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Neuroscience : exploring the brain
\"Surveys the organization and function of the human nervous system ... in a way that is accessible to both science and nonscience students alike. The level of the material is comparable to an introductory college text in general biology. The book is divided into four parts: Part I, Foundations; Part II, Sensory and motor systems; Part III, The brain and behavior; and Part IV, The changing brain\"--Provided by publisher.
Book
Success and failure of the cellular immune response against HIV-1
Understanding the success and failure of the HIV-specific cellular immune response has implications for immunotherapies and vaccines for HIV-1. Migueles and Connors discuss the mechanisms that are most likely responsible for durable and potent immunologic control of HIV-1 by the cellular immune response.
The cellular immune response to HIV-1 has now been studied in extraordinary detail. A very large body of data provides the most likely reasons that the HIV-specific cellular immune response succeeds in a small number of people but fails in most. Understanding the success and failure of the HIV-specific cellular immune response has implications that extend not only to immunotherapies and vaccines for HIV-1 but also to the cellular immune response in other disease states. This Review focuses on the mechanisms that are most likely responsible for durable and potent immunologic control of HIV-1. Although we now have a detailed picture of the cellular immune responses to HIV-1, important questions remain regarding the nature of these responses and how they arise.
Journal Article
Broad and potent neutralization of HIV-1 by a gp41-specific human antibody
Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes ∼98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical arginine or lysine just before the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 envelope glycoprotein.
A novel neutralizing antibody from a healthy HIV-1-infected donor that is specific for the membrane proximal region of gp41 is reported; the antibody has high potency and breadth, is not autoreactive and does not bind phospholipids.
Target for HIV/AIDS vaccine
Jinghe Huang
et al
. report a novel neutralizing antibody from a healthy HIV-1-infected donor that is specific for the membrane-proximal region of gp41. The antibody has high potency and breadth, is not autoreactive and does not bind phospholipids. This work demonstrates a conserved site of gp41 vulnerability that is an important target antigen for HIV neutralization, with implications for efforts to elicit broadly neutralizing antibodies with vaccines.
Journal Article
Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques
The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.
Journal Article
Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody
The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.
Journal Article
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1
Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1-infected individuals, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of initial CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1-infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of glycoprotein 120, an important insight for future HIV-1 vaccine design.
Journal Article
Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing
Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1—infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.
Journal Article
Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization
Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1-neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined \"neutralization fingerprints\" for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of polyclonal sera from 24 HIV-1-infected donors and a chimeric siman-human immunodeficiency virus-infected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection.
Journal Article
Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections
There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10[mu]g/ml total for bnAbs and combinations, and 5[mu]g/ml for bispecifics. We used IC.sub.80 breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection ( 98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95-97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8-iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa.
Journal Article
Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals
Multiple antibodies fight HIV
Serologic memory is an important factor in long-term vaccine efficacy, but there is little understanding of the antibodies produced by memory B cells in individuals infected with important human pathogens such as HIV. To examine the memory antibody response to HIV, Scheid
et al
. cloned more than 500 antibodies from HIV-specific memory B cells from six HIV-infected patients with high serum titres of broadly neutralizing antibodies. The B-cell memory response to HIV in these patients was composed of up to 50 independent expanded B clones expressing a heterogeneous collection of antibodies to different viral epitopes, several of which may be important for broad HIV neutralization and effective vaccination.
This study clones and characterizes antibodies present in six HIV-infected subjects with low-to-intermediate viral loads.
Antibodies to conserved epitopes on the human immunodeficiency virus (HIV) surface protein gp140 can protect against infection in non-human primates, and some infected individuals show high titres of broadly neutralizing immunoglobulin (Ig)G antibodies in their serum. However, little is known about the specificity and activity of these antibodies
1
,
2
,
3
. To characterize the memory antibody responses to HIV, we cloned 502 antibodies from HIV envelope-binding memory B cells from six HIV-infected patients with broadly neutralizing antibodies and low to intermediate viral loads. We show that in these patients, the B-cell memory response to gp140 is composed of up to 50 independent clones expressing high affinity neutralizing antibodies to the gp120 variable loops, the CD4-binding site, the co-receptor-binding site, and to a new neutralizing epitope that is in the same region of gp120 as the CD4-binding site. Thus, the IgG memory B-cell compartment in the selected group of patients with broad serum neutralizing activity to HIV is comprised of multiple clonal responses with neutralizing activity directed against several epitopes on gp120.
Journal Article