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Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms. Author summary: In this study, we demonstrate a novel mechanism for binding of human adenoviruses (HAdVs) to cells that is dependent upon interactions with α-defensin host defense peptides but is independent of known viral receptors and co-receptors. To block normal receptor-mediated HAdV infection, we made genetic changes to both host cells and HAdVs. Under these conditions, α-defensins restored cell binding; however, infection still required the function of HAdV integrin co-receptors. This was true for multiple types of HAdVs that use different primary receptors and for cells that are either naturally devoid of HAdV receptors or were engineered to be receptor deficient. These observations suggest that in the presence of concentrations of α-defensins that would be found naturally in the lung or intestine, there are two parallel pathways for HAdV binding to cells that converge on integrins for productive infection. Moreover, these binding pathways function independently, and both operate in mixed culture. Thus, we have found that viruses can co-opt host defense molecules to expand their tropism. [ABSTRACT FROM AUTHOR]

Non-replicating adenovirus-based vectors have been broadly used for the development of prophylactic vaccines in humans and are licensed for COVID-19 and Ebola virus disease prevention. Adenovirus-based vectored vaccines encode for one or more disease specific transgenes with the aim to induce protective immunity against the target disease. The magnitude and duration of transgene expression of adenovirus 5- based vectors (human type C) in the host are key factors influencing antigen presentation and adaptive immune responses. Here we characterize the magnitude, duration, and organ biodistribution of transgene expression after single intramuscular administration of adenovirus 26-based vector vaccines in mice and evaluate the differences with adenovirus 5-based vector vaccine to understand if this is universally applicable across serotypes. We demonstrate a correlation between peak transgene expression early after adenovirus 26-based vaccination and transgene-specific cellular and humoral immune responses for a model antigen and SARS-CoV-2 spike protein, independent of innate immune activation. Notably, the memory immune response was similar in mice immunized with adenovirus 26-based vaccine and adenovirus 5-based vaccine, despite the latter inducing a higher peak of transgene expression early after immunization and a longer duration of transgene expression. Together these results provide further insights into the mode of action of adenovirus 26-based vector vaccines. [ABSTRACT FROM AUTHOR]

Thailand has had over 30 years of experiences and development in fighting HIV/AIDS with successful results in terms of providing access to prevention, testing, antiretroviral treatment (ART) and care for over 90% of the affected patients. As a consequence, approximately 400,000 patients on ART currently have undetectable viral load, lead normal lives, and are untransmittable. However, ART must remain in place forever or else the viral load in blood will rebound. Recent advance in stem cell transplant, gene editing, and therapeutic HIV vaccine development yields hope on designing novel approach for an HIV elimination or functional cure. The National AIDS Prevention and Alleviation Committee of Thailand has set up the Subcommittee on HIV Vaccine Trials to oversee and endorse experimental vaccine regimen with sound and adequate scientific background to be tested in Thailand. So far, at least 23 small and large studies have been conducted in collaboration with the international organizations and at least 10 articles were published after the studies ended and cited over 2,726 times. One landmarked trial using notable vaccine regimen, evaluated in the RV144 trial, has shown effectiveness in reducing new infections by 31.2%. The conduction of these research in Thailand have facilitated the development of infrastructure, networking, and experience sufficiently to further support future field trial with a notable HIV cure approach. Since there are over 400,000 HIV cases with undetectable viral load in Thailand, this condition poses an excellent opportunity for testing a novel HIV cure approaches to eliminate HIV or functional HIV cure. The Subcommittee has reviewed current novel methods in this regard and strongly welcomed international organizations with similar aim, to test an innovative therapeutic HIV vaccine or a combination therapy to finally end HIV/AIDS in Thailand by the year 2030. [ABSTRACT FROM AUTHOR]

The recently published AMP trial (HVTN 703/HPTN 081 and HVTN704/HPTN 085) results have validated broad neutralising antibodies (bNAbs) as potential anti-HIV-1 agents. However, single bNAb preparations are unlikely to cope with the onslaught of existing and de novo resistance mutations, thus necessitating the use of bNAb combinations to achieve clinically relevant results. Specifically engineered antibodies incorporating two bNAbs into a single antibody structure have been developed. These bispecific antibodies (bibNAbs) retain the benefits of bNAb combinations, whilst several conformations exhibit improved neutralisation potency over the parental bNAbs. Here we report on the engineering of a bibNAb comprising of an HIV-1 spike targeting bNAb N6 and a host CD4 targeting antibody ibalizumab (iMab). Antibodies were expressed in HEK293T cells and purified by protein-A affinity chromatography followed by size exclusion chromatography to achieve homogenous, monomeric, bibNAb preparations. Antibody purity was confirmed by SDS-PAGE whilst epitope specificity and binding were confirmed by ELISA. Finally, antibody breadth and potency data were generated by HIV-1 neutralisation assay (n = 21, inclusive of the global panel). iMab-N6 exhibited better neutralisation breadth (100% coverage) in comparison to its parental bNAbs iMab (90%) and N6 (95%). This is encouraging as exceptional neutralisation breadth is necessary for HIV-1 treatment or prevention. Unfortunately, iMab-N6 did not exhibit any enhancement in potency over the most potent parental antibody, iMab (p = 0.1674, median IC50 of 0.0475 µg/ml, and 0.0665 µg/ml respectively) or the parental combination, iMab + N6 (p = 0.1964, median IC50: combination 0.0457 µg/ml). This result may point to a lack of dual engagement of the bibNAb Fab moieties necessary for potency enhancement. Against the previously reported bibNAbs; iMab-CAP256, 10E08-iMab, and PG9-iMab; iMab-N6 was the lowest performing bibNAb. The re-engineering of iMab-N6 to enhance its potency, while retaining breadth, is a worthwhile endeavour due to its clinical potential. [ABSTRACT FROM AUTHOR]

