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Axel Mann,
Nikolas Friedrich,
Anders Krarup,
Jacqueline Weber,
Emanuel Stiegeler,
Birgit Dreier,
Pavel Pugach,
Melissa Robbiani,
Tina Riedel,
Kerstin Moehle,
John A Robinson,
Peter Rusert,
Andreas Plückthun, Alexandra Trkola
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ABSTRACT: Here we applied the Designed Ankyrin Repeat Protein (DARPin) technology to develop novel gp120-directed binding molecules with HIV entry-inhibiting capacity. DARPins are interesting molecules for HIV envelope inhibitor design, as their high affinity binding differs from that of antibodies. DARPins in general prefer epitopes with a defined folded structure. Here we probed whether this capacity favors the selection of novel gp120-reactive molecules with specificities in epitope recognition and inhibitory activity that differ from those found amongst neutralizing antibodies. The preference of DARPins for defined structures was notable in our selections, since of the four gp120 modifications probed as selection target, gp120 arrested by CD4 ligation proved the most successful. Of note, all gp120 specific DARPin clones with HIV neutralizing activity isolated, recognized their target domains in a conformation-dependent manner. This was particularly pronounced for the V3-loop-specific DARPin 5m3_D12. In stark contrast to V3-specific antibodies, 5m3_D12 preferentially recognized the V3 loop in a specific conformation, as probed by structurally arrested V3 mimetic peptides, but bound linear V3 peptides only very weakly. Most notably, this conformation-dependent V3 recognition allowed 5m3_D12 to bypass V1V2 shielding of several tier 2 HIV isolates and to neutralize these viruses. These data provide a proof of concept that the DARPin technology holds promise for the development HIV entry inhibitors with a unique mechanism of action.
Journal of Virology 03/2013; · 5.40 Impact Factor
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ABSTRACT: HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs) and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs) directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo.
PLoS Pathogens 04/2012; 8(4):e1002634. · 9.13 Impact Factor
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Claudia F Althaus,
Valentina Vongrad,
Barbara Niederöst,
Beda Joos,
Francesca Di Giallonardo,
Philip Rieder,
Jovan Pavlovic, Alexandra Trkola,
Huldrych F Günthard,
Karin J Metzner,
Marek Fischer
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ABSTRACT: The various classes of small noncoding RNAs (sncRNAs) are important regulators of gene expression across divergent types of organisms. While a rapidly increasing number of sncRNAs has been identified over recent years, the isolation of sncRNAs of low abundance remains challenging. Virally encoded sncRNAs, particularly those of RNA viruses, can be expressed at very low levels. This is best illustrated by HIV-1 where virus encoded sncRNAs represent approximately 0.1-1.0% of all sncRNAs in HIV-1 infected cells or were found to be undetected. Thus, we applied a novel, sequence targeted enrichment strategy to capture HIV-1 derived sncRNAs in HIV-1 infected primary CD4+ T-lymphocytes and macrophages that allows a greater than 100-fold enrichment of low abundant sncRNAs.
Eight hundred and ninety-two individual HIV-1 sncRNAs were cloned and sequenced from nine different sncRNA libraries derived from five independent experiments. These clones represent up to 90% of all sncRNA clones in the generated libraries. Two hundred and sixteen HIV-1 sncRNAs were distinguishable as unique clones. They are spread throughout the HIV-1 genome, however, forming certain clusters, and almost 10% show an antisense orientation. The length of HIV-1 sncRNAs varies between 16 and 89 nucleotides with an unexpected peak at 31 to 50 nucleotides, thus, longer than cellular microRNAs or short-interfering RNAs (siRNAs). Exemplary HIV-1 sncRNAs were also generated in cells infected with different primary HIV-1 isolates and can inhibit HIV-1 replication.
HIV-1 infected cells generate virally encoded sncRNAs, which might play a role in the HIV-1 life cycle. Furthermore, the enormous capacity to enrich low abundance sncRNAs in a sequence specific manner highly recommends our selection strategy for any type of investigation where origin or target sequences of the sought-after sncRNAs are known.
