AIDS Vaccine Clinical Trials
A, C. G., C. E. Gomez, V. Diaz-Brito, J. Pich, J. A. Arnaiz, B. Perdiguero, J. Garcia-Arriaza, N. Gonzalez, C. O. S. Sorzano, L. Jimenez, J. L. Jimenez, M. A. Munoz-Fernandez, J. M. Gatell, J. Alcami, M. Esteban, J. C. Lopez Bernaldo de Quiros, F. Garcia and M. Plana (2017). “Safety and vaccine-induced HIV-1 immune responses in healthy volunteers following a late MVA-B boost 4 years after the last immunization.” PLoS One 12(10): e0186602.
BACKGROUND: We have previously shown that an HIV vaccine regimen including three doses of HIV-modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B) was safe and elicited moderate and durable (1 year) T-cell and antibody responses in 75% and 95% of HIV-negative volunteers (n = 24), respectively (RISVAC02 study). Here, we describe the long-term durability of vaccine-induced responses and the safety and immunogenicity of an additional MVA-B boost. METHODS: 13 volunteers from the RISVAC02 trial were recruited to receive a fourth dose of MVA-B 4 years after the last immunization. End-points were safety, cellular and humoral immune responses to HIV-1 and vector antigens assessed by ELISPOT, intracellular cytokine staining (ICS) and ELISA performed before and 2, 4 and 12 weeks after receiving the boost. RESULTS: Volunteers reported 64 adverse events (AEs), although none was a vaccine-related serious AE. After 4 years from the 1st dose of the vaccine, only 2 volunteers maintained low HIV-specific T-cell responses. After the late MVA-B boost, a modest increase in IFN-gamma T-cell responses, mainly directed against Env, was detected by ELISPOT in 5/13 (38%) volunteers. ICS confirmed similar results with 45% of volunteers showing that CD4+ T-cell responses were mainly directed against Env, whereas CD8+ T cell-responses were similarly distributed against Env, Gag and GPN. In terms of antibody responses, 23.1% of the vaccinees had detectable Env-specific binding antibodies 4 years after the last MVA-B immunization with a mean titer of 96.5. The late MVA-B boost significantly improved both the response rate (92.3%) and the magnitude of the systemic binding antibodies to gp120 (mean titer of 11460). HIV-1 neutralizing antibodies were also enhanced and detected in 77% of volunteers. Moreover, MVA vector-specific T cell and antibody responses were boosted in 80% and 100% of volunteers respectively. CONCLUSIONS: One boost of MVA-B four years after receiving 3 doses of the same vaccine was safe, induced moderate increases in HIV-specific T cell responses in 38% of volunteers but significantly boosted the binding and neutralizing antibody responses to HIV-1 and to the MVA vector. TRIAL REGISTRATION: ClinicalTrials.gov NCT01923610.
AIDS Vaccine Design Immunogenicity Efficacy
Fauci, A. S. (2017). “An HIV Vaccine Is Essential for Ending the HIV/AIDS Pandemic.” JAMA 318(16): 1535-1536.
Jafarzade, B. S., S. M. Sadat, R. Yaghobi and A. Bolhassani (2017). “Improving the potency of DNA vaccine encoding HIV-1 Nef antigen using two endogenous adjuvants in mouse model.” Bratisl Lek Listy 118(9): 564-569.