Nonhuman primates (NHPs) are well-established basic and translational research models for human immunodeficiency virus (HIV) infections and pathophysiology, hematopoietic stem cell (HSC) transplantation, and assisted reproductive technologies. Recent advances in CRISPR/Cas9 gene editing technologies present opportunities to refine NHP HIV models for investigating genetic factors that affect HIV replication and designing cellular therapies that exploit genetic barriers to HIV infections, including engineering mutations into CCR5 and conferring resistance to HIV/simian immunodeficiency virus (SIV) infections. In this report, we provide an overview of recent advances and challenges in gene editing NHP embryos and discuss the value of genetically engineered animal models for developing novel stem cell-based therapies for curing HIV. [ABSTRACT FROM AUTHOR]

Both SIV and SHIV are powerful tools for evaluating antibody-mediated prevention and treatment of HIV-1. However, owing to a lack of rhesus-derived SIV broadly neutralizing antibodies (bnAbs), testing of bnAbs for HIV-1 prevention or treatment has thus far been performed exclusively in the SHIV NHP model using bnAbs from HIV-1-infected individuals. Here we describe the isolation and characterization of multiple rhesus-derived SIV bnAbs capable of neutralizing most isolates of SIV. Eight antibodies belonging to two clonal families, ITS102 and ITS103 which target unique epitopes in the CD4bs region, were found to be broadly neutralizing and together neutralized all SIV strains tested. A rare feature of these bnAbs and two additional antibody families, ITS92 and ITS101 which mediate strain-specific neutralizing activity against SIV from sooty mangabeys (SIVsm), was their ability to achieve near complete (i.e. 100%) neutralization of moderately and highly neutralization-resistant SIV. Overall, these newly identified SIV bnAbs highlight the potential for evaluating HIV-1 prophylactic and therapeutic interventions using fully simian, rhesus-derived bnAbs in the SIV NHP model, thereby circumventing issues related to rapid antibody clearance of human-derived antibodies, Fc mismatch and limited genetic diversity of SHIV compared to SIV. Author summary: Antibodies that can bind to a virus and block infection are called neutralizing antibodies. In human immunodeficiency virus (HIV), antibodies that can block multiple strains of HIV circulating globally are known as broadly neutralizing antibodies. These broadly neutralizing antibodies have the potential to be used to treat HIV-infected individuals or to prevent HIV infection altogether. However, before these broadly neutralizing antibodies can safely be used in humans, they must first be tested in monkeys. Simian immunodeficiency virus (SIV), which causes an acquired immunodeficiency syndrome (AIDS)-like illness in Asian macaques that is similar to AIDS in humans, makes it possible to perform pre-clinical testing in monkeys but requires the use of antibodies that are specific to SIV. Another important consideration for testing antibodies in monkeys is that, like HIV, there are many different strains of SIV and some of these are highly resistant to neutralization. In this study we used blood from SIV-infected macaques to isolate several antibodies that can neutralize multiple strains of SIV, including strains that are typically resistant to neutralization. These SIV broadly neutralizing antibodies closely resemble HIV broadly neutralizing antibodies, making it possible now to test antibody-based vaccines or therapies for HIV using the SIV nonhuman primate model of AIDS. [ABSTRACT FROM AUTHOR]

Background: Recent studies have indicated that broadly neutralizing antibodies (bnAbs) in children may develop earlier after human immunodeficiency virus (HIV) infection compared to adults.Methods: We evaluated plasma from 212 antiretroviral therapy-naive children with HIV (1-3 years old). Neutralization breadth and potency was assessed using a panel of 10 viruses and compared to adults with chronic HIV. The magnitude, epitope specificity, and immunoglobulin (Ig)G subclass distribution of Env-specific antibodies were assessed using a binding antibody multiplex assay.Results: One-year-old children demonstrated neutralization breadth comparable to chronically infected adults, whereas 2- and 3-year-olds exhibited significantly greater neutralization breadth (P = .014). Likewise, binding antibody responses increased with age, with levels in 2- and 3-year-old children comparable to adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. It is interesting to note that the neutralization activity was mapped to a single epitope (CD4 binding site, V2 or V3 glycans) in only 5 of 38 pediatric broadly neutralizing samples, which suggests that most children may develop a polyclonal neutralization response.Conclusions: These results contribute to a growing body of evidence suggesting that initiating HIV immunization early in life may present advantages for the development of broadly neutralizing antibody responses. [ABSTRACT FROM AUTHOR]

Adeno-associated viruses (AAV) are considered non-pathogenic in humans, and thus have been developed into powerful vector platforms for in vivo gene therapy. Although the various AAV serotypes display broad tropism, frequently infecting multiple tissues and cell types, vectors for specific and efficient targeting of human CD4+ T lymphocytes are largely missing. In fact, a substantial translational bottleneck exists in the field of therapeutic gene transfer that would require in vivo delivery into peripheral disease-related lymphocytes for subsequent genome editing. To solve this issue, capsid modification for retargeting AAV tropism, and in turn improving vector potency, is considered a promising strategy. Here, we genetically modified the minor AAV2 capsid proteins, VP1 and VP2, with a set of novel nanobodies with high-affinity for the human CD4 receptor. These novel vector variants demonstrated improved targeting of human CD4+ cells, including primary human peripheral blood mononuclear cells (PBMC) and purified human CD4+ T lymphocytes. Thus, the technical approach presented here provides a promising strategy for developing specific gene therapy vectors, particularly targeting disease-related peripheral blood CD4+ leukocytes. [ABSTRACT FROM AUTHOR]

