The V1-V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and altered sensitivity to entry inhibitors

<p>Abstract</p> <p>Background</p> <p>HIV-1 infects macrophages and microglia in the brain and can cause neurological disorders in infected patients. We and others have shown that brain-derived envelope glycoproteins (Env) have lower CD4 dependence and higher avidity for CD4 than those from peripheral isolates, and we have also observed increased fusogenicity and reduced sensitivity to the fusion inhibitor T-1249. Due to the genetic differences between brain and spleen <it>env </it>from one individual throughout gp120 and in gp41's heptad repeat 2 (HR2), we investigated the viral determinants for the phenotypic differences by performing functional studies with chimeric and mutant Env.</p> <p>Results</p> <p>Chimeric Env showed that the V1/V2-C2-V3 region in brain's gp120 determines the low CD4 dependence and high avidity for CD4, as well as macrophage tropism and reduced sensitivity to the small molecule BMS-378806. Changes in brain gp41's HR2 region did not contribute to the increased fusogenicity or to the reduced sensitivity to T-1249, since a T-1249-based peptide containing residues found in brain's but not in spleen's HR2 had similar potency than T-1249 and interacted similarly with an immobilized heptad repeat 1-derived peptide in surface plasmon resonance analysis. However, the increased fusogenicity and reduced T-1249 sensitivity of brain and certain chimeric Env mostly correlated with the low CD4 dependence and high avidity for CD4 determined by brain's V1-V3 region. Remarkably, most but not all of these low CD4-dependent, macrophage tropic envelopes glycoproteins also had increased sensitivity to the novel allosteric entry inhibitor HNG-105. The gp120's C2 region asparagine 283 (N283) has been previously associated with macrophage tropism, brain infection, lower CD4 dependence and higher CD4 affinity. Therefore, we introduced the N283T mutation into an <it>env </it>clone from a brain-derived isolate and into a brain tissue-derived <it>env </it>clone, and the T283N change into a spleen-derived <it>env </it>from the same individual; however, we found that their phenotypes were not affected.</p> <p>Conclusion</p> <p>We have identified that the V1-V3 region of a brain-derived envelope glycoprotein seems to play a crucial role in determining not only the low CD4 dependence and increased macrophage tropism, but also the augmented fusogenicity and reduced sensitivity to T-1249 and BMS-378806. By contrast, increased sensitivity to HNG-105 mostly correlated with low CD4 dependence and macrophage tropism but was not determined by the presence of the brain's V1-V3 region, confirming that viral determinants of phenotypic changes in brain-derived envelope glycoproteins are likely complex and context-dependent.</p

The V1-V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and altered sensitivity to entry inhibitors

<p>Abstract</p> <p>Background</p> <p>HIV-1 infects macrophages and microglia in the brain and can cause neurological disorders in infected patients. We and others have shown that brain-derived envelope glycoproteins (Env) have lower CD4 dependence and higher avidity for CD4 than those from peripheral isolates, and we have also observed increased fusogenicity and reduced sensitivity to the fusion inhibitor T-1249. Due to the genetic differences between brain and spleen <it>env </it>from one individual throughout gp120 and in gp41's heptad repeat 2 (HR2), we investigated the viral determinants for the phenotypic differences by performing functional studies with chimeric and mutant Env.</p> <p>Results</p> <p>Chimeric Env showed that the V1/V2-C2-V3 region in brain's gp120 determines the low CD4 dependence and high avidity for CD4, as well as macrophage tropism and reduced sensitivity to the small molecule BMS-378806. Changes in brain gp41's HR2 region did not contribute to the increased fusogenicity or to the reduced sensitivity to T-1249, since a T-1249-based peptide containing residues found in brain's but not in spleen's HR2 had similar potency than T-1249 and interacted similarly with an immobilized heptad repeat 1-derived peptide in surface plasmon resonance analysis. However, the increased fusogenicity and reduced T-1249 sensitivity of brain and certain chimeric Env mostly correlated with the low CD4 dependence and high avidity for CD4 determined by brain's V1-V3 region. Remarkably, most but not all of these low CD4-dependent, macrophage tropic envelopes glycoproteins also had increased sensitivity to the novel allosteric entry inhibitor HNG-105. The gp120's C2 region asparagine 283 (N283) has been previously associated with macrophage tropism, brain infection, lower CD4 dependence and higher CD4 affinity. Therefore, we introduced the N283T mutation into an <it>env </it>clone from a brain-derived isolate and into a brain tissue-derived <it>env </it>clone, and the T283N change into a spleen-derived <it>env </it>from the same individual; however, we found that their phenotypes were not affected.</p> <p>Conclusion</p> <p>We have identified that the V1-V3 region of a brain-derived envelope glycoprotein seems to play a crucial role in determining not only the low CD4 dependence and increased macrophage tropism, but also the augmented fusogenicity and reduced sensitivity to T-1249 and BMS-378806. By contrast, increased sensitivity to HNG-105 mostly correlated with low CD4 dependence and macrophage tropism but was not determined by the presence of the brain's V1-V3 region, confirming that viral determinants of phenotypic changes in brain-derived envelope glycoproteins are likely complex and context-dependent.</p