BACKGROUND: DNA immunization can induce long-term immune responses, which are required to design an effective HIV vaccine. It was shown that antigen-expressing plasmids can increase the protective immunity against infectious diseases such as: influenza and malaria. However, DNA-based immunizations have poor immunogenicity, thus the use of potent immunoadjuvants can enhance their potency. METHODS: In the current study, preparation of the recombinant HIV-1 Nef, Gp96 and HMGB1 DNA constructs was performed in bacterial system. Then, the immunogenicity of DNA construct harboring HIV-1 Nef gene (pcDNA-Nef) was studied using two endogenous adjuvants (pcDNA-HMGB1 and pcDNA-Gp96) in BALB/c mouse model. RESULTS: Our data showed that co-injection of pcDNA-Nef with pcDNA-HMGB1 effectively raised both humoral and cell-mediated immune responses in mice as compared to pcDNA-Nef adjuvanted with pcDNA-gp96. Indeed, co-immunization of HIV-1 Nef DNA with HMGB1 DNA significantly induced high levels of IgG2a and IFN-gamma directed toward Th1 responses and also cytotoxic T lymphocytes (CTLs) activity in comparison with other immunized groups. CONCLUSION: These findings suggest that the full length of HMGB1 gene could be a more efficient adjuvant for improvement of therapeutic HIV DNA-based immunization compared to the full length of gp96 gene (Tab. 1, Fig. 3, Ref. 58).
Psomas, C. K., T. J. Barber, S. Rutsaert and S. Kinloch-de Loes (2017). “Highlights from the 9th IAS Conference on HIV Science, 23-26 July 2017, Paris, France.” J Virus Erad 3(4): 242-249.
Reiss, S., A. E. Baxter, K. M. Cirelli, J. M. Dan, A. Morou, A. Daigneault, N. Brassard, G. Silvestri, J. P. Routy, C. Havenar-Daughton, S. Crotty and D. E. Kaufmann (2017). “Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells.” PLoS One 12(10): e0186998.
The identification and study of antigen-specific CD4 T cells, both in peripheral blood and in tissues, is key for a broad range of immunological research, including vaccine responses and infectious diseases. Detection of these cells is hampered by both their rarity and their heterogeneity, in particular with regards to cytokine secretion profiles. These factors prevent the identification of the total pool of antigen-specific CD4 T cells by classical methods. We have developed assays for the highly sensitive detection of such cells by measuring the upregulation of surface activation induced markers (AIM). Here, we compare two such assays based on concurrent expression of CD69 plus CD40L (CD154) or expression of OX40 plus CD25, and we develop additional AIM assays based on OX40 plus PD-L1 or 4-1BB. We compare the relative sensitivity of these assays for detection of vaccine and natural infection-induced CD4 T cell responses and show that these assays identify distinct, but overlapping populations of antigen-specific CD4 T cells, a subpopulation of which can also be detected on the basis of cytokine synthesis. Bystander activation had minimal effect on AIM markers. However, some T regulatory cells upregulate CD25 upon antigen stimulation. We therefore validated AIM assays designed to exclude most T regulatory cells, for both human and non-human primate (NHP, Macaca mulatta) studies. Overall, through head-to-head comparisons and methodological improvements, we show that AIM assays represent a sensitive and valuable method for the detection of antigen-specific CD4 T cells.
AIDS Vaccine Envelope Design
Herschhorn, A., C. Gu, F. Moraca, X. Ma, M. Farrell, A. B. Smith, 3rd, M. Pancera, P. D. Kwong, A. Schon, E. Freire, C. Abrams, S. C. Blanchard, W. Mothes and J. G. Sodroski (2017). “The beta20-beta21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions.” Nat Commun 8(1): 1049.
The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 beta20-beta21 element as a major regulator of Env transitions. Several amino acid changes in the beta20-beta21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.
Jiang, X., F. Feyertag and D. L. Robertson (2017). “Protein structural disorder of the envelope V3 loop contributes to the switch in human immunodeficiency virus type 1 cell tropism.” PLoS One 12(10): e0185790.
Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an intrinsically disordered (unstructured/disordered) protein as it contains regions that do not fold into well-defined protein structures. These disordered regions play important roles in HIV’s life cycle, particularly, V3 loop-dependent cell entry, which determines how the virus uses two coreceptors on immune cells, the chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the majority of infections. Why does this ‘rewiring’ event occur in HIV-1 infected patients? As changes in the charge of the V3 loop are associated with this receptor switch and it has been suggested that charged residues promote structure disorder, we hypothesise that the intrinsic disorder of the V3 loop is permissive to sequence variation thus contributing to the switch in cell tropism. To test this we use three independent data sets of gp120 to analyse V3 loop disorder. We find that the V3 loop of X4 virus has significantly higher intrinsic disorder tendency than R5 and R5X4 virus, while R5X4 virus has the lowest. These results indicate that structural disorder plays an important role in HIV-1 cell tropism and CXCR4 binding. We discuss the potential evolutionary mechanisms leading to the fixation of disorder promoting mutations and the adaptive potential of protein structural disorder in viral host adaptation.
Tolbert, W. D., N. Gohain, N. Alsahafi, V. Van, C. Orlandi, S. Ding, L. Martin, A. Finzi, G. K. Lewis, K. Ray and M. Pazgier (2017). “Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region.” Structure.
Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 A resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal “eighth strand” of a critical beta sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment. In prior entry states, this sandwich comprises only seven strands, with the eighth strand instead pairing with a portion of the gp120 C terminus. The conformational gymnastics of HIV-1 gp120 thus includes altered beta-strand pairing, possibly to reduce immunogenicity, although nevertheless still recognized by the human immune system.
Emerging Infectious Diseases
Salam, A. P. and P. W. Horby (2017). “The Breadth of Viruses in Human Semen.” Emerg Infect Dis 23(11): 1922-1924.
Zika virus RNA is frequently detected in the semen of men after Zika virus infection. To learn more about persistence of viruses in genital fluids, we searched PubMed for relevant articles. We found evidence that 27 viruses, across a broad range of virus families, can be found in human semen.
HIV – Africa
Chang, L. W., I. Mbabali, X. Kong, H. Hutton, K. R. Amico, C. E. Kennedy, F. Nalugoda, D. Serwadda, R. C. Bollinger, T. C. Quinn, S. J. Reynolds, R. Gray, M. Wawer and G. Nakigozi (2017). “Impact of a community health worker HIV treatment and prevention intervention in an HIV hotspot fishing community in Rakai, Uganda (mLAKE): study protocol for a randomized controlled trial.” Trials 18(1): 494.
BACKGROUND: Effective yet practical strategies are needed to increase engagement in HIV treatment and prevention services, particularly in high-HIV-prevalence hotspots. We designed a community-based intervention called “Health Scouts” to promote uptake and adherence to HIV services in a highly HIV-prevalent fishing community in Rakai, Uganda. Using a situated Information, Motivation, and Behavioral skills theory framework, the intervention consists of community health workers, called Health Scouts, who use motivational interviewing strategies and mobile health tools to promote engagement in HIV treatment and prevention services. METHODS/DESIGN: The Health Scout intervention is being evaluated through a pragmatic, parallel, cluster-randomized controlled trial with an allocation ratio of 1:1. The study setting is a single high-HIV-prevalence fishing community in Rakai, Uganda divided into 40 contiguous neighborhood clusters each containing about 65 households. Twenty clusters received the Health Scout Intervention; 20 clusters received standard of care. The Health Scout intervention is delivered within the community at the household level, targeting all residents aged 15 years or older. The primary programmatic outcomes are self-reported HIV care, antiretroviral therapy, and male circumcision coverage; the primary biologic outcome is population-level HIV viremia prevalence. Follow-up is planned for about 3 years. DISCUSSION: HIV treatment and prevention service engagement remains suboptimal in HIV hotspots. New, community-based implementation approaches are needed. If found to be effective in this trial, the Health Scout intervention may be an important component of a comprehensive HIV response. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02556957 . Registered on 20 September 2015.
Sileo, K. M., M. Kintu and S. M. Kiene (2017). “The intersection of intimate partner violence and HIV risk among women engaging in transactional sex in Ugandan fishing villages.” AIDS Care: 1-9.
