A Human Antibody to the CD4 Binding Site of gp120 Capable of Highly Potent but Sporadic Cross Clade Neutralization of Primary HIV-1

Broadly HIV-1 neutralizing VRC01-class antibodies bind the CD4-binding site of the HIV-1 envelope (Env) and contain VH1-2*02-derived heavy chains paired with light chains expressing five amino acid long CDRL3s. Their unmutated forms do not recognize Env or neutralize HIV-1. The lack of elicitation of VRC01-class antibodies in human clinical trials could potentially be due to the absence of activation of the corresponding naive B cells by the vaccine Env immunogens. To address this point directly, we examined Env-specific BCR sequences from participants in the HVTN 100 clinical trial. Of all the sequences analyzed only one displayed sequence homology to VRC01-class antibodies, but the corresponding antibody (FH1) recognized the C1C2 gp120 domain. For FH1 to switch epitope recognition to the CD4-binding site, alterations in both the CDRH3 and CDRL3 were necessary. Our findings support the use of specifically designed immunogens to activate VRC01-class B cells in future human vaccine trials.

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3D-QSAR and Molecular Docking Studies of HIV-1 Entry Inhibitors Targeting GP120-CD4 Binding Site

Anti-Infective Agents ◽

10.2174/2211352515666170809151958 ◽

2018 ◽

Vol 15 (2) ◽

Author(s):

Bhumika D. Patel ◽

Nidhi Choksi ◽

Kinjal Patel ◽

Qureshi Gulamnizami

Keyword(s):

Molecular Docking ◽

Binding Site ◽

3D Qsar ◽

Docking Studies ◽

Molecular Docking Studies ◽

Entry Inhibitors ◽

Cd4 Binding Site ◽

Hiv 1

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An HIV-1 Envelope Immunogen with W427S Mutation in CD4 Binding Site Induced More T Follicular Helper Memory Cells and Reduced Non-Specific Antibody Responses

PLoS ONE ◽

10.1371/journal.pone.0115047 ◽

2014 ◽

Vol 9 (12) ◽

pp. e115047 ◽

Cited By ~ 3

Author(s):

Hao-Tong Yu ◽

Dan Tian ◽

Jia-Ye Wang ◽

Cai-Xia Guo ◽

Yan Li ◽

...

Keyword(s):

Binding Site ◽

Specific Antibody ◽

Antibody Responses ◽

Memory Cells ◽

Follicular Helper ◽

Cd4 Binding Site ◽

Hiv 1

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Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas

mBio ◽

10.1128/mbio.00296-15 ◽

2015 ◽

Vol 6 (2) ◽

Cited By ~ 17

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20120423 ◽

2012 ◽

Vol 209 (8) ◽

pp. 1469-1479 ◽

Cited By ~ 123

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.

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Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120–CD4-binding site from long-term survivors of HIV infection

AIDS ◽

10.1097/qad.0b013e3283376e88 ◽

2010 ◽

Vol 24 (6) ◽

pp. 875-884 ◽

Cited By ~ 21

Author(s):

Stephanie Planque ◽

Maria Salas ◽

Yukie Mitsuda ◽

Marcin Sienczyk ◽

Miguel A Escobar ◽

...

Keyword(s):

Hiv Infection ◽

Binding Site ◽

Iga Antibodies ◽

Cd4 Binding Site ◽

Long Term Survivors ◽

Hiv 1

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Structure of the Fab Fragment of F105, a Broadly Reactive Anti-Human Immunodeficiency Virus (HIV) Antibody That Recognizes the CD4 Binding Site of HIV Type 1 gp120

Journal of Virology ◽

10.1128/jvi.79.20.13060-13069.2005 ◽

2005 ◽

Vol 79 (20) ◽

pp. 13060-13069 ◽

Cited By ~ 25

Author(s):

Royce A. Wilkinson ◽

Chayne Piscitelli ◽

Martin Teintze ◽

Lisa A. Cavacini ◽

Marshall R. Posner ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Binding Site ◽

Neutralizing Antibody ◽

Binding Pocket ◽

Human Antibody ◽

Fab Fragment ◽

Outer Domain ◽

Immunodeficiency Virus ◽

Cd4 Binding Site ◽

The Difference

ABSTRACT We have determined the crystal structure of the Fab fragment from F105, a broadly reactive human antibody with limited potency that recognizes the CD4 binding site of gp120. The structure reveals an extended CDR H3 loop with a phenylalanine residue at the apex and shows a striking pattern of serine and tyrosine residues. Modeling the interaction between gp120 and F105 suggests that the phenylalanine may recognize the binding pocket of gp120 used by Phe43 of CD4 and that numerous tyrosine and serine residues form hydrogen bonds with the main chain atoms of gp120. A comparison of the F105 structure to that of immunoglobulin G1 b12, a much more potent and broadly neutralizing antibody with an overlapping epitope, suggests similarities that contribute to the broad recognition of human immunodeficiency virus by both antibodies. While the putative epitope for F105 shows significant overlap with that predicted for b12, it appears to differ from the b12 epitope in extending across the interface between the inner and outer domains of gp120. In contrast, the CDR loops of b12 appear to interact predominantly with the outer domain of gp120. The difference between the predicted epitopes for b12 and F105 suggests that the unique potency of b12 may arise from its ability to avoid the interface between the inner and outer domains of gp120.

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