, viral phylogenetics, and probabilistic transmission models to quantify the relative contribution of viral introductions into communities versus community- and household-based transmission to HIV incidence. Individuals living in households with HIV-incident (n = 189) or HIV-prevalent (n = 1,597) persons were 3.2 (95% CI: 2.7-3.7) times more likely to be HIV infected themselves compared to the population in general, but spatial clustering outside of households was relatively weak and was confined to distances <500 m. Phylogenetic analyses of gag and env genes suggest that chains of transmission frequently cross community boundaries. A total of 95 phylogenetic clusters were identified, of which 44% (42/95) were two individuals sharing a household. Among the remaining clusters, 72% (38/53) crossed community boundaries. Using the locations of self-reported sexual partners, we estimate that 39% (95% CI: 34%-42%) of new viral transmissions occur within stable household partnerships, and that among those infected by extra-household sexual partners, 62% (95% CI: 55%-70%) are infected by sexual partners from outside their community. These results rely on the representativeness of the sample and the quality of self-reported partnership data and may not reflect HIV transmission patterns outside of Rakai.Conclusions:Our findings suggest that HIV introductions into communities are common and account for a significant proportion of new HIV infections acquired outside of households in rural Uganda, though the extent to which this is true elsewhere in Africa remains unknown. Our results also suggest that HIV prevention efforts should be implemented at spatial scales broader than the community and should target key populations likely responsible for introductions into communities.Please see later in the article for the Editors' Summary
Analysis of Genetic Linkage of HIV From Couples Enrolled in the HIV Prevention Trials Network 052 Trial
Background. The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early initiation of antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) transmission from HIV-infected adults (index participants) to their HIV-uninfected sexual partners. We analyzed HIV from 38 index-partner pairs and 80 unrelated index participants (controls) to assess the linkage of seroconversion events
Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved.
CAPRISA, 2014.Abstract available in pdf
A transcriptomic analysis of bermudagrass (Cynodon dactylon) provides novel insights into the basis of low temperature tolerance
ThymosinB4- A novel regulator of Low density lipoprotein receptor related protein 1(LRP1) in vascular disease
Cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm (AAA), are amongst the foremost causes of global morbidity. Despite decades of research, the mechanisms underlying disease progression remain unresolved, resulting in a lack of efficient pharmacological therapies to prevent disease progression. Maintaining vascular stability is fundamental to protect against disease pathogenesis. Contractile smooth muscle cells (VSMCs) and elastin-rich extracellular matrix (ECM) are major determinants of vascular stability and tone. Injury-induced growth factors stimulate phenotypic modulation of VSMCs, from their quiescent contractile state to a more active, synthetic phenotype, that proliferate, migrate and accelerate progression of atherosclerosis and AAA. Inhibiting VSMC phenotypic transformation has thus been shown to attenuate disease progression. Thymosin β4 (Tβ4), a small actin-binding peptide, promotes VSMC differentiation during development and preserves VSMC differentiation postnatally in the healthy aorta. Tβ4 interacts with Low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of PDGFRβ signalling in VSMCs, and LRP1 variants have been identified by GWAS as major risk loci for AAA and coronary artery disease. We hypothesised that Tβ4 may function to protect against vascular disease via LRP1 mediated growth factor signalling. Using well-characterised models of atherosclerosis and AAA, increased susceptibility to disease was confirmed in mice lacking Tβ4. Tβ4-null mice displayed increased susceptibility to AAA, ranging from aortic dilation to overt medial dissection and rupture in <5 days. Similarly, in the aortic root and descending aorta, mice lacking Tβ4 on ApoE-/- background develop more unstable atherosclerotic plaques, with large necrotic cores. Diseased vessels were characterised by enhanced contractile-synthetic VSMC switching and increased elastin degradation, underpinned by augmented LRP1-PDGFRβ signalling. Primary aortic VSMCs lacking Tβ4 show enhanced sensitivity to PDGF-BB, coinciding with dysregulated intra-cellular trafficking, leading to increased recycling of LRP1-PDGFRβ and reduced lysosomal targeting. Given that exogenous Tβ4 can regulate endocytosis, and due to the known anti-fibrotic, anti-inflammatory and anti-apoptotic properties of Tβ4, the therapeutic potential of exogenously administered Tβ4 was evaluated in the AAA model. Simultaneous administration of Tβ4 and AngII in C57BL/6J mice reduced aneurysms and the associated elastin degradation, preserved contractile VSMC phenotype, and attenuated activation of PDGFRβ. This research identifies endogenous Tβ4 as a novel regulator of LRP1 in the aorta to protect against atherosclerosis and AAA and reveals the potential for using Tβ4 as a therapeutic agent to protect against vascular disease. However, further studies are required to validate these findings and to elucidate the exact molecular mechanisms through which protection is achieved.</p