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CURATOR
A pinboard by
Endre Szvetnik

I cover science and tech news for Sparrho and work with Sparrho Heroes to curate, translate and disseminate scientific research to the wider public.

PINBOARD SUMMARY

We are getting closer to a treatment for HIV patients that doesn’t require taking drugs daily.

In 10 seconds? Scientists have achieved promising results using compounds that track and suppress the HIV better than current antiretroviral drugs.

What was the discovery? Lab monkeys infected with a virus mimicking human HIV were given bNAbs and molecules to stimulate the immune system along with an initial dose of conventional antiretroviral drugs. The result was that the animals did not need any other treatment for six months, as the virus was suppressed.

So why is this significant? This opens up the possibility for HIV infections to be treated by taking drugs only a few times a year, or even prevented in the future. The goal is “remission”, a state where the patient has no symptoms. Modern antiretroviral drugs reduce the HIV levels to small numbers in the body, but the trade-off is that they have to be taken daily. In their absence, the virus quickly multiplies.

Okay, and what are bNAbs? They are ‘broadly neutralising’ antibodies, because they bind to a large number of virus strains. As antibodies, their job is to attach themselves to infections, and then either disable or illuminate them so that immune cells can find and destroy the invaders.

Why are bNAbs effective against HIV? Because they are like heat-seeking missiles that ‘lock’ on to their target. The HIV can play cat and mouse by rapidly mutating and hiding in infected immune cells, making the immune system unable to identify and neutralise it. But bNAbs can spot parts of the virus that don’t mutate and bind to them.

So are we talking about a possible HIV vaccine? You’ve got that right! Coming up with an effective vaccine would be equal to finding the Holy Grail in HIV research. Researchers are trying to unlock the mechanism whereby the human immune system can produce bNAbs – currently only a small number of HIV-infected patients develop them. If possible, this would open the path to preventing or suppressing HIV infection through a vaccine.


Why would bNAbs be a breakthrough in HIV treatment and prevention?

There are around 35 million HIV-positive people living on the planet who require daily drugs to save them from developing lethal AIDS.

Therefore finding an alternative to daily medication would save a large amount of money for national healthcare systems.

Additionally, according to WHO estimates, there are 17 million HIV-infected people globally who don’t receive antiretroviral therapy, so a different therapy could help to save their lives too.

This board was co-curated by Kayla Sprenger, PhD

18 ITEMS PINNED

Optimal Sequential Immunization Can Focus Antibody Responses against Diversity Loss and Distraction.

Abstract: Affinity maturation is a Darwinian process in which B lymphocytes evolve potent antibodies to encountered antigens and generate immune memory. Highly mutable complex pathogens present an immense antigenic diversity that continues to challenge natural immunity and vaccine design. Induction of broadly neutralizing antibodies (bnAbs) against this diversity by vaccination likely requires multiple exposures to distinct but related antigen variants, and yet how affinity maturation advances under such complex stimulation remains poorly understood. To fill the gap, we present an in silico model of affinity maturation to examine two realistic new aspects pertinent to vaccine development: loss in B cell diversity across successive immunization periods against different variants, and the presence of distracting epitopes that entropically disfavor the evolution of bnAbs. We find these new factors, which introduce additional selection pressures and constraints, significantly influence antibody breadth development, in a way that depends crucially on the temporal pattern of immunization (or selection forces). Curiously, a less diverse B cell seed may even favor the expansion and dominance of cross-reactive clones, but only when conflicting selection forces are presented in series rather than in a mixture. Moreover, the level of frustration due to evolutionary conflict dictates the degree of distraction. We further describe how antigenic histories select evolutionary paths of B cell lineages and determine the predominant mode of antibody responses. Sequential immunization with mutationally distant variants is shown to robustly induce bnAbs that focus on conserved elements of the target epitope, by thwarting strain-specific and distracted lineages. An optimal range of antigen dose underlies a fine balance between efficient adaptation and persistent reaction. These findings provide mechanistic guides to aid in design of vaccine strategies against fast mutating pathogens.

Pub.: 31 Jan '17, Pinned: 29 Mar '18

Virological control by the CD4-binding site antibody N6 in SHIV-infected rhesus monkeys.

