scholarly journals Synthetic Mimetics of the CD4 Binding Site of HIV-1 gp120 for the Design of Immunogens

2007 ◽  
Vol 46 (8) ◽  
pp. 1253-1255 ◽  
Author(s):  
Raimo Franke ◽  
Tatjana Hirsch ◽  
Heike Overwin ◽  
Jutta Eichler
Keyword(s):  
Binding Site ◽  
Cd4 Binding Site ◽  
Hiv 1

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

AIDS ◽  
2010 ◽  
Vol 24 (6) ◽  
pp. 875-884 ◽  
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

scholarly journals MiniCD4 protein resistance mutations affect binding to the HIV-1 gp120 CD4 binding site and decrease entry efficiency

Retrovirology ◽  
2012 ◽  
Vol 9 (1) ◽  
pp. 36 ◽  
Author(s):  
Katrijn Grupping ◽  
Philippe Selhorst ◽  
Johan Michiels ◽  
Katleen Vereecken ◽  
Leo Heyndrickx ◽  
...  
Keyword(s):  
Binding Site ◽  
Resistance Mutations ◽  
Protein Resistance ◽  
Cd4 Binding Site ◽  
Hiv 1 ◽  
Entry Efficiency

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 Changes in the Immunogenic Properties of Soluble gp140 Human Immunodeficiency Virus Envelope Constructs upon Partial Deletion of the Second Hypervariable Region

2003 ◽  
Vol 77 (4) ◽  
pp. 2310-2320 ◽  
Author(s):  
Indresh K. Srivastava ◽  
Keating VanDorsten ◽  
Lucia Vojtech ◽  
Susan W. Barnett ◽  
Leonidas Stamatatos
Keyword(s):  
Human Immunodeficiency Virus ◽  
Binding Site ◽  
Hypervariable Region ◽  
V3 Loop ◽  
Virus Envelope ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Hiv Envelope ◽  
Immunogenic Properties ◽  
Hiv 1

ABSTRACT Immunization of macaques with the soluble oligomeric gp140 form of the SF162 envelope (SF162gp140) or with an SF162gp140-derived construct lacking the central region of the V2 loop (ΔV2gp140) results in the generation of high titers of antibodies capable of neutralizing the homologous human immunodeficiency virus type 1 (HIV-1), SF162 virus (Barnett et al. J. Virol. 75 :5526-5540, 2001). However, the ΔV2gp140 immunogen is more effective than the SF162gp140 immunogen in eliciting the generation of antibodies capable of neutralizing heterologous HIV-1 isolates. This indicates that deletion of the V2 loop alters the immunogenicity of the SF162gp140 protein. The present studies were aimed at identifying the envelope regions whose immunogenicity is altered following V2 loop deletion. We report that the antibodies elicited by the SF162gp140 immunogen recognize elements of the V1, V2, and V3 loops, the CD4-binding site, and the C1 and C2 regions on the homologous SF162 gp120. With the exception of the V1 and V2 loops, the same regions are recognized on heterologous gp120 proteins. Surprisingly, although a minority of the SF162gp140-elicited antibodies target the V3 loop on the homologous gp120, the majority of the antibodies elicited by this immunogen that are capable of binding to the heterologous gp120s tested recognize their V3 loops. Deletion of the V2 loop has two effects. First, it alters the immunogenicity of the V3 and V1 loops, and second, it renders the C5 region immunogenic. Although deletion of the V2 loop does not result in an increase in the immunogenicity of the CD4-binding site per se, the relative ratio of anti-CD4-binding site to anti-V3 loop antibodies that bind to the heterologous gp120s tested is higher in sera collected from the ΔV2gp140-immunized animals than in the SF162gp140-immunized animals. Overall, our studies indicate that it is possible to alter the immunogenic structure of the HIV envelope by introducing specific modifications.

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