Intimate partner violence (IPV) may increase risk for HIV/AIDS among women engaging in transactional sex in Ugandan fishing communities. In this cross-sectional study, 115 women reporting engaging in transactional sex in Lake Victoria fishing communities completed a computerized interview. We tested associations between IPV and other HIV risk factors, with unprotected sex and HIV status, and tested moderators of the IPV-HIV risk relationship. Women reporting recent sexual IPV reported 3.36 times more unprotected sex acts (AdjExp[B] = 3.36, 95% CI = 1.29-8.69, p = 0.07). The effect of sexual IPV on sexual risk was significantly greater among alcohol and fish sellers compared to sex workers (interaction: Exp[B] = 12.29, 95% CI = 5.06-29.85, p < 0.001). Women reporting any sexual IPV were nearly four times more likely to report being HIV positive than women reporting no sexual IPV (AOR = 3.94, 95% CI = 1.22-12.66, p = 0.02). Integrated IPV and HIV interventions are needed in this context, especially among alcohol and fish sellers engaging in transactional sex.
HIV – Cures & Treatments
Mehraj, V., P. Ghali, R. Ramendra, C. Costiniuk, B. Lebouche, R. Ponte, R. Reinhard, J. Sousa, N. Chomont, E. A. Cohen, P. Ancuta and J. P. Routy (2017). “The evaluation of risk-benefit ratio for gut tissue sampling in HIV cure research.” J Virus Erad 3(4): 212-217.
INTRODUCTION: Antiretroviral therapy (ART) does not cure HIV infection due to the persistence of HIV reservoirs in long-lived memory CD4 T cells present in the blood, lymph nodes, intestinal tract, and other tissues. Interest grows in obtaining gut-tissue samples for HIV persistence studies, which poses an ethical challenge to provide study volunteers with adequate information on risks and benefits. Herein we assess the risks and benefits of undergoing gut biopsy procedures for HIV pathogenesis and reservoir studies. METHODS: A group discussion was organised with physicians and community representatives on performing either a flexible sigmoidoscopy or a colonoscopy. Consensus was reached on conducting colonoscopy in persons >/=50 years. Thirty HIV-infected, ART-treated and nine uninfected participants were recruited. Colonoscopy was performed to collect 30 gut mucosal biopsies. When present, polyps were removed and abnormal mucosal findings were biopsied for pathological analysis. Participants were interviewed on potential discomfort following colonoscopic examination. RESULTS: The HIV-infected and uninfected groups were comparable in terms of age and gender with more men who have sex with men (MSM) in the former group. Abnormal colonoscopic findings were observed in 43.6% of all the participants and did not differ by HIV status. In total, 24 polyps were removed with a higher mean number of polyps removed in HIV-infected versus uninfected participants (1.7 vs 1.0, P=0.013). The number of polyps marginally correlated with inverted CD4:CD8 ratio. Based on our findings, colonoscopic examination was safe to use for gut biopsy procedures where almost half of the participants had polyps removed. CONCLUSION: Participation in the study provided colon cancer screening as an ancillary benefit that participants could have received in standard medical care, thus mitigating burdens of invasive procedures. Dialogue between community representatives and clinical researchers can increase participation and advance HIV cure research.
HIV – IMMUNE ACTIVATION
Mwimanzi, F., M. Toyoda, M. Mahiti, J. K. Mann, J. N. Martin, D. Bangsberg, M. A. Brockman, P. Goulder, F. Kirchhoff, Z. L. Brumme, T. Ndung’u and T. Ueno (2017). “Relative resistance of MHC-B to Nef-mediated downregulation is conserved among primate lentiviruses and influences antiviral T cell responses in HIV-1-infected individuals.” J Virol.