Introduction: The last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV‐specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention. Discussion: Recently, two antibody‐mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof‐of‐concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub‐analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM‐bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody‐inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best‐in‐class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi‐ and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half‐life and improve genital tissue persistence offer additional advantages. Conclusions: Iterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi‐ and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy. [ABSTRACT FROM AUTHOR]

HIV-1 broadly neutralizing antibodies (bNAbs) targeting the viral envelope have shown significant promise in both HIV prevention and viral clearance, including pivotal results against sensitive strains in the recent Antibody Mediated Prevention (AMP) trial. Studies of bNAb passive transfer in infected patients have demonstrated transient reduction of viral load at high concentrations that rebounds as bNAb is cleared from circulation. While neutralization is a crucial component of therapeutic efficacy, numerous studies have demonstrated that bNAbs can also mediate effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement deposition (ADCD). These functions have been shown to contribute towards protection in several models of HIV acquisition and in viral clearance during chronic infection, however the role of target epitope in facilitating these functions, as well as the contribution of individual innate functions in protection and viral clearance remain areas of active investigation. Despite their potential, the transient nature of antibody passive transfer limits the widespread use of bNAbs. To overcome this, we and others have demonstrated vectored antibody delivery capable of yielding long-lasting expression of bNAbs in vivo. Two clinical trials have shown that adeno-associated virus (AAV) delivery of bNAbs is safe and capable of sustained bNAb expression for over 18 months following a single intramuscular administration. Here, we review key concepts of effector functions mediated by bNAbs against HIV infection and the potential for vectored immunoprophylaxis as a means of producing bNAbs in patients. [ABSTRACT FROM AUTHOR]

The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this effect, with IgG3 associated with improved HIV control and vaccine efficacy. We recently showed that an IgG3 variant of bNAb CAP256-VRC26.25 exhibited more potent neutralization and phagocytosis than its IgG1 counterpart. Here, we expanded this analysis to include additional bNAbs targeting all major epitopes. A total of 15 bNAbs were expressed as IgG1 or IgG3, and pairs were assessed for neutralization potency against the multi-subtype global panel of 11 HIV strains. Binding to the neonatal Fc receptor (FcRn) and Fcγ receptors were measured using ELISA and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis were measured using infectious viruses and global panel Env SOSIP trimers, respectively. IgG3 bNAbs generally showed similar or increased (up to 60 fold) neutralization potency than IgG1 versions, though the effect was virus-specific. This improvement was statistically significant for CAP256-VRC26.25, 35022, PGT135 and CAP255.G3. IgG3 bNAbs also showed significantly improved binding to FcγRIIa which correlated with enhanced phagocytosis of all trimeric Env antigens. Differences in ADCC were epitope-specific, with IgG3 bNAbs to the MPER, CD4 binding site and gp120-gp41 interface showing increased ADCC. We also explored the pH dependence of IgG1 and IgG3 variants for FcRn binding, as this determines the half-life of antibodies. We observed reduced pH dependence, associated with shorter half-lives for IgG3 bNAbs, with κ-light chains. However, IgG3 bNAbs that use λ-light chains showed similar pH dependence to their IgG1 counterparts. This study supports the manipulation of the constant region to improve both the neutralizing and Fc effector activity of bNAbs, and suggests that IgG3 versions of bNAbs may be preferable for passive immunity given their polyfunctionality. [ABSTRACT FROM AUTHOR]

The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection. [ABSTRACT FROM AUTHOR]

Despite the discovery that the human immunodeficiency virus 1 (HIV-1) is the pathogen of acquired immunodeficiency syndrome (AIDS) in 1983, there is still no effective anti-HIV-1 vaccine. The major obstacle to the development of HIV-1 vaccine is the extreme diversity of viral genome sequences. Nonetheless, a number of broadly neutralizing antibodies (bNAbs) against HIV-1 have been made and identified in this area. Novel strategies based on using these bNAbs as an efficacious preventive and/or therapeutic intervention have been applied in clinical. In this review, we summarize the recent development of bNAbs and its application in HIV-1 acquisition prevention as well as discuss the innovative approaches being used to try to convey protection within individuals at risk and being treated for HIV-1 infection. [ABSTRACT FROM AUTHOR]

Infection with distinct Zika virus (ZIKV) strains in in vitro and in vivo models has demonstrated that the host's response to infection is strain-dependent. There has been no analysis of the impact of infection with different ZIKV strains on miRNA expression in human cells. We investigated miRNA expression in PNT1A cells upon infection with an African ZIKV strain (MR766) and a Brazilian ZIKV strain (ZIKVBR) using PCR array. Sixteen miRNAs were modulated in PNT1A cells: six miRNAs were modulated by both strains, while a set of ten miRNAs were modulated exclusively by ZIKVBR infection. In silico analysis showed that nine significant KEGG pathways and eight significant GO terms were predicted to be enriched upon ZIKVBR infection, and these pathways were related to cancer, environmental information processing, metabolism, and extracellular matrix. Differential modulation of miRNA expression suggests that distinct strains of ZIKV can differentially modulate the host response through the action of miRNAs. [ABSTRACT FROM AUTHOR]