The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects

The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b–restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1b. Target cell recognition depended on T cell receptor and Qa-1b interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8+ T cells. Our data reveal that Qa-1b, and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8+ T cells

Management of intraoral stents for radiotherapy during COVID-19 pandemic

Radiotherapy is being performed in many situations as a curative approach for head and neck cancer instead of surgery due to the current novel coronavirus disease (COVID-19) pandemic. A recent publication reported that even hypofractionation was being conducted in order to reduce the daily exposure of both patients and the medical staff involved in cancer therapies. As a result, dental teams may be requested more frequently than usual to fabricate intraoral stents (IOS). Given that IOS may be a potential source of COVID-19 contagion, the main purpose of the present correspondence is to offer a guide on how health professionals may be safely presented in the room, on the management of the IOS and also how to sanitize the stents. 

Obturator prostheses versus free tissue transfers: a systematic review of the optimal approach to improving the quality of life for patients with maxillary defects

Patient perspectives on the treatment options for maxillary defects, which include free tissue transfers or obturator prostheses, may help eliminate current uncertainty as to the best choice of treatment plan. The purpose of this systematic review was to evaluate the quality of life (QoL) of patients with maxillary defects who had undergone restoration with obturator prostheses and/or free tissue transfers. A systematic search of Medline/PubMed and Web of Science databases for articles published before April 2015 was performed by 2 independent reviewers. A manual search of articles published from January 2005 to March 2015 was also conducted. Studies published in English that evaluated the QoL in patients with head and neck cancers were included. The Cohen kappa method was used to calculate inter-reviewer agreement. Ten studies were included. The University of Washington Head and Neck Questionnaire (UW-QOL) was most commonly used to measure QoL. The majority of maxillary defects were Class IIa-b. Two studies reported that the global QoL for patients with obturator prostheses is equivalent to or even better than that of other chronic disease populations. One study revealed no significant difference in QoL when the 2 treatment options were compared. The limited data indicate that the QoL of patients treated with obturator prostheses and that of patients free of tumors is similar. Well-designed clinical studies are necessary to draw definitive conclusions about how obturator prostheses compare with free tissue transfers in terms of affecting patient QoL

Broad-Spectrum Anti-Human Immunodeficiency Virus (HIV) Potential of a Peptide HIV Type 1 Entry Inhibitor

The AIDS epidemic continues to spread at an alarming rate worldwide, especially in developing countries. One approach to solving this problem is the generation of anti-human immunodeficiency virus (HIV) compounds with inhibition spectra broad enough to include globally prevailing forms of the virus. We have examined the HIV type 1 (HIV-1) envelope specificity of a recently identified entry inhibitor candidate, HNG-105, using surface plasmon resonance spectroscopy and pseudovirus inhibition assays. The combined results suggest that the HNG-105 molecule may be effective across the HIV-1 subtypes, and they highlight its potential as a lead for developing therapeutic and microbicidal agents to help combat the spread of AIDS

A systematic comparison of bar-clips versus magnets

Statement of problem. Currently, which type of suprastructure is preferred when fabricating implant-retained craniofacial prostheses is unknown. Purpose. The purpose of this systematic review was to identify the best retention system (bar-clips versus magnets) for implant-retained craniofacial prostheses. Material and methods. This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic search of Medline/PubMed and Web of Science databases for clinical trials was conducted on implant-retained craniofacial prostheses published between 2005 and 2015. English -language studies that directly compared different types of retention systems or presented information on implant survival, periimplant soft tissue reactions, and prosthetic complications were included. Nonclinical studies were excluded to eliminate bias. Results. A total to 173 studies were identified, of which 10 satisfied the inclusion criteria. In total, 492 participants were included in these studies. Four selected studies displayed detailed information with regard to the number of implant failures according to the retention system. As reported, 29 (18.2%) of 159 implants with magnets failed, whereas 25 (31.6%) of 79 implants with bars failed. Overall auricular superstructures showed the highest survival (99.08%). In addition, 55.4% of all participants in the selected studies showed grade 0 of periimplant soft tissue reactions. Conclusions. A systematic search for clinical studies resulted in few studies with a short-term follow-up and small number of participants. The limited data collected indicated that magnets show fewer complications than bar superstructures; however, no hard conclusions could be drawn. Further research, preferably in the form of clinical trials, is needed to validate these findings