Patient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses, and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate MHC-A and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A on average 11-32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (N=168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A vs. HLA-B downregulation activity. Nef clones harboring non-consensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring consensus at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8+ effector cells in vitro Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reduced ex vivo HIV-specific T-cell responses. Our results demonstrate that Nef’s inferior ability to downregulate MHC-B compared to MHC-A is conserved across primate lentiviruses, and suggest that this property influences antiviral cellular immune responses. IMPORTANCE Primate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentiviral lineages downregulate MHC-A approximately 20% more effectively than MHC-B. We further identify a naturally polymorphic site at Nef position 9 that contributes to MHC-B downregulation function in HIV-1 subtype C, and show that carriage of Nef variants with enhanced MHC-B downregulation ability is associated with reduced breadth and magnitude of MHC-B-restricted cellular immune responses in HIV-infected individuals. Our study underscores an evolutionally conserved interaction between lentiviruses and primate immune systems that may contribute to pathogenesis.
HIV – Neutralizing Antibodies
Hake, A. and N. Pfeifer (2017). “Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time.” PLoS Comput Biol13(10): e1005789.
Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient’s viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population.
Sun, Z., L. Yan, J. Tang, Q. Qian, J. Lenberg, D. Zhu, W. Liu, K. Wu, Y. Wang and S. Lu (2017). “Brief Introduction of Current Technologies in Isolation of Broadly Neutralizing HIV-1 Antibodies.” Virus Res.
HIV/AIDS has become a worldwide pandemic. Before an effective HIV-1 vaccine eliciting broadly neutralizing monoclonal antibodies (bnmAbs) is fully developed, passive immunization for prevention and treatment of HIV-1 infection may alleviate the burden caused by the pandemic. Among HIV-1 infected individuals, about 20% of them generated cross-reactive neutralizing antibodies two to four years after infection, the details of which could provide knowledge for effective vaccine design. Recent progress in techniques for isolation of human broadly neutralizing antibodies has facilitated the study of passive immunization. The isolation and characterization of large panels of potent human broadly neutralizing antibodies has revealed new insights into the principles of antibody-mediated neutralization of HIV. In this paper, we review the current effective techniques in broadly neutralizing antibody isolation.
Sumner, R. P., L. G. Thorne, D. L. Fink, H. Khan, R. S. Milne and G. J. Towers (2017). “Are Evolution and the Intracellular Innate Immune System Key Determinants in HIV Transmission?” Front Immunol 8: 1246.
HIV-1 is the single most important sexually transmitted disease in humans from a global health perspective. Among human lentiviruses, HIV-1 M group has uniquely achieved pandemic levels of human-to-human transmission. The requirement to transmit between hosts likely provides the strongest selective forces on a virus, as without transmission, there can be no new infections within a host population. Our perspective is that evolution of all of the virus-host interactions, which are inherited and perpetuated from host-to-host, must be consistent with transmission. For example, CXCR4 use, which often evolves late in infection, does not favor transmission and is therefore lost when a virus transmits to a new host. Thus, transmission inevitably influences all aspects of virus biology, including interactions with the innate immune system, and dictates the biological niche in which the virus exists in the host. A viable viral niche typically does not select features that disfavor transmission. The innate immune response represents a significant selective pressure during the transmission process. In fact, all viruses must antagonize and/or evade the mechanisms of the host innate and adaptive immune systems that they encounter. We believe that viewing host-virus interactions from a transmission perspective helps us understand the mechanistic details of antiviral immunity and viral escape. This is particularly true for the innate immune system, which typically acts from the very earliest stages of the host-virus interaction, and must be bypassed to achieve successful infection. With this in mind, here we review the innate sensing of HIV, the consequent downstream signaling cascades and the viral restriction that results. The centrality of these mechanisms to host defense is illustrated by the array of countermeasures that HIV deploys to escape them, despite the coding constraint of a 10 kb genome. We consider evasion strategies in detail, in particular the role of the HIV capsid and the viral accessory proteins highlighting important unanswered questions and discussing future perspectives.
Milligan, G. N., G. Vargas, K. L. Vincent, Y. Zhu, N. Bourne and M. Motamedi (2017). “Evaluation of immunological markers of ovine vaginal irritation: Implications for preclinical assessment of non-vaccine HIV preventive agents.” J Reprod Immunol 124: 38-43.