With the discovery of antiretroviral therapy, HIV-1 infection has transitioned into a manageable but chronic illness, which requires lifelong treatment. Nevertheless, complete eradication of the virus has still eluded us. This is partly due to the virus's ability to remain in a dormant state in tissue reservoirs, 'hidden' from the host's immune system. Also, the high mutation rate of HIV-1 results in escape mutations in response to many therapeutics. Regardless, the development of novel cures for HIV-1 continues to move forward with a range of approaches from immunotherapy to gene editing. However, to evaluate in vivo pathogenesis and the efficacy and safety of therapeutic approaches, a suitable animal model is necessary. To this end, the humanized mouse was developed by McCune in 1988 and has continued to be improved on over the past 30 years. Here, we review the variety of humanized mouse models that have been utilized through the years and describe their specific contribution in translating HIV-1 cure strategies to the clinic. [ABSTRACT FROM AUTHOR]

Antibodies are considered as an excellent foundation to neutralize pathogens and as highly specific therapeutic agents. Antibodies are generated in response to a vaccine but little use as immunotherapy to combat virus infections. A new generation of broadly cross-reactive and highly potent antibodies has led to a unique chance for them to be used as a medical intervention. Neutralizing antibodies (monoclonal and polyclonal antibodies) are desirable for pharmaceutical products because of their ability to target specific epitopes with their variable domains by precise neutralization mechanisms. The isolation of neutralizing antiviral antibodies has been achieved by Phage displayed antibody libraries, transgenic mice, B cell approaches, and hybridoma technology. Antibody engineering technologies have led to efficacy improvements, to further boost antibody in vivo activities. "Although neutralizing antiviral antibodies have some limitations that hinder their full development as therapeutic agents, the potential for prevention and treatment of infections, including a range of viruses (HIV, Ebola, MERS-COV, CHIKV, SARS-CoV, and SARS-CoV2), are being actively pursued in human clinical trials." [ABSTRACT FROM AUTHOR]

Enteric alpha-defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to defensins and even appropriate them to enhance infection despite neutralization of closely related microbes. We therefore hypothesized that defensins impose selective pressure during fecal-oral transmission. Upon passaging a defensin-sensitive serotype of adenovirus in the presence of a human defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of defensin antiviral activity. Infection and biochemical assays suggest that a balance between increased cell binding and a downstream block in intracellular trafficking mediated by defensin interactions with all of the major capsid proteins dictates the outcome of infection. These results extensively revise our understanding of the interplay between defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses. Author summary: Defensins are potent antimicrobial peptides that are found on human mucosal surfaces and can directly neutralize viruses. They are abundant in the small intestine, which is constantly challenged by ingested viral pathogens. Interestingly, non-enveloped viruses, such as adenovirus, that infect the gastrointestinal system are unaffected by defensins or can even appropriate defensins to enhance their infection. In contrast, respiratory adenoviruses are neutralized by the same defensins. How enteric viruses overcome defensin neutralization is not well understood. Our studies are the first to show that defensins can drive the evolution of non-enveloped viruses. Furthermore, we identify important components within human adenovirus that dictate sensitivity to defensins. This new insight into defensin-virus interactions informs our understanding of mucosal immunity to viral infections. [ABSTRACT FROM AUTHOR]

Purpose of Review: The application of immunotherapies to HIV presents a new horizon of treatment options, but little is known about what impact they may have on the central nervous system (CNS). Here we review the most promising immunotherapeutic strategies that can be used to target HIV in the CNS and focus on identifying their potential benefits while exploring the challenges that remain in their application. Recent Findings: We have identified five immunotherapeutic strategies that hold potential in managing CNS disease among HIV-infected patients. These include broadly neutralizing antibodies, multi-affinity antibodies, CAR-T cell therapy, checkpoint inhibitors, and therapeutic vaccines. Summary: Each class of immunotherapy presents unique mechanisms by which CNS viremia and latency may be addressed but are faced with several challenges. CAR-T cell therapy and multi-affinity antibodies seem to hold promise, but combination therapy is likely to be most effective. However, more human trials are needed before the clinical benefits of these therapies are realized. [ABSTRACT FROM AUTHOR]

Unusual reaction proceeding via the electrophilic activation of nitroalkanes in the presence of polyphosphoric acid has been discovered. Subsequent nucleophilic attack with semicarbazides or thiosemicarbazides allows to access 2-amino-1,3,4-oxadiazoles and 2-amino-1,3,4-thiadiazoles, respectively. [ABSTRACT FROM AUTHOR]

Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs. [ABSTRACT FROM AUTHOR]

In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and potency over most individual antibodies and are entering advanced clinical development. Genetic engineering of the Fc regions has markedly improved bnAb half-life, increased mucosal tissue concentrations of antibodies (especially in the genital tract), and enhanced immunomodulatory and Fc effector functionality, all of which improve antibodies' preventative and therapeutic potential. Human-derived monoclonal antibodies are likely to enter the realm of primary care prevention and therapy for viral infections in the near future. [ABSTRACT FROM AUTHOR]