Retrovirology 03/2012; 9:27. · 6.47 Impact Factor
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ABSTRACT: Conformationally constrained peptidomimetics could be of great value in the design of vaccines targeting protective epitopes on viral and bacterial pathogens. But the poor immunogenicity of small synthetic molecules represents a serious obstacle for their use in vaccine development. Here, we show how a constrained epitope mimetic can be rendered highly immunogenic through multivalent display on the surface of synthetic virus-like nanoparticles. The target epitope is the V3 loop from the gp120 glycoprotein of HIV-1 bound to the neutralizing antibody F425-B4e8. The antibody-bound V3 loop adopts a β-hairpin conformation, which is effectively stabilized by transplantation onto a D-Pro-L-Pro template. The resulting mimetic after coupling to synthetic virus-like particles elicited antibodies in rabbits that recognized recombinant gp120. The elicited antibodies also blocked infection by the neutralization sensitive tier-1 strain MN of HIV-1, as well as engineered viruses with the V1V2 loop deleted; this result is consistent with screening of V3 by the V1V2 loop in intact trimeric viral gp120 spikes. The results provide new insights into HIV-1 vaccine design based on the V3 loop, and illustrate how knowledge from structural biology can be exploited for the design of constrained epitope mimetics, which can be delivered to the immune system by using a highly immunogenic synthetic nanoparticle delivery system.
ChemBioChem 11/2011; 12(18):2829-36. · 3.94 Impact Factor
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ABSTRACT: The HIV-1 envelope trimer adopts a quaternary conformation that effectively shields neutralization-sensitive domains and thus represents a major obstacle for natural and vaccine-elicited antibody responses. By using a structure-function analysis based on a specifically devised mathematical model, we demonstrate in this study that protection from neutralization is enforced by intersubunit contact between the variable loops 1 and 2 (V1V2) and domains of neighboring gp120 subunits in the trimer encompassing the V3 loop. Our data are consistent with an interaction of the V1V2 and V3 loop at the spike apex as proposed by cryoelectron tomography experiments. By defining the orientation of the V1V2 loop within the trimer toward the neighboring gp120 subunit's V3 loop, our data close an important gap in the understanding of the architecture of the trimeric spike. Knowledge on how the V1V2 barrier functions in the context of the trimer to mask conserved epitopes on gp120 may aid future vaccine design.
Journal of Experimental Medicine 06/2011; 208(7):1419-33. · 13.85 Impact Factor
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Claudia R Ruprecht,
Anders Krarup,
Lucy Reynell,
Axel M Mann,
Oliver F Brandenberg,
Livia Berlinger,
Irene A Abela,
Roland R Regoes,
Huldrych F Günthard,
Peter Rusert, Alexandra Trkola
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ABSTRACT: Interference with virus entry is known to be the principle mechanism of HIV neutralization by antibodies, including 2F5 and 4E10, which bind to the membrane-proximal external region (MPER) of the gp41 envelope protein. However, to date, the precise molecular events underlying neutralization by MPER-specific antibodies remain incompletely understood. In this study, we investigated the capacity of these antibodies to irrevocably sterilize HIV virions. Long-term effects of antibodies on virions can differ, rendering neutralization either reversible or irreversible. MPER-specific antibodies irreversibly neutralize virions, and this capacity is associated with induction of gp120 shedding. Both processes have similar thermodynamic properties and slow kinetics requiring several hours. Antibodies directed to the CD4 binding site, V3 loop, and the MPER can induce gp120 shedding, and shedding activity is detected with high frequency in plasma from patients infected with divergent genetic HIV-1 subtypes. Importantly, as we show in this study, induction of gp120 shedding is closely associated with MPER antibody inhibition, constituting either a primary event leading to virion neutralization or representing an immediate consequence thereof, and thus needs to be factored into the mechanistic processes underlying their activity.
Journal of Experimental Medicine 02/2011; 208(3):439-54. · 13.85 Impact Factor
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ABSTRACT: A helical tyrosine-sulfated epitope in CCR5 that is recognized by the human immunodeficiency virus type-1 envelope glycoprotein gp120 in its CD4-induced conformation can be mimicked structurally by a cyclic β-hairpin peptide containing two sulfated tyrosine residues at positions i and i + 2 along one β-strand.
