AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges

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Abstract

Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs) ^{1,
2}. However even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (IC ₈₀ > 5 μg/ml), suggesting that high concentrations of these antibodies would be necessary to achieve general protection ^{3–
6}. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean IC ₅₀ < 0.05 μg/ml). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2, and SIV isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46, and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17 to 77 μg/ml of fully functional rhesus eCD4-Ig for 40 weeks, and these macaques were protected from multiple infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.

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Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

C. A. Derdeyn, J M Decker, J Sfakianos … (2000)

T-20 is a synthetic peptide that potently inhibits replication of human immunodeficiency virus type 1 by interfering with the transition of the transmembrane protein, gp41, to a fusion active state following interactions of the surface glycoprotein, gp120, with CD4 and coreceptor molecules displayed on the target cell surface. Although T-20 is postulated to interact with an N-terminal heptad repeat within gp41 in a trans-dominant manner, we show here that sensitivity to T-20 is strongly influenced by coreceptor specificity. When 14 T-20-naive primary isolates were analyzed for sensitivity to T-20, the mean 50% inhibitory concentration (IC(50)) for isolates that utilize CCR5 for entry (R5 viruses) was 0.8 log(10) higher than the mean IC(50) for CXCR4 (X4) isolates (P = 0. 0055). Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 and X4 viruses, we found that determinants of coreceptor specificity contained within the gp120 V3 loop modulate this sensitivity to T-20. The IC(50) for all chimeric envelope viruses containing R5 V3 sequences was 0.6 to 0.8 log(10) higher than that for viruses containing X4 V3 sequences. In addition, we confirmed that the N-terminal heptad repeat of gp41 determines the baseline sensitivity to T-20 and that the IC(50) for viruses containing GIV at amino acid residues 36 to 38 was 1.0 log(10) lower than the IC(50) for viruses containing a G-to-D substitution. The results of this study show that gp120-coreceptor interactions and the gp41 N-terminal heptad repeat independently contribute to sensitivity to T-20. These results have important implications for the therapeutic uses of T-20 as well as for unraveling the complex mechanisms of virus fusion and entry.

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The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.

H. Choe, M Farzan, Y. Sun … (1996)

We examined the ability of chemokine receptors and related G protein-coupled receptors to facilitate infection by primary, clinical HIV-1 isolates. CCR5, when expressed along with CD4, the HIV-1 receptor, allowed cell lines resistant to most primary HIV-1 isolates to be infected. CCR3 facilitated infection by a more restricted subset of primary viruses, and binding of the CCR3 ligand, eotaxin, inhibited infection by these isolates. Utilization of CCR3 and CCR5 on the target cell depended upon the sequence of the third variable (V3) region of the HIV-1 gp120 exterior envelope glycoprotein. The ability of various members of the chemokine receptor family to support the early stages of HIV-1 infection helps to explain viral tropism and beta-chemokine inhibition of primary HIV-1 isolates.

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Antibody-based Protection Against HIV Infection by Vectored ImmunoProphylaxis

Alejandro B. Balazs, Joyce Chen, Christin Hong … (2011)

Despite tremendous efforts, development of an effective vaccine against HIV has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing the vast majority of circulating HIV strains 1–5 . These antibodies all exhibit an unusually high level of somatic mutation 6 , presumably due to extensive affinity maturation over the course of continuous exposure to an evolving antigen 7 . While substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes 8–10 , it remains uncertain whether a conventional vaccine will be able to elicit analogs of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus (AAV) vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.

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Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 15 February 2015

Publication date (Electronic): 18 February 2015

Publication date (Print): 5 March 2015

Publication date PMC-release: 05 September 2015

Volume: 519

Issue: 7541

Pages: 87-91

Affiliations

[1 ]Department of Infectious Diseases, The Scripps Research Institute, Jupiter, FL 33458, USA

[2 ]Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA

[3 ]Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA

[4 ]Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA

[5 ]Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

[6 ]Immunathon Inc., Cambridge, MA 02141, USA

[7 ]Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA

[8 ]Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA

[9 ]Department of Immunology, Institut Pasteur, Paris, 75015, France

[10 ]Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA

[11 ]Department of Immunology and Microbial Science, IAVI Neutralizing Antibody Center, and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA

[12 ]Howard Hughes Medical Institute, New York, NY 10065, USA

[13 ]Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA

[14 ]AIDS and Cancer Virus Program, Leidos Biomedical Research, Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA

[15 ]Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655, USA

[16 ]Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53711, USA

[17 ]Beth Israel Deaconess Medical Center, Boston, MA 02215, USA

Author notes

[* ]To whom correspondence should be addressed: mfarzan@ 123456scripps.edu

[†]

These authors contributed equally to this work.

Article

Manuscript ID: NIHMS659286

DOI: 10.1038/nature14264

PMC ID: 4352131

PubMed ID: 25707797

SO-VID: efd14ddb-d6eb-4b88-8b29-5f737c0cc1a3

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AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges

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Most cited references 40

Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.

Antibody-based Protection Against HIV Infection by Vectored ImmunoProphylaxis

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