Broadly neutralizing antibodies (bNAbs) protect against HIV infection in non-human primates and their efficacy may be enhanced through interaction with Fc receptors on immune cells. Antibody isotype is a modulator of this binding with the IgG3 subclass mediating potent Fc effector function and is associated with HIV vaccine efficacy and HIV control. BNAb functions are typically assessed independently of the constant region with which they are naturally expressed. To examine the role of natural isotype in the context of a bNAb lineage we studied CAP256, an HIV-infected individual that mounted a potent V2-specific bNAb response. CAP256 expressed persistently high levels of plasma IgG3 which we found mediated both broad neutralizing activity and potent Fc function. Sequencing of germline DNA and the constant regions of V2-directed bNAbs from this donor revealed the expression of a novel IGHG3 allele as well as IGHG3*17, an allele that produces IgG3 antibodies with increased plasma half-life. Both allelic variants were used to generate CAP256-VRC26.25 and CAP256-VRC26.29 IgG3 bNAbs and these were compared to IgG1 versions. IgG3 variants were shown to have significantly higher phagocytosis and trogocytosis compared to IgG1 versions, which corresponded to increased affinity for FcγRIIa. Neutralization potency was also significantly higher for IgG3 bNAbs, particularly against viruses lacking the N160 glycan. By exchanging hinge regions between subclass variants, we showed that hinge length modulated both neutralization potency and Fc function. This study showed that co-operation between the variable and natural IgG3 constant regions enhanced the polyfunctionality of antibodies, indicating the value of leveraging genetic variation which could be exploited for passive immunity. Author summary: In the only partially effective HIV vaccine trial to date, reduced risk of infection correlated with IgG3 antibodies that bound to the V2 region of the HIV envelope. IgG3 antibodies potently mediate the broadest range of Fc cytotoxic functions such as complement deposition, cellular lysis, engulfment and membrane nibbling. The relevance of different IgG3 alleles in antibody function is not typically examined, nor are antibodies usually assessed in the context of their natural isotype. Here we show that IgG3 V2-specific broadly neutralizing antibodies from donor CAP256 mediated both enhanced cytotoxic functions and neutralization potency compared to an IgG1 variant. We demonstrate that the long hinge region of IgG3 facilitated this increased functionality. These data suggest that isotype may be tuned to enhance both neutralization and cytotoxic activity of broadly neutralizing antibodies that can be used to improve the efficacy of passive immunization strategies for HIV prevention. [ABSTRACT FROM AUTHOR]

Purpose of Review: Pre-exposure prophylaxis (PrEP) is a potent HIV prevention strategy, but uptake of daily oral PrEP remains low. This review covers PrEP agents currently available and agents and modalities under investigation. Recent Findings: Injectable ARV preparations have high acceptability among users but are likely to require adherence to 8-week interval injections. Topical microbicide gels and vaginal rings have underperformed by intention-to-treat analyses in efficacy studies, at least in large part due to challenges with adherence and/or sustained use. However, daily oral TDF-FTC also underperformed in randomized, placebo-controlled trials compared to expectations and subsequent real-world pragmatic use. Summary: On-demand (2-1-1 dosing strategy for MSM) and injectable PrEP appear to be acceptable among participants in clinical trials. These modalities are particularly compelling alternatives for individuals who either do not want to take a daily medication (both on-demand and injectable) and/or want to take PrEP without a long commitment (on-demand). Emerging modalities such as vaginal films, microneedles, and subdermal implants have numerous advantages but are still in early stages of development. [ABSTRACT FROM AUTHOR]

Chimeric Simian-Human Immunodeficiency Viruses (SHIVs) are an important tool for evaluating anti-HIV Env interventions in nonhuman primate (NHP) models. However, most unadapted SHIVs do not replicate well in vivo limiting their utility. Furthermore, adaptation in vivo often negatively impacts fundamental properties of the Env, including neutralization profiles. Transmitted/founder (T/F) viruses are particularly important to study since they represent viruses that initiated primary HIV-1 infections and may have unique attributes. Here we combined in vivo competition and rational design to develop novel subtype C SHIVs containing T/F envelopes. We successfully generated 19 new, infectious subtype C SHIVs, which were tested in multiple combinatorial pools in Indian-origin rhesus macaques. Infected animals attained peak viremia within 5 weeks ranging from 103 to 107 vRNA copies/mL. Sequence analysis during primary infection revealed 7 different SHIVs replicating in 8 productively infected animals with certain clones prominent in each animal. We then generated 5 variants each of 6 SHIV clones (3 that predominated and 3 undetectable after pooled in vivo inoculations), converting a serine at Env375 to methionine, tyrosine, histidine, tryptophan or phenylalanine. Overall, most Env375 mutants replicated better in vitro and in vivo than wild type with both higher and earlier peak viremia. In 4 of these SHIV clones (with and without Env375 mutations) we also created mutations at position 281 to include serine, alanine, valine, or threonine. Some Env281 mutations imparted in vitro replication dynamics similar to mutations at 375; however, clones with both mutations did not exhibit incremental benefit. Therefore, we identified unique subtype C T/F SHIVs that replicate in rhesus macaques with improved acute phase replication kinetics without altering phenotype. In vivo competition and rational design can produce functional SHIVs with globally relevant HIV-1 Envs to add to the growing number of SHIV clones for HIV-1 research in NHPs. [ABSTRACT FROM AUTHOR]

Novel broadly neutralizing antibodies targeting HIV-1 hold promise for their use in the prevention and treatment of HIV-1 infection. Pre-clinical results have encouraged the evaluation of these antibodies in healthy and HIV-1-infected humans. In first clinical trials, highly potent broadly neutralizing antibodies have demonstrated their safety and significant antiviral activity by reducing viremia and delaying the time to viral rebound in individuals interrupting antiretroviral therapy. While emerging antibody-resistant viral variants have indicated limitations of antibody monotherapy, strategies to enhance the efficacy of broadly neutralizing antibodies in humans are under investigation. These include the use of antibody combinations to prevent viral escape, antibody modifications to increase the half-life and the co-administration of latency-reversing agents to target the cellular reservoir of HIV-1. We provide an overview of the results of pre-clinical and clinical studies of broadly HIV-1 neutralizing antibodies, discuss their implications and highlight approaches for the ongoing advancement into humans. [ABSTRACT FROM AUTHOR]