Chemical Communications 11/2010; 46(41):7754-6. · 6.17 Impact Factor
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ABSTRACT: Hyperactivation of CD4+ T cells is a hallmark of untreated HIV-1 infection. The antigenic specificities of activated CD4+ T cells and the underlying mechanisms leading to their activation remain thus far elusive. We report here that during HIV rebound the dynamics of HIV-specific CD4+ T cells is highly correlated with the dynamics of CD4+ T cells specific for persistent antigens derived from various members of the herpes virus family, whereas CD4 responses towards non-persistent antigens were unaffected by HIV replication. Notably, the dynamics of HIV and herpes viral antigen-specific CD4+ T cells responses correlated with the expression level of activation markers on dendritic cells (DCs) and activated DCs were more potent in restimulating memory T cells. These data strongly suggest that HIV replication costimulates activation of CD4+ T cells specific for persistent herpes viral antigens via activation of DCs. We propose that a large proportion of activated T cells during untreated HIV infection may be specific for herpes viral antigens and identify a novel mechanism contributing to chronic immune activation in untreated HIV-1 infection.
EMBO Molecular Medicine 06/2010; 2(6):231-44. · 10.33 Impact Factor
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ABSTRACT: Therapeutic antibodies have evolved into an important drug class and have achieved considerable success in combating cancers and autoimmune diseases. Although their potential in the treatment of viral infections has not yet been fully explored, recently established approaches have the potential to aid the development of HIV specific antibody therapies. Antibody engineering has led to improvements in antibody isolation and increases in antibody efficacy and potency. Strategies have been developed to tailor Fc recruitment of effector functions, and conjugation of monoclonals to toxins endows them with the ability to mediate destruction of specific target cells. These technical advances introduce the possibility of designing a therapy to target and clear cells infected with a broad range of HIV strains and recommend some hypothetical clinical settings in which advanced antibody therapeutics could be employed in prophylaxis or therapy for HIV infection.
Current pharmaceutical design 01/2010; 16(33):3754-66. · 4.41 Impact Factor
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ABSTRACT: The recently described Designed Ankyrin Repeat Protein (DARPin) technology can produce highly selective ligands to a variety of biological targets at a low production cost.
To investigate the in vivo use of DARPins for future application to novel anti-HIV strategies, we identified potent CD4-specific DARPins that recognize rhesus CD4 and followed the fate of intravenously injected CD4-specific DARPin 57.2 in rhesus macaques. The human CD4-specific DARPin 57.2 bound macaque CD4(+) cells and exhibited potent inhibitory activity against SIV infection in vitro. DARPin 57.2 or the control E3_5 DARPin was injected into rhesus macaques and the fate of cell-free and cell-bound CD4-specific DARPin was evaluated. DARPin-bound CD4(+) cells were detected in the peripheral blood as early as 30 minutes after the injection, decreasing within 6 hours and being almost undetectable within 24 hours. The amount of DARPin bound was dependent on the amount of DARPin injected. CD4-specific DARPin was also detected on CD4(+) cells in the lymph nodes within 30 minutes, which persisted with similar kinetics to blood. More extensive analysis using blood revealed that DARPin 57.2 bound to all CD4(+) cell types (T cells, monocytes, dendritic cells) in vivo and in vitro with the amount of binding directly proportional to the amount of CD4 on the cell surface. Cell-free DARPins were also detected in the plasma, but were rapidly cleared from circulation.
We demonstrated that the CD4-specific DARPin can rapidly and selectively bind its target cells in vivo, warranting further studies on possible clinical use of the DARPin technology.
PLoS ONE 01/2010; 5(8):e12455. · 4.09 Impact Factor
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ABSTRACT: Successful HIV vaccine and entry inhibitor development depends on use of assay systems that closely reflect in-vivo activities. Recent reports suggest that the currently most widely used assay format, which relies on the genetically engineered target cell line TZM-bl, can fail to detect certain neutralization activities detected on primary peripheral blood mononuclear cell (PBMC)-based assay systems. In the present study, we investigate the influence the target cell context bears on HIV entry inhibition.
In a comprehensive survey, the effect of 11 neutralizing antibodies and inhibitors in blocking entry of 30 envelope pseudotyped virus strains in two types of target cells, PBMC and TZM-bl, was evaluated.
Env-pseudotyped HIV infection of PBMC and TZM-bl cells.
We demonstrate here that depending on the type of inhibitor, relative neutralization potencies are shifted to a variable extent and direction on TZM-bl and PBMC cells. In our assay set up, differences in inhibitor activity were solely effected by the target cell environment and amounted up to 2-3 logs lower activity on TZM-bl cells in several cases. Overall, neutralizing antibodies, 2G12, 2F5 and 4E10, were less active in the TZM-bl system, whereas CD4 binding site directed inhibitor activities were detected equally well on both target cells, raising concerns that the TZM-bl assay may overrate the relevance of CD4 binding site specific responses.