Abstract: Passive immunotherapies against HIV-1 will most likely require broadly neutralizing antibodies (bnAb) with maximum breadth and potency to assure therapeutic efficacy. Recently, the novel CD4 binding site antibody N6 demonstrated extraordinary neutralization breadth and potency against large panels of cross clade pseudoviruses. We evaluated the in-vivo antiviral activity of N6-LS, alone or in combination with the established V3-glycan antibody PGT121, in chronically SHIV-SF162P3 infected macaques. A single dose of N6-LS suppressed plasma viral loads in 4 out of 5 animals at day 7 (mean 1.1 log10 RNA copies/ml reduction), while the combination of both antibodies suppressed all animals (mean 0.92 log10 RNA copies/ml reduction). Interestingly, the combination of both antibodies had no additive antiviral effect, compared to a single dose of PGT121, potentially reflecting the nearly 10-fold higher potency of PGT121 against this SHIV. Viral rebound occurred in the majority of suppressed animals and was linked to declining plasma bnAb levels over time. In addition to the effect on plasma viremia, bnAb administration resulted in significantly reduced proviral DNA levels in PBMCs after 2 weeks and in lymphnode cells after 10 weeks. Autologous NAb responses and SIV/SHIV specific CD8+ T-cell responses were not significantly enhanced in the bnAb treated animals compared to control animals, arguing against their contribution to the viral effects observed. These results confirm the robust antiviral activity of N6-LS in-vivo, supporting the further clinical development of this antibody.IMPORTANCE Monocloncal antibodies (mAbs) are being considered for passive immunotherapies of HIV-1 infection. A critical requirement for such strategies is the identification of mAbs that recognize the diversity of variants within circulating but also reservoir viruses and mAb combinations might be needed to achieve this goal. This study evaluates the novel bnAb N6-LS, that has superior in-vitro antiviral characteristics, alone or in combination with the bnAb PGT121 in rhesus macauqes that are chronically infected with chimeric simian-human immunodeficiency virus (SHIV). The results demonstrate that N6-LS potently suppressed plasma viral loads in the majority of animals but that the combination with PGT121 was not superior than PGT121 alone in delaying time to viral rebound or reducing PBMC or lymphnode cell proviral DNA levels. The occurrence of viral escape variants in an N6-LS mono-treated animal, however, argues for the critical need to maximize breadth and anti-viral efficacy by combining bnAbs for therapeutic indications.

Pub.: 26 May '17, Pinned: 29 Mar '18

Protective Efficacy of Broadly Neutralizing Antibodies with Incomplete Neutralization Activity against Simian-Human Immunodeficiency Virus in Rhesus Monkeys.

Abstract: HIV broadly neutralizing antibodies (bnAbs) have been shown to occasionally display unusual virus neutralization profiles with nonsigmoidal slopes and plateaus at <100% neutralization against a variety of viruses. The significance of incomplete neutralization for the ability of bnAbs to mediate protective effects in vivo, however, is undetermined. In the current study, we selected two bnAbs, PGT121 and 3BNC117, as they incompletely neutralize the clade C simian-human immunodeficiency virus (SHIV) stock (SHIV-327c) at 85% and 70%, respectively, and performed a protection study in rhesus macaques. The animals were intravenously (i.v.) administered PGT121 or 3BNC117 at 10 and 2 mg/kg of body weight before being rectally challenged with a single high dose of SHIV-327c. PGT121 protected 6 out of 7 monkeys, while 6 out of 7 3BNC117-pretreated animals became infected, although with significantly delayed plasma viremia compared to the control animals. These data suggest that complete neutralization is not imperative for bnAbs to prevent infection but that with increasing levels of incomplete neutralization the sterilizing activity diminishes.IMPORTANCE Multiple antibodies have been identified that potently neutralize a broad range of circulating HIV strains. However, not every virus-antibody combination results in complete neutralization of the input virus, suggesting that a fraction of virus particles are resistant to antibody neutralization despite high antibody concentrations. This observation of "incomplete neutralization" is associated with nonsigmoidal neutralization curves plateauing below 100% neutralization, but the significance of the phenomenon for the ability of neutralizing antibodies to mediate protective effects in vivo is undetermined. In this study, we show that the broadly neutralizing antibody PGT121, which neutralized only up to 85% of the SHIV-327c challenge stock in vitro, protected 6 out of 7 rhesus macaques against infection while the antibody 3BNC117, which neutralized up to 70% of SHIV-327c in vitro, did not prevent, though it significantly delayed, establishment of infection, suggesting that with increasing levels of incomplete neutralization the ability of a bnAb to mediate sterilizing protection diminishes.

Pub.: 05 Aug '17, Pinned: 29 Mar '18

Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage.

Abstract: Broadly neutralizing antibodies (bnAbs) to HIV-1 can evolve after years of an iterative process of virus escape and antibody adaptation that HIV-1 vaccine design seeks to mimic. To enable this, properties that render HIV-1 envelopes (Env) capable of eliciting bnAb responses need to be defined. Here, we followed the evolution of the V2 apex directed bnAb lineage VRC26 in the HIV-1 subtype C superinfected donor CAP256 to investigate the phenotypic changes of the virus populations circulating before and during the early phases of bnAb induction. Longitudinal viruses that evolved from the VRC26-resistant primary infecting (PI) virus, the VRC26-sensitive superinfecting (SU) virus and ensuing PI-SU recombinants revealed substantial phenotypic changes in Env, with a switch in Env properties coinciding with early resistance to VRC26. Decreased sensitivity of SU-like viruses to VRC26 was linked with reduced infectivity, altered entry kinetics and lower sensitivity to neutralization after CD4 attachment. VRC26 maintained neutralization activity against cell-associated CAP256 virus, indicating that escape through the cell-cell transmission route is not a dominant escape pathway. Reduced fitness of the early escape variants and sustained sensitivity in cell-cell transmission are both features that limit virus replication, thereby impeding rapid escape. This supports a scenario where VRC26 allowed only partial viral escape for a prolonged period, possibly increasing the time window for bnAb maturation. Collectively, our data highlight the phenotypic plasticity of the HIV-1 Env in evading bnAb pressure and the need to consider phenotypic traits when selecting and designing Env immunogens. Combinations of Env variants with differential phenotypic patterns and bnAb sensitivity, as we describe here for CAP256, may maximize the potential for inducing bnAb responses by vaccination.

