scholarly journals Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Hannah J. Barbian ◽  
Julie M. Decker ◽  
Frederic Bibollet-Ruche ◽  
Rachel P. Galimidi ◽  
Anthony P. West ◽  
...  
Keyword(s):  
T Cells ◽  
Binding Site ◽  
Pan Troglodytes ◽  
Neutralizing Antibodies ◽  
Gorilla Gorilla ◽  
Protective Capacity ◽  
Content Type ◽  
Ccr5 Receptor ◽  
Cd4 Binding Site ◽  
Hiv 1

ABSTRACTBroadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytestroglodytes) (SIVcpzPtt) and eastern (Pan troglodytesschweinfurthii) (SIVcpzPts) chimpanzees (n= 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n= 1). We found that bNabs directed against the CD4 binding site (n= 10), peptidoglycans at the base of variable loop 3 (V3) (n= 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n= 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n= 3) as well as llama-derived (heavy chain only) antibodies (n= 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPttstrains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4+T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection.IMPORTANCESIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4+T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes.

scholarly journals Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein

2012 ◽  
Vol 209 (8) ◽  
pp. 1469-1479 ◽  
Author(s):  
Florian Klein ◽  
Christian Gaebler ◽  
Hugo Mouquet ◽  
D. Noah Sather ◽  
Clara Lehmann ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Protein ◽  
Neutralizing Antibodies ◽  
Conformational Epitope ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Capture Method ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Viral Isolates

Two to three years after infection, a fraction of HIV-1–infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti–HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti–HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti–HIV-1 serologic breadth and potency should not be limited to single epitopes.

scholarly journals Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site

2012 ◽  
Vol 86 (10) ◽  
pp. 5844-5856 ◽  
Author(s):  
X. Wu ◽  
C. Wang ◽  
S. O'Dell ◽  
Y. Li ◽  
B. F. Keele ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Selection Pressure ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Hiv 1

scholarly journals Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site

2013 ◽  
Vol 8 (5) ◽  
pp. 382-392 ◽  
Author(s):  
Ivelin S. Georgiev ◽  
M. Gordon Joyce ◽  
Tongqing Zhou ◽  
Peter D. Kwong
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Hiv 1

scholarly journals HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Briana Quitadamo ◽  
Paul J. Peters ◽  
Alexander Repik ◽  
Olivia O'Connell ◽  
Zhongming Mou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Binding Site ◽  
Envelope Protein ◽  
High Avidity ◽  
Immune Tissue ◽  
Coreceptor Binding ◽  
Cd4 Binding Site ◽  
Low Levels ◽  
Hiv 1

ABSTRACTHIV-1 R5 variants exploit CCR5 as a coreceptor to infect both T cells and macrophages. R5 viruses that are transmitted or derived from immune tissue and peripheral blood are mainly inefficient at mediating infection of macrophages. In contrast, highly macrophage-tropic (mac-tropic) R5 viruses predominate in brain tissue and can be detected in cerebrospinal fluid but are infrequent in immune tissue or blood even in late disease. These mac-tropic R5 variants carry envelope glycoproteins (Envs) adapted to exploit low levels of CD4 on macrophages to induce infection. However, it is unclear whether this adaptation is conferred by an increased affinity of the Env trimer for CD4 or is mediated by postbinding structural rearrangements in the trimer that enhance the exposure of the coreceptor binding site and facilitate events leading to fusion and virus entry. In this study, we investigated CD4 binding to mac-tropic and non-mac-tropic Env trimers and showed that CD4-IgG binds efficiently to mac-tropic R5 Env trimers, while binding to non-mac-tropic trimers was undetectable. Our data indicated that the CD4 binding site (CD4bs) is highly occluded on Env trimers of non-mac-tropic R5 viruses. Such viruses may therefore infect T cells via viral synapses where Env and CD4 become highly concentrated. This environment will enable high-avidity interactions that overcome extremely low Env-CD4 affinities.IMPORTANCEHIV R5 variants bind to CD4 and CCR5 receptors on T cells and macrophages to initiate infection. Transmitted HIV variants infect T cells but not macrophages, and these viral strains persist in immune tissue even in late disease. Here we show that the binding site for CD4 present on HIV's envelope protein is occluded on viruses replicating in immune tissue. This occlusion likely prevents antibody binding to this site and neutralization of the virus, but it makes it difficult for virus-CD4 interactions to occur. Such viruses probably pass from T cell to T cell via cell contacts where CD4 is highly concentrated and allows infection via inefficient envelope-CD4 binding. Our data are highly relevant for vaccines that aim to induce antibodies targeting the CD4 binding site on the envelope protein.

scholarly journals Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

2021 ◽  
Author(s):  
Zhi Yang ◽  
Kim-Marie A. Dam ◽  
Michael D. Bridges ◽  
Magnus A.G. Hoffmann ◽  
Andrew T. DeLaitsch ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Resonance Spectroscopy ◽  
Broadly Neutralizing Antibodies ◽  
Receptor Binding Site ◽  
Double Electron ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Double Electron Electron Resonance ◽  
Hiv 1

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterized Ab1303 and Ab1573, neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding was observed only when Env trimers were not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures showed that both antibodies recognized the CD4bs on Env trimer with an occluded-open conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation included outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, did not exhibit V1V2 displacement, co-receptor binding site exposure, or a 4-stranded gp120 bridging sheet. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggested an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.

scholarly journals Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies

2012 ◽  
Vol 86 (22) ◽  
pp. 12105-12114 ◽  
Author(s):  
S. M. O'Rourke ◽  
B. Schweighardt ◽  
P. Phung ◽  
K. A. Mesa ◽  
A. L. Vollrath ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Glycoprotein Gp41 ◽  
Hiv 1

scholarly journals Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site

2015 ◽  
Vol 11 (5) ◽  
pp. e1004932 ◽  
Author(s):  
Ema T. Crooks ◽  
Tommy Tong ◽  
Bimal Chakrabarti ◽  
Kristin Narayan ◽  
Ivelin S. Georgiev ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Tier 2 ◽  
Cd4 Binding Site ◽  
Hiv 1

scholarly journals Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
Willy M. J. M. Bogers ◽  
Susan W. Barnett ◽  
Herman Oostermeijer ◽  
Ivonne G. Nieuwenhuis ◽  
Niels Beenhakker ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Binding Site ◽  
T Helper ◽  
Cell Responses ◽  
Cd4 Receptor ◽  
Cd4 Binding Site ◽  
B Cell Responses ◽  
Hiv Envelope ◽  
Hiv 1

ABSTRACT Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4+ T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell (P < 0.001) response kinetics and superior ADCC (P < 0.014) in a group receiving the CD4bs-occluded vaccine compared to those of animals immunized with gp140. Of the cytokines examined, Ag-specific interleukin-4 (IL-4) T-helper enzyme-linked immunosorbent spot (ELISpot) assays of the CD4bs-occluded group increased earlier (P = 0.025) during the inductive phase. Importantly, CD4bs-occluded gp140 antigen induced superior B-cell and ADCC responses, and the elevated B-cell responses proved to be remarkably durable, lasting more than 60 weeks postimmunization. IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.

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