Our data strongly argue that preclinical assessment should not be restricted to a single type of assay, as systematic underestimation or overestimation of activities would be inevitable.
AIDS (London, England) 08/2009; 23(11):1319-27. · 4.91 Impact Factor
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ABSTRACT: Using clinical isolates from a recent passive immunization trial with antibody 2G12, we probed the capacity of frequently used neutralization formats - the primary peripheral blood mononuclear cell (PBMC)-based and the TZM-bl cell-based assay systems - to predict in-vivo activity of 2G12.
Antibodies and entry inhibitors of established efficacy were used to neutralize HIV-1 isolates in different in-vitro assay setups.
Single round infection with Env-pseudotyped and multiple round infection with replication-competent virus was studied on PBMCs and a variety of engineered cell lines.
Six out of 12 isolates with high sensitivity to 2G12 in the replication-competent PBMC assay lacked sensitivity to the monoclonal antibody in the env-pseudotype TZM-bl assay. Outcome of passive immunization with 2G12 corroborated the PBMC-assay in-vitro data, as escape mutations to 2G12 emerged, proving the monoclonal antibody's impact on HIV in vivo. Failure to inhibit pseudotype infection of TZM-bl was not due to sequence differences or the pseudotype infection per se, as infection of PBMCs with the identical pseudotyped viruses was sensitive to 2G12 inhibition. Similar shifts in efficacy, though less extreme, were noted for other neutralizing antibodies and inhibitors. Exploration of causes for the observed differences between assay systems revealed that both target cell and virus producer properties influence sensitivity of virus entry to inhibition.
Our observation that neutralization assay systems employing engineered reporter cell lines can miss in-vivo relevant neutralizing activities strongly argues that preclinical assessment should not be restricted to a single assay type.
AIDS (London, England) 08/2009; 23(13):1659-67. · 4.91 Impact Factor
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ABSTRACT: HIV RNA levels are influenced by genetic characteristics of both the host and the virus. Here we applied machine learning techniques to determine if plasma-derived HIV-1 amino acid sequences can be used to predict spontaneous virologic control. We studied the relationship between HIV-1 env genotype and viral load in 20 chronically infected patients undergoing treatment interruptions (SSITT, Swiss-Spanish Intermittent Treatment Trial) and in 104 primary HIV infected (PHI) patients before antiretroviral therapy (cART) and where applicable also after treatment stop. Extensive longitudinal sampling during the interruptions was performed in nine SSITT patients. Sequences obtained from these nine patients during the first virus rebound were used as a training data set and revealed a strong genetic signature (accuracy 98.6% in cross-validation) associated with control of viremia at levels below 5000copies/mL of viral RNA maintained for at least 2 months after the final cART stop. The simple sequence pattern at gp120 positions 268E/358T was confirmed to be predictive of control in the clonal sequences originating from these patients during all subsequent rebounds. Sequences from the remaining 11 SSITT patients with less frequent sampling and from the PHI patients were used for external validation. High sensitivities (71-100%) and negative predictive values (80-100%) but low positive predictive values (12-40%) were achieved in the patient-wise analysis which was based on presence of the genetic pattern in all clones. These results suggest that presence of virus lacking the amino acid pattern 268E/358T is associated with VL >5000 at baseline of PHI and with low probability of spontaneous virologic control after treatment stop. Conversely, however, presence of 268E/358T does not predict control of viremia. These residues in HIV gp120 might affect in vivo HIV-1 fitness either at the level of Env function or influence susceptibility to adaptive or innate immune response.
Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 07/2009; 10(3):365-72. · 3.22 Impact Factor
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ABSTRACT: A human immunodeficiency virus type 2 (HIV-2)-infected woman experienced asymptomatic superinfection with HIV-1 subtype AG. She did not have cross-neutralizing autologous HIV-1 antibodies before and shortly after HIV-1 superinfection. This evidence supports a mechanism other than cross-neutralizing antibodies for the mild course of HIV-1 infection in this woman.