The presence of genital inflammatory responses and a compromised vaginal epithelial barrier have been linked to an increased risk of HIV acquisition. It is important to assure that application of candidate microbicides designed to limit HIV transmission will not cause these adverse events. We previously developed high resolution in vivo imaging methodologies in sheep to assess epithelial integrity following vaginal application of a model microbicide, however characterization of genital inflammation in sheep has not been previously possible. In this study, we significantly advanced the sheep model by developing approaches to detect and quantify inflammatory responses resulting from application of a nonoxynol-9-containing gel known to elicit vaginal irritation. Vaginal application of this model microbicide resulted in foci of disrupted epithelium detectable by confocal endomicroscopy. Leukocytes also infiltrated the treated mucosa and the number and composition of leukocytes obtained by cervicovaginal lavage (CVL) were determined by differential staining and flow cytometry. By 18h post-treatment, a population comprised predominantly of granulocytes and monocytes infiltrated the vagina and persisted through 44h post-treatment. The concentration of proinflammatory cytokines and chemokines in CVL was determined by quantitative ELISA. Concentrations of IL-8 and IL-1beta were consistently significantly increased after microbicide application suggesting these cytokines are useful biomarkers for epithelial injury in the sheep model. Together, the results of these immunological assessments mirror those obtained in previous animal models and human trials with the same compound and greatly extend the utility of the sheep vaginal model in assessing the vaginal barrier and immune microenvironment.
Pahari, S., D. Chatterjee, S. Negi, J. Kaur, B. Singh and J. N. Agrewala (2017). “Morbid Sequences Suggest Molecular Mimicry between Microbial Peptides and Self-Antigens: A Possibility of Inciting Autoimmunity.” Front Microbiol 8: 1938.
Understanding etiology of autoimmune diseases has been a great challenge for designing drugs and vaccines. The pathophysiology of many autoimmune diseases may be attributed to molecular mimicry provoked by microbes. Molecular mimicry hypothesizes that a sequence homology between foreign and self-peptides leads to cross-activation of autoreactive T cells. Different microbial proteins are implicated in various autoimmune diseases, including multiple sclerosis, human type 1 diabetes, primary biliary cirrhosis and rheumatoid arthritis. It may be imperative to identify the microbial epitopes that initiate the activation of autoreactive T cells. Consequently, in the present study, we employed immunoinformatics tools to delineate homologous antigenic regions between microbes and human proteins at not only the sequence level but at the structural level too. Interestingly, many cross-reactive MHC class II binding epitopes were detected from an array of microbes. Further, these peptides possess a potential to skew immune response toward Th1-like patterns. The present study divulges many microbial target proteins, their putative MHC-binding epitopes, and predicted structures to establish the fact that both sequence and structure are two important aspects for understanding the relationship between molecular mimicry and autoimmune diseases. Such findings may enable us in designing potential immunotherapies to tolerize autoreactive T cells.
Lu, L. L., T. J. Suscovich, S. M. Fortune and G. Alter (2017). “Beyond binding: antibody effector functions in infectious diseases.” Nat Rev Immunol.
Antibodies play an essential role in host defence against pathogens by recognizing microorganisms or infected cells. Although preventing pathogen entry is one potential mechanism of protection, antibodies can control and eradicate infections through a variety of other mechanisms. In addition to binding and directly neutralizing pathogens, antibodies drive the clearance of bacteria, viruses, fungi and parasites via their interaction with the innate and adaptive immune systems, leveraging a remarkable diversity of antimicrobial processes locked within our immune system. Specifically, antibodies collaboratively form immune complexes that drive sequestration and uptake of pathogens, clear toxins, eliminate infected cells, increase antigen presentation and regulate inflammation. The diverse effector functions that are deployed by antibodies are dynamically regulated via differential modification of the antibody constant domain, which provides specific instructions to the immune system. Here, we review mechanisms by which antibody effector functions contribute to the balance between microbial clearance and pathology and discuss tractable lessons that may guide rational vaccine and therapeutic design to target gaps in our infectious disease armamentarium.