Despite numerous efforts, we still do not have prophylactic vaccines for many clinically relevant viruses, such as HIV, hepatitis C virus, Zika virus, and respiratory syncytial virus. Several factors have contributed to the current lack of effective vaccines, including the high rate of viral mutation, low immunogenicity of recombinant viral antigens, instability of viral antigenic proteins administered in vivo, sophisticated mechanisms of viral immune evasion, and inefficient induction of mucosal immunity by vaccine models studied to date. Some of these obstacles could be partially overcome by the use of vaccine adjuvants. Nanoparticles have been intensively investigated as vaccine adjuvants because they possess chemical and structural properties that improve immunogenicity. The use of nanotechnology in the construction of immunization systems has developed into the field of viral nanovaccinology. The purpose of this paper is to review and correlate recent discoveries concerning nanoparticles and specific properties that contribute to the immunogenicity of viral nanoparticle vaccines, bio-nano interaction, design of nanoparticle vaccines for clinically relevant viruses, and future prospects for viral nanoparticle vaccination. [ABSTRACT FROM AUTHOR]

Background: Part of the missing heritability in Genome Wide Association Studies (GWAS) is expected to be explained by interactions between genetic variants, also called epistasis. Various statistical methods have been developed to detect epistasis in case-control GWAS. These methods face major statistical challenges due to the number of tests required, the complexity of the Linkage Disequilibrium (LD) structure, and the lack of consensus regarding the definition of epistasis. Their limited impact in terms of uncovering new biological knowledge might be explained in part by the limited amount of experimental data available to validate their statistical performances in a realistic GWAS context. In this paper, we introduce a simulation pipeline for generating real scale GWAS data, including epistasis and realistic LD structure. We evaluate five exhaustive bivariate interaction methods, fastepi, GBOOST, SHEsisEpi, DSS, and IndOR. Two hundred thirty four different disease scenarios are considered in extensive simulations. We report the performances of each method in terms of false positive rate control, power, area under the ROC curve (AUC), and computation time using a GPU. Finally we compare the result of each methods on a real GWAS of type 2 diabetes from the Welcome Trust Case Control Consortium. Results: GBOOST, SHEsisEpi and DSS allow a satisfactory control of the false positive rate. fastepi and IndOR present an increase in false positive rate in presence of LD between causal SNPs, with our definition of epistasis. DSS performs best in terms of power and AUC in most scenarios with no or weak LD between causal SNPs. All methods can exhaustively analyze a GWAS with 6.105 SNPs and 15,000 samples in a couple of hours using a GPU. Conclusion: This study confirms that computation time is no longer a limiting factor for performing an exhaustive search of epistasis in large GWAS. For this task, using DSS on SNP pairs with limited LD seems to be a good strategy to achieve the best statistical performance. A combination approach using both DSS and GBOOST is supported by the simulation results and the analysis of the WTCCC dataset demonstrated that this approach can detect distinct genes in epistasis. Finally, weak epistasis between common variants will be detectable with existing methods when GWAS of a few tens of thousands cases and controls are available. [ABSTRACT FROM AUTHOR]

Traditional restriction endonuclease-based cloning has been routinely used to generate replication-competent simian-human immunodeficiency viruses (SHIV) and simian tropic HIV (stHIV). This approach requires the existence of suitable restriction sites or the introduction of nucleotide changes to create them. Here, using an In-Fusion cloning technique that involves homologous recombination, we generated SHIVs and stHIVs based on epidemiologically linked clade C transmitted/founder HIV molecular clones from Zambia. Replacing vif from these HIV molecular clones with vif of SIVmac239 resulted in chimeric genomes used to generate infectious stHIV viruses. Likewise, exchanging HIV env genes and introducing N375 mutations to enhance macaque CD4 binding site and cloned into a SHIVAD8-EO backbone. The generated SHIVs and stHIV were infectious in TZMbl and ZB5 cells, as well as macaque PBMCs. Therefore, this method can replace traditional methods and be a valuable tool for the rapid generation and testing of molecular clones of stHIV and SHIV based on primary clinical isolates will be valuable to generate rapid novel challenge viruses for HIV vaccine/cure studies. [ABSTRACT FROM AUTHOR]

Integrins are a large family of adhesion molecules under cellular control that could act bilabially in different situations; on the other hand, they play a significant role in adsorption and entry of immune system cells or other helper cells. Furthermore, they could be good targets for entry, localization and replication of infectious viruses into cells. As viruses apply various strategies for entry and infiltration to cells, comparison of these ways (especially integrin mediated), elucidates effective mechanisms in the inception of viral infection and the host cells interactions. At this point, the present study reviewed the relationships between common viruses such as Adenovirus, Papillomavirus, Herpesvirus, Hantavirus, Rotavirus, Echovirus, foot-and-mouth disease virus, Coxsackievirus type 9, Parechovirus type 1 and Human immunodeficiency virus type 1 with integrins and their viable interactions for therapeutical issues and better recognition of the commencement process of the infection by these viruses. [ABSTRACT FROM AUTHOR]