Clinical Infectious Diseases 05/2009; 48(11):e117-20. · 9.15 Impact Factor
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ABSTRACT: To enter target cells, human immunodeficiency virus (HIV) first attaches to the cells and fuses with the cell membrane. Attachment and fusion involve envelope glycoprotein trimers on the surface of the virion and the CD4 receptor and chemokine coreceptors on the surface of the target cell. The stoichiometry of entry, that is, the number of bonds between such trimers and CD4 that are required for infection, is unknown. Pseudotyped virions that express mixed trimers consisting of functional and nonfunctional envelope proteins have been used to study how many trimer-receptor interactions are required for virus entry. However, to extract information on the stoichiometry of entry from data generated in in vitro infectivity assays with such viruses, mathematical models are required. Here, we describe mathematical models that can be used to infer the stoichiometry of entry. By fitting our simplest model to previously published data (X. Yang, S. Kurteva, X. Ren, S. Lee, and J. Sodroski, J. Virol. 79: 12132-12147, 2005), we estimated that the number of trimer-receptor interactions required for HIV to infect a target cell is approximately eight, which is higher than previous estimates. We also consider model extensions that explain some systematic deviations of the data from the prediction of the simplest model. However, these extended models yield very different estimates of the stoichiometry of entry ranging from 2 to 19. These results strongly suggest that, based on our present knowledge of HIV entry, the stoichiometry of this process cannot be reliably estimated. Our study identifies parameters that need to be defined to render the estimation of the stoichiometry of HIV entry possible.
Journal of Virology 12/2008; 83(3):1523-31. · 5.40 Impact Factor
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ABSTRACT: Rapid rebound of plasma viremia in patients after interruption of long-term combination antiretroviral therapy (cART) suggests persistence of low-level replicating cells or rapid reactivation of latently infected cells. To further characterize rebounding virus, we performed extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions and exploited the temporal relationships of rebounding plasma viruses with regard to pretreatment sequences in 20 chronically HIV-1-infected patients having undergone multiple 2-week structured treatment interruptions (STI). Rebounding virus during the short STI was homogeneous, suggesting mono- or oligoclonal origin during reactivation. No evidence for a temporal structure of rebounding virus in regard to pretreatment sequences was found. Furthermore, expansion of distinct lineages at different STI cycles emerged. Together, these findings imply stochastic reactivation of different clones from long-lived latently infected cells rather than expansion of viral populations replicating at low levels. After treatment was stopped, diversity increased steadily, but pretreatment diversity was, on average, achieved only >2.5 years after the start of STI when marked divergence from preexisting quasispecies also emerged. In summary, our results argue against persistence of ongoing low-level replication in patients on suppressive cART. Furthermore, a prolonged delay in restoration of pretreatment viral diversity after treatment interruption demonstrates a surprisingly sustained evolutionary bottleneck induced by punctuated antiretroviral therapy.
Proceedings of the National Academy of Sciences 10/2008; 105(43):16725-30. · 9.68 Impact Factor
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Andreas Schweizer,
Peter Rusert,
Livia Berlinger,
Claudia R Ruprecht,
Axel Mann,
Stéphanie Corthésy,
Stuart G Turville,
Meropi Aravantinou,
Marek Fischer,
Melissa Robbiani,
Patrick Amstutz, Alexandra Trkola
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ABSTRACT: Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin) technology. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. Selected pool members interacted specifically with CD4 and competed with gp120 for binding to CD4. DARPin proteins derived in the initial selection series inhibited HIV in a dose-dependent manner, but showed a relatively high variability in their capacity to block replication of patient isolates on primary CD4 T cells. In consequence, a second series of CD4-specific DARPins with improved affinity for CD4 was generated. These 2nd series DARPins potently inhibit infection of genetically divergent (subtype B and C) HIV isolates in the low nanomolar range, independent of coreceptor usage. Importantly, the actions of the CD4 binding DARPins were highly specific: no effect on cell viability or activation, CD4 memory cell function, or interference with CD4-independent virus entry was observed. These novel CD4 targeting molecules described here combine the unique characteristics of DARPins-high physical stability, specificity and low production costs-with the capacity to potently block HIV entry, rendering them promising candidates for microbicide development.
