Allosteric Modulation of the HIV-1 gp120-gp41 Association Site by Adjacent gp120 Variable Region 1 (V1) N-Glycans Linked to Neutralization Sensitivity

The HIV-1 gp120-gp41 complex, which mediates viral fusion and cellular entry, undergoes rapid evolution within its external glycan shield to enable escape from neutralizing antibody (NAb). Understanding how conserved protein determinants retain functionality in the context of such evolution is important for their evaluation and exploitation as potential drug and/ or vaccine targets. In this study, we examined how the conserved gp120-gp41 association site, formed by the N- and Cterminal segments of gp120 and the disulfide-bonded region (DSR) of gp41, adapts to glycan changes that are linked to neutralization sensitivity. To this end, a DSR mutant virus (K601D) with defective gp120-association was sequentially passaged in peripheral blood mononuclear cells to select suppressor mutations. We reasoned that the locations of suppressors point to structural elements that are functionally linked to the gp120-gp41 association site. In culture 1, gp120 association and viral replication was restored by loss of the conserved glycan at Asn136 in V1 (T138N mutation) inconjunction with the L494I substitution in C5 within the association site. In culture 2, replication was restored with deletion of the N139INN sequence, which ablates the overlapping Asn141-Asn142-Ser-Ser potential N-linked glycosylation sequons inV1, in conjunction with D601N in the DSR. The 136 and 142 glycan mutations appeared to exert their suppressive effects by altering the dependence of gp120-gp41 interactions on the DSR residues, Leu593, Trp596 and Lys601. The 136 and/or 142glycan mutations increased the sensitivity of HIV-1 pseudovirions to the glycan-dependent NAbs 2G12 and PG16, and also pooled IgG obtained from HIV-1-infected individuals. Thus adjacent V1 glycans allosterically modulate the distal gp120-gp41 association site. We propose that this represents a mechanism for functional adaptation of the gp120-gp41 association site to an evolving glycan shield in a setting of NAb selection

Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections

Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413–415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response

Smooth Dynamics, Good Performance in Cognitive-Agent Congestion Problems

In a congestion game, individuals exhaust a common resource out of selfish behavior. In this scenario, drivers create traffic jams by choosing the shortest route according to their individual knowledge. They can avoid them by communicating their belief states about the traffic situation in real-time through a peer-to-peer network, assuming unlimited bandwidth. We study two potential, cognitively inspired models of human behavior: 1) categorization (quantized memorization and communication), which dampens communication and belief adoption, but leads to undesired oscillations and lower performance. 2) Instance-based blending with memory decay, which achieves good dynamics and near-optimal performance without the same bandwidth needs. We argue that this supports our hypothesis of co-adaptation of cognitive function and communicating communities

The soul of form: Karl Kraus, essayism and Jewish identity in fin-de-siecle Vienna

This study examines the connection between Karl Kraus's innovative journalistic style and the construction of German Jewish identity. Its argument is that the discourse of Jewish mimesis played a key role in discussions of Jewish identity among Kraus's contemporaries in Vienna, and that the formal features of Kraus's writing engaged productively with this discourse for some of Kraus's most prominent readers. Prompted by Kraus's style, Walter Benjamin, Franz Kafka, Gershom Scholem and Berthold Viertel, rehabilitated the antisemitic stereotype of Jewish mimesis. In their responses to Kraus's journalism, this marker of German Jewish intellectual inauthenticity is transformed into an emblem of Jewish intellectual authenticity.The focus in the long-standing debate on Kraus's Jewish identity has been his willfully contradictory and often antisemitic utterances about Jews and Jewish culture. The leading contemporary participants in this dispute have maintained that Kraus was a Jewish antisemite and an inspired critic of antisemitism who occasionally identified with Jewish traditions. This position is accurate but also limited. For it cannot account for responses to Kraus in which his writing becomes a significant answer to the problem of German Jewish identity. By explaining these responses to Kraus, this study thus contributes to the debate on Kraus's Jewish identity.This study also contributes to the scholarly literature on the relation of crises of German Jewish identity and formal innovation in Viennese modernism. Studies of this connection have emphasized the causal link between cultural alienation and artistic creativity, maintaining that crises of German Jewish identity led to prominent formal innovations, such as Schonberg's atonal music. According to these readings, innovative modernist works by German Jews might be seen as expressions of problems of German Jewish identity. Such readings have neglected an important aspect of the relation they examine: the ways in which modernist formal innovation participated in the construction of German Jewish identity. Combining historical and literary analysis, the present study demonstrates how Kraus's innovative writing became caught up in, and contributed to, a discourse in which journalistic writing was treated as a marker of German Jewish identity. (Abstract shortened by UMI.)Thesis (Ph.D.)--University of California, Berkeley, 1999.School code: 0028

A case report of septic shock syndrome caused by S. pneumoniae in an immunocompromised patient despite of vaccination

Abstract Background and case presentation We report a case of septic shock syndrome caused by Streptococcus pneumoniae in a patient who had undergone splenectomy due to an autoimmune lymphoproliferative syndrome (ALPS), which is characterized as a dysfunction of immunoregulation. Although the patient was vaccinated with a conjugated polysaccharide vaccine after the splenectomy, he was still susceptible to S. pneumoniae infection, because the isolated serovar (24F), a serovar long thought to be apathogenic, is not covered by any vaccine currently approved, neither a conjugated nor an unconjugated polysaccharide one. Conclusions This case demonstrates that, due to presence of different serovars, also infections with bacteria against which patients are vaccinated have to be considered as differential diagnosis. Although vaccine development has extended the coverage of S. pneumoniae from 7 to 23 serovars within recent years, there is still demand for novel vaccines which can provide broader protection also against so-thought “apathogenic” strains, especially for groups at high risk