B cell follicles in secondary lymphoid tissues represent an immune privileged sanctuary for AIDS viruses, in part because cytotoxic CD8+ T cells are mostly excluded from entering the follicles that harbor infected T follicular helper (TFH) cells. We studied the effects of native heterodimeric IL-15 (hetIL-15) treatment on uninfected rhesus macaques and on macaques that had spontaneously controlled SHIV infection to low levels of chronic viremia. hetIL-15 increased effector CD8+ T lymphocytes with high granzyme B content in blood, mucosal sites and lymph nodes, including virus-specific MHC-peptide tetramer+ CD8+ cells in LN. Following hetIL-15 treatment, multiplexed quantitative image analysis (histo-cytometry) of LN revealed increased numbers of granzyme B+ T cells in B cell follicles and SHIV RNA was decreased in plasma and in LN. Based on these properties, hetIL-15 shows promise as a potential component in combination immunotherapy regimens to target AIDS virus sanctuaries and reduce long-term viral reservoirs in HIV-1 infected individuals. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Introduction: Prevention of infection remains the ultimate goal for HIV vaccination, and there is compelling evidence that antibodies directed to Envelope are necessary to block infection. Generating antibodies that are sufficiently broad, potent, and sustained to block infection by the diverse HIV-1 strains circulating worldwide remains an area of intense study. Areas covered: In this review, we have summarized progress from publications listed as PubMed citations in 2016–17 in the areas of passive antibody studies using human neutralizing monoclonal antibodies in nonhuman primates, HIV Envelope vaccine development and active vaccination studies to generate potent neutralizing antibodies. Expert commentary: Passive transfer studies in nonhuman primates using human neutralizing monoclonal antibodies have informed the potency, specificity, and cooperativity of antibodies needed to prevent infection, leading to clinical studies now testing potent antibodies for prevention of HIV. Progress in understanding the structure of Envelope has led to novel vaccine constructs, including mimetics, scaffolds and native-like proteins. As yet, no single approach ensures protection against the circulating global HIV-1 strains, but there is progress in understanding why, and intense research continues in these and other areas for a solution. We offer perspectives on how this knowledge may shape the design of future HIV vaccines. [ABSTRACT FROM PUBLISHER]

The aim of rational drug design is to develop small molecules using a quantitative approach to optimize affinity. This should enhance the development of chemical compounds that would specifically, selectively, reversibly, and with high affinity interact with a target protein. It is not yet possible to develop such compounds using computational (i.e., in silico) approach and instead the lead molecules are discovered in high-throughput screening searches of large compound libraries. The main reason why in silico methods are not capable to deliver is our poor understanding of the compound structure–thermodynamics and structure–kinetics correlations. There is a need for databases of intrinsic binding parameters (e.g., the change upon binding in standard Gibbs energy (ΔGint), enthalpy (ΔHint), entropy (ΔSint), volume (ΔVintr), heat capacity (ΔCp,int), association rate (ka,int), and dissociation rate (kd,int)) between a series of closely related proteins and a chemically diverse, but pharmacophoric group-guided library of compounds together with the co-crystal structures that could help explain the structure–energetics correlations and rationally design novel compounds. Assembly of these data will facilitate attempts to provide correlations and train data for modeling of compound binding. Here, we report large datasets of the intrinsic thermodynamic and kinetic data including over 400 primary sulfonamide compound binding to a family of 12 catalytically active human carbonic anhydrases (CA). Thermodynamic parameters have been determined by the fluorescent thermal shift assay, isothermal titration calorimetry, and by the stopped-flow assay of the inhibition of enzymatic activity. Kinetic measurements were performed using surface plasmon resonance. Intrinsic thermodynamic and kinetic parameters of binding were determined by dissecting the binding-linked protonation reactions of the protein and sulfonamide. The compound structure–thermodynamics and kinetics correlations reported here helped to discover compounds that exhibited picomolar affinities, hour-long residence times, and million-fold selectivities over non-target CA isoforms. Drug-lead compounds are suggested for anticancer target CA IX and CA XII, antiglaucoma CA IV, antiobesity CA VA and CA VB, and other isoforms. Together with 85 X-ray crystallographic structures of 60 compounds bound to six CA isoforms, the database should be of help to continue developing the principles of rational target-based drug design. [ABSTRACT FROM AUTHOR]

Preclinical and early human clinical studies of broadly neutralizing antibodies (bNAbs) to prevent and treat HIV infection support the clinical utility and potential of bNAbs for prevention, postexposure prophylaxis, and treatment of acute and chronic infection. Observed and potential limitations of bNAbs from these recent studies include the selection of resistant viral populations, immunogenicity resulting in the development of antidrug (Ab) responses, and the potentially toxic elimination of reservoir cells in regeneration-limited tissues. Here, we review opportunities to improve the clinical utility of HIV Abs to address these challenges and further accomplish functional targets for anti-HIV Ab therapy at various stages of exposure/infection. Before exposure, bNAbs' ability to serve as prophylaxis by neutralization may be improved by increasing serum half-life to necessitate less frequent administration, delivering genes for durable in vivo expression, and targeting bNAbs to sites of exposure. After exposure and/or in the setting of acute infection, bNAb use to prevent/reduce viral reservoir establishment and spread may be enhanced by increasing the potency with which autologous adaptive immune responses are stimulated, clearing acutely infected cells, and preventing cell--cell transmission of virus. In the setting of chronic infection, bNAbs may better mediate viral remission or "cure" in combination with antiretroviral therapy and/or latency reversing agents, by targeting additional markers of tissue reservoirs or infected cell types, or by serving as targeting moieties in engineered cell therapy. While the clinical use of HIV Abs has never been closer, remaining studies to precisely define, model, and understand the complex roles and dynamics of HIV Abs and viral evolution in the context of the human immune system and anatomical compartmentalization will be critical to both optimize their clinical use in combination with existing agents and define further strategies with which to enhance their clinical safety and efficacy. [ABSTRACT FROM AUTHOR]

In a Perspective, Lynn Morris and Nonhlanhla Mkhize discuss the prospects for broadly neutralizing antibodies to be used in preventing HIV infection. [ABSTRACT FROM AUTHOR]