PLoS Pathogens 07/2008; 4(7):e1000109. · 9.13 Impact Factor
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Michael Huber,
Viktor von Wyl,
Christoph G Ammann,
Herbert Kuster,
Gabriela Stiegler,
Hermann Katinger,
Rainer Weber,
Marek Fischer,
Heribert Stoiber,
Huldrych F Günthard, Alexandra Trkola
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ABSTRACT: To evaluate the contribution of complement-mediated lysis to the in vivo activities of neutralizing antibodies, we analyzed the influence of complement activation on treatment success in a recent passive immunization trial with the neutralizing monoclonal antibodies 2G12, 2F5, and 4E10. Administration of monoclonal antibodies led to an immediate, high activation of the complement system even in the absence of viremia in the 14 participating human immunodeficiency virus-infected individuals. Lysis activity measured in patient plasma increased during passive immunization; however, the increases were modest and only partially attributable to the administration of antibodies. We found that unlike neutralization activity, lysis activity was not associated with treatment success in this trial. Compared to complement lysis mounted by the polyclonal antibody response in vivo, monoclonal antibodies were weak inducers of this activity, suggesting that polyclonal responses are more effective in reaching the required threshold of complement activation. Importantly, strong neutralization activity of the monoclonal antibodies did not predict complement lysis activity against patient and reference viruses, suggesting that these activities are not linked. In summary, our data support the notion that the in vivo activities of 2G12, 2F5, and 4E10 are likely due to direct neutralization or Fc receptor-mediated mechanisms such as phagocytosis and antibody-dependent cellular cytotoxicity.
Journal of Virology 05/2008; 82(8):3834-42. · 5.40 Impact Factor
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ABSTRACT: The definition of plasma neutralizing antibody titers capable of controlling human immunodeficiency virus (HIV) infection in vivo is considered a critical step in vaccine development. Here we provide estimates for effective neutralization titers by assessing samples from a recent passive immunization trial with the neutralizing monoclonal antibodies (MAbs) 2G12, 2F5, and 4E10 using an analytic strategy that dissects the contributions of these MAbs to the total neutralization activity in patient plasma. Assessment of neutralization activities for six responding patients with partial or complete control of viremia during the MAb treatment and for the eight nonresponding patients revealed a significant difference between these groups: Among responders, MAb-mediated activity exceeded the autologous neutralization response by 1 to 2 log units (median difference, 43.3-fold), while in the nonresponder group, the autologous activity prevailed (median difference, 0.63-fold). In order to reach a 50% proportion of the responders in our study cohort, MAb neutralizing titers higher than 1:200 were required based on this analysis. The disease stage appears to have a significant impact on the quantities needed, since titers above 1:1,000 were needed to reach the same effect in chronic infection. Although our analysis is based on very small sample numbers and thus cannot be conclusive, our data provide a first estimate on how in vitro-measured neutralizing antibody activity can relate to in vivo efficacy in controlling HIV infection and may therefore provide valuable information for vaccine development. Interestingly, lower neutralizing antibody levels showed an effect in acute compared to chronic infection, suggesting that in early disease stages, therapeutic vaccination may show promise. Equally, this raises hopes that a preventive vaccine could become effective at comparatively lower neutralizing antibody titers.
Journal of Virology 03/2008; 82(3):1591-9. · 5.40 Impact Factor
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ABSTRACT: HIV-1 establishes persistent infections characterized by high levels of viral replication. This finding is remarkable given the presence of apparently vigorous HIV-specific cellular and humoral immune responses. We review the dynamics of antibody responses and viral escape from these responses during primary HIV-1 infection.
Many B cell dysfunctions appear early in HIV-1 infection, and compromise humoral responses to HIV-1 and other pathogens. The rate of viral escape from autologous neutralization varies greatly between individuals with primary HIV-1 infection, and is on average higher than the rate of escape in chronically infected individuals. Mutations, changes in glycosylation and insertions and deletions in the viral envelope may all contribute to viral escape. There may be differences in neutralization sensitivity and evolution of neutralization escape between different HIV-1 subtypes. Although several broadly neutralizing monoclonal antibodies have been identified, the factors that contribute to the development of broad heterologous responses remain unclear.
The rapid escape of HIV-1 in response to neutralizing antibodies and the plethora of B cell dysfunctions that occur during HIV infection pose significant obstacles to the design of an effective HIV-1 vaccine. The study of large cohorts of individuals enrolled during primary HIV-1 infection using high-throughput immunoassays, sequencing of the virus and the host, and new statistical tools may help to elucidate the pathways of viral escape, to elicit broadly neutralizing antibody responses, and to suggest means of minimizing the impact of HIV-1 on humoral immunity.
Current opinion in HIV and AIDS 02/2008; 3(1):45-51. · 4.75 Impact Factor