Pub.: 26 Jan '18, Pinned: 29 Mar '18

FUNCTIONAL OPTIMIZATION OF BROADLY NEUTRALIZING HIV-1 ANTIBODY 10E8 BY PROMOTING MEMBRANE INTERACTIONS.

Abstract: The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41, and is among the broadest known neutralizing antibodies against HIV-1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency. Here, we hypothesized that by increasing the net positive charge in similar polar surface-patches, the neutralization potency of the antibody may be enhanced. We found that increased positive charge at this paratope surface strengthened an electrostatic interaction between antibody and lipid bilayers, enabling 10E8 to interact spontaneously with membranes. Notably, the modified 10E8 did not gain any observable polyreactivity and neutralized with significantly greater potency. Binding analyses indicated that the optimized 10E8 bound with higher affinity to the epitope peptide anchored in lipid bilayers, and to Env spikes on virions. Overall our data provide a proof-of-principle for rational optimization of 10E8 via manipulation of its interaction with the membrane element of its epitope. However, the observation that a similar mutation strategy did not affect potency of the first-generation anti-MPER antibody 4E10, shows possible limitations of this principle. Altogether, our results emphasize the crucial role played by the viral membrane in the antigenicity of the MPER-TMD of HIV-1.IMPORTANCE The broadly neutralizing antibody (bnAb) 10E8 blocks infection by nearly all HIV-1 isolates, a capacity which vaccine design seeks to reproduce. Engineered versions of this antibody also represent a promising treatment for HIV infection by passive immunization. Understanding its mechanism of action is therefore important to help develop effective vaccines and biologics to combat HIV/AIDS. 10E8 engages with its helical MPER epitope where the base of the envelope spike submerges into the viral membrane. To enable this interaction, this antibody evolved an unusual property: the ability to interact with the membrane surface. Here, we provide evidence that 10E8 can be made more effective by enhancing its interactions with membranes. Our findings strengthen the idea that to elicit antibodies similar to 10E8, vaccines must reproduce the membrane environment where these antibodies perform their function.

Pub.: 02 Feb '18, Pinned: 29 Mar '18

Potential HIV-1 fusion inhibitors mimicking gp41-specific broadly neutralizing antibody 10E8: In silico discovery and prediction of antiviral potency.

Abstract: An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations. As a result, eight hits-able to mimic pharmacophore properties of bNAb 10E8 by specific and effective interactions with the MPER region of the HIV-1 protein gp41 were selected as the most probable 10E8-mimetic candidates. Similar to 10E8, the predicted compounds target the critically important residues of a highly conserved hinge region of the MPER peptide that provides a conformational flexibility necessary for its functioning in cell-virus membrane fusion process. In light of the data obtained, the identified small molecules may present promising HIV-1 fusion inhibitor scaffolds for the design of novel potent antiviral drugs.

Pub.: 15 Feb '18, Pinned: 29 Mar '18

Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice.

Abstract: The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral drug therapy (cART). Here, we investigate the potential of an engineered tandem bi-specific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving two scFv binding domains of each parental bnAb, a single-gene-encoded tandem bs-bnAb, namely BiIA-SG, displayed significantly improved breadth and potency. BiIA-SG neutralized all 124 HIV-1 pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, and variants less or not susceptible to parental and many bnAbs, with an average IC50 value of 0.073 µ/ml (range < 0.001 to 1.03 µg/ml). In humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains. Moreover, while BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of AAV-transferred BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb-based biomedical intervention for prevention and treatment of HIV-1 infections.

Pub.: 21 Feb '18, Pinned: 29 Mar '18

Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site.

Abstract: Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs-specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades.

Pub.: 09 Mar '18, Pinned: 29 Mar '18

Characterization of broadly neutralizing antibody responses to HIV-1 in a cohort of long term non-progressors.

Abstract: Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia. Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses. bNAb specificities were studied by ELISA using mutated gp120, neutralization assays with mutated viruses, and peptide competition. Epitope specificities were also elucidated from the serum pattern of neutralization against a panel of diverse HIV-1 isolates. Broadly neutralizing sera were found among 9.3% LTNPs, both elite (7%) and viremic controllers (14%). Within the broadly neutralizing sera, CD4 binding site antibodies were detected by ELISA in 4/12 LTNPs (33%), and 16/33 of TPs (48%). Anti-MPER antibodies were detected in 6/12 LTNPs (50%) and 14/33 TPs (42%) whereas glycan-dependent HIV-1 bNAbs were more frequent in LTNPs (11/12, 92%) as compared to TPs (12/33, 36%). A good concordance between standard serum mapping and neutralization-based mapping was observed. LTNPs, both viremic and elite controllers, showed broad humoral immune responses against HIV-1, including activity against many major epitopes involved in bNAbs-mediated protection.

Pub.: 21 Mar '18, Pinned: 29 Mar '18