Vaccine Design Immunogenicity Efficacy
Jones, C. H., G. Zhang, R. Nayerhoda, M. Beitelshees, A. Hill, P. Rostami, Y. Li, B. A. Davidson, P. Knight, 3rd and B. A. Pfeifer (2017). “Comprehensive vaccine design for commensal disease progression.” Sci Adv 3(10): e1701797.
Commensal organisms with the potential to cause disease pose a challenge in developing treatment options. Using the example featured in this study, pneumococcal disease begins with Streptococcus pneumoniae colonization, followed by triggering events that prompt the release of a virulent subpopulation of bacteria. Current vaccines focus on colonization prevention, which poses unintended consequences of serotype niche replacement. In this study, noncovalent colocalization of two classes of complementary antigens, one to prevent the colonization of the most aggressive S. pneumoniae serotypes and another to restrict virulence transition, provides complete vaccine effectiveness in animal subjects and the most comprehensive coverage of disease reported to date. As a result, the proposed vaccine formulation offers universal pneumococcal disease prevention with the prospect of effectively managing a disease that afflicts tens to hundreds of millions globally. The approach more generally puts forth a balanced prophylactic treatment strategy in response to complex commensal-host dynamics.
Xia, L., R. Su, Z. An, T. M. Fu and W. Luo (2017). “Human Cytomegalovirus vaccine development: Immune responses to look into vaccine strategy.” Hum Vaccin Immunother: 0.
Human cytomegalovirus (HCMV) causes considerable morbidity and disability in high risk, immunocompromised populations including recipients of solid organ transplants, and fetuses whose immune systems are not yet mature. Vaccines aimed at ameliorating the severity of disease and preventing HCMV infection can be categorized into two main approaches of vaccine design, with one focusing on virus modification and the other on individual antigens. However, no candidates in either class have been successful in achieving durable and protective immunity. Recent studies on the natural immune response provide new insight into HCMV vaccine strategy. In particular, studies have demonstrated that the incorporation of a pentameric complex is necessary for a vaccine to generate the potent neutralizing antibodies often seen in seropositive individuals. This review summarizes recent findings in the development of HCMV vaccines and key considerations that should be taken into vaccine design based on improved understanding of natural HCMV immunity.
Vaccine Design – Vectors
Vitelli, A., A. Folgori, E. Scarselli, S. Colloca, S. Capone and A. Nicosia (2017). “Chimpanzee adenoviral vectors as vaccines – Challenges to move the technology into the fast lane.” Expert Rev Vaccines.
INTRODUCTION: In recent years, replication-defective chimpanzee-derived adenoviruses have been extensively evaluated as genetic vaccines. These vectors share desirable properties with human adenoviruses like the broad tissue tropism and the ease of large-scale manufacturing. Additionally, chimpanzee adenoviruses have the advantage to overcome the negative impact of pre-existing anti-human adenovirus immunity. Areas covered: Here the authors review current pre-clinical research and clinical trials that utilize chimpanzee-derived adenoviral vectors as vaccines. A wealth of studies are ongoing to evaluate different vector backbones and administration routes with the aim of improving immune responses. The challenges associated with the identification of an optimal chimpanzee vector and immunization strategies for different immunological outcomes will be discussed. Expert commentary: The demonstration that chimpanzee adenoviruses can be safely used in humans has paved the way to the use of a whole new array of vectors of different stereotypes. However, so far no predictive signature of vector immunity in humans has been identified. The high magnitude of T cell responses elicited by chimpanzee adenoviruses has allowed dissecting the qualitative aspects that may be important for protective immunity. Ultimately, only the results from the most clinically advanced products will help establish the efficacy of the vaccine vector platform in the field of disease prevention.