Archaeological and palaeoecological studies throughout the Americas have documented widespread landscape and environmental transformation during the pre-Columbian era. The highly dynamic Formative (or Neolithic) period in northern Chile (ca. 3700–1550 yr BP) brought about the local establishment of agriculture, introduction of new crops (maize, quinoa, manioc, beans, etc.) along with a major population increase, new emergent villages and technological innovations. Even trees such as the Algarrobos (Prosopis section Algarobia) may have been part of this transformation. Here, we provide evidence that these species were not native to the Atacama Desert of Chile (18–27°S), appearing only in the late Holocene and most likely due to human actions. We assembled a database composed of 41 taxon specific AMS radiocarbon dates from archaeobotanical and palaeoecological records (rodent middens, leaf litter deposits), as well an extensive bibliographical review comprising archaeobotanical, paleoecological, phylogenetic and taxonomic data to evaluate the chronology of introduction and dispersal of these trees. Although Algarrobos could have appeared as early as 4200 yr BP in northernmost Chile, they only became common throughout the Atacama over a thousand years later, during and after the Formative period. Cultural and natural factors likely contributed to its spread and consolidation as a major silvicultural resource. [ABSTRACT FROM AUTHOR]

Antibodies have a long history in antiviral therapy, but until recently, they have not been actively pursued for HIV-1 due to modest potency and breadth of early human monoclonal antibodies ( MAbs) and perceived insurmountable technical, financial, and logistical hurdles. Recent advances in the identification and characterization of MAbs with the ability to potently neutralize diverse HIV-1 isolates have reinvigorated discussion and testing of these products in humans, since new broadly neutralizing MAbs (bn MAbs) are more likely to be effective against worldwide strains of HIV-1. In animal models, there is abundant evidence that bn MAbs can block infection in a dose-dependent manner, and the more potent bn MAbs will allow clinical testing at infusion doses that are practically achievable. Moreover, recent advances in antibody engineering are providing further improvements in MAb potency, breadth, and half-life. This review summarizes the current state of the field of bn MAb protection in animal models as well as a review of variables that are critical for antiviral activity. Several bn MAbs are currently in clinical testing, and we offer perspectives on their use as pre-exposure prophylaxis (Pr EP), potential benefits beyond sterilizing immunity, and a discussion of future approaches to engineer novel molecules. [ABSTRACT FROM AUTHOR]

Integrins are an important family of adhesion molecules that were first discovered two decades ago. Integrins are transmembrane heterodimeric glycoprotein receptors consisting of α and β subunits, and are comprised of an extracellular domain, a transmembrane domain, and a cytoplasmic tail. Therein, integrin cytoplasmic domains may associate directly with numerous cytoskeletal proteins and intracellular signaling molecules, which are crucial for modulating fundamental cell processes and functions including cell adhesion, proliferation, migration, and survival. The purpose of this review is to describe the unique structure of each integrin subunit, primary cytoplasmic association proteins, and transduction signaling pathway of integrins, with an emphasis on their biological functions. [ABSTRACT FROM AUTHOR]

Lentiviruses are able to establish persistent infection in their respective hosts despite a potent type-I interferon (IFN-I) response following transmission. A number of IFN-I-induced host factors that are able to inhibit lentiviral replication in vitro have been identified, and these studies suggest a role for IFN-induced factors as barriers to cross-species transmission. However, the ability of these factors to inhibit viral replication in vivo has not been well characterized, nor have the viral determinants that contribute to evasion or antagonism of the host IFN-I response. In this study, we hypothesized that the host IFN-I response serves as a strong selective pressure in the context of SIV/HIV chimeric virus (SHIV) infection of macaques and sought to identify the viral determinants that contribute to IFN-I resistance. We assessed the ability of SHIVs encoding HIV-1 sequences adapted by serial passage in macaques versus SHIVs encoding HIV sequences isolated directly from infected individuals to replicate in the presence of IFNα in macaque lymphocytes. We demonstrate that passage in macaques selects for IFNα resistant viruses that have higher replication kinetics and increased envelope content. SHIVs that encode HIV-1 sequences derived directly from infected humans were sensitive to IFNα –induced inhibition whereas SHIVs obtained after passage in macaques were not. This evolutionary process was directly observed in viruses that were serially passaged during the first few months of infection–a time when the IFNα response is high. Differences in IFNα sensitivity mapped to HIV-1 envelope and were associated with increased envelope levels despite similar mRNA expression, suggesting a post-transcriptional mechanism. These studies highlight critical differences in IFNα sensitivity between HIV-1 sequences in infected people and those used in SHIV models. [ABSTRACT FROM AUTHOR]

SHIV/macaque model is critical for pre-clinical HIV-1 research. The ability of this model to predict efficacious intervention(s) in humans depends on how faithfully the model recapitulates key features of HIV-1 transmission and pathogenesis. Here, we provide insights for rationally designing SHIVs with transmitted HIV-1 variants for vaccine and prevention research. [ABSTRACT FROM AUTHOR]

The success of gene therapy relies heavily on the performance of vectors that can effectively deliver transgenes to desired cell populations. As viruses have evolved to deliver genetic material into cells, a prolific area of research has emerged over the last several decades to leverage the innate properties of viruses as well as to engineer new features into them. Specifically, the field of synthetic virology aims to capitalize on knowledge accrued from fundamental virology research in order to design functionally enhanced gene delivery vectors. The enhanced viral vectors, or 'bionic' viruses, feature engineered components, or 'parts', that are natural (intrinsic to viruses or from other organisms) and synthetic (such as man-made polymers or inorganic nanoparticles). Various design strategies-rational, combinatorial, and pseudo-rational-have been pursued to create the hybrid viruses. The gene delivery vectors of the future will likely criss-cross the boundaries between natural and synthetic domains to harness the unique strengths afforded by the various functional parts that can be grafted onto virus capsids. Such research endeavors will further expand and enable enhanced control over the functional capacity of these nanoscale devices for biomedicine. WIREs Nanomed Nanobiotechnol 2014, 6:548-558. doi: 10.1002/wnan.1287 For further resources related to this article, please visit the . Conflict of interest: The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]