Host Anti-antibody Responses Following Adeno-associated Virus–mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys

Martinez-Navío, José M.; Fuchs, Sebastian; Pedreño-López, Sònia; Rakasz, Eva G.; Gao, Guangping; Desrosiers, Ronald C.

doi:10.1038/mt.2015.191

Cited by 61 publications

(91 citation statements)

References 41 publications

(69 reference statements)

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“…17, 18, 33 Comparable to our previous studies using AAV 17, 33 the anti-4L6 responses in our present study with recombinant RRV were higher than the measured responses against 5L7. Furthermore, both recombinant RRV-4L6 recipients showed clear anti-antibody responses, whereas only one of the two recombinant RRV-5L7 recipients exhibited measurable anti-antibodies; this also reflects the AAV results where anti-anti responses were consistently observed in six of six monkeys with 4L6 delivery but only in three of six monkeys with 5L7 delivery.…”

Section: Discussionsupporting

confidence: 61%

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Use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys

et al. 2017

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The gamma-2 herpesvirus of rhesus monkeys, rhesus monkey rhadinovirus (RRV), persists principally in B cells of its host. We constructed recombinant strains of RRV expressing the rhesus monkey-derived anti-SIV monoclonal antibodies 4L6 and 5L7 and compared the RRV-mediated in vivo delivery of these antibodies in rhesus monkeys with previous studies that utilized intramuscular delivery with adeno-associated virus (AAV) vector. Recombinant RRV-4L6 and RRV-5L7 were both shown to stably produce the antibodies in persistently infected B cell lines in culture. Two RRV-negative rhesus monkeys were experimentally infected with recombinant RRV-4L6 and two with recombinant RRV-5L7. Following infection, the appearance of the delivered antibody was readily detected in all four animals. However, the levels of the delivered antibody were considerably lower than what has been typically observed following intramuscular AAV delivery. Furthermore, three of the four monkeys had an antibody response to the delivered antibody as had been observed previously with intramuscular AAV delivery of these same antibodies. We conclude that this recombinant herpesvirus has no inherent advantage over AAV for delivery of potentially therapeutic monoclonal antibodies in a rhesus monkey model.

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Section: Discussionsupporting

confidence: 61%

“…36, 37 The data of Martinez-Navio et al indicates that the magnitude of the anti-anti response is directly proportional to the distance from the germline of the antibody being delivered. 33 …”

Section: Discussionmentioning

confidence: 99%

Use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys

et al. 2017

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“…5B). We observed that the G382R/H442Y variant remained as resistant to the SIV neutralizing antibodies 4L6 and 5L7 (16,17) as wild-type SIVmac239 Env up to concentrations of 50 g/ml, whereas pseudovirus expressing the SIVmac316 Env was efficiently neutralized at the lowest concentration assayed (0.0032 g/ml). Similarly, both the SIVmac239 Env and the G382R/ H442Y variant remained more than 400ϫ more resistant to sera from two infected macaques than SIVmac316.…”

Section: Resultsmentioning

confidence: 86%

“…Expi293 cells were grown in Expi293 expression medium (Thermo Fisher Scientific). Plasmids V132 and V82 for the expression of antibodies 4L6 and 5L7, respectively, were provided by Ronald Desrosiers, as were plasmids encoding SIV mac 239 SpX, SIV mac 316 open SpX, and SIVsmE543-3 full-length viral genomes, and SIVmac251 stock virus (5,16,17,38). SIVmac1A11 infectious molecular clone, also from the NIH AIDS reagent program, was supplied by Paul Luciw (39).…”

Section: Methodsmentioning

confidence: 99%

Simian Immunodeficiency Virus SIVmac239, but Not SIVmac316, Binds and Utilizes Human CD4 More Efficiently than Rhesus CD4

Fellinger

Gardner

Bailey

et al. 2017

J Virol

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Rhesus macaques are used to model human immunodeficiency virus type 1 (HIV-1) infections, but they are not natural hosts of HIV-1 or any simian immunodeficiency virus (SIV). Rather, they became infected with SIV through cross-species transfer from sooty mangabeys in captivity. It has been shown that HIV-1 utilizes rhesus CD4 less efficiently than human CD4. However, the relative ability of SIV envelope glycoproteins to bind or utilize these CD4 orthologs has not been reported. Here we show that several SIV isolates, including SIVmac239, are more efficiently neutralized by human CD4-Ig (huCD4-Ig) than by the same molecule bearing rhesus CD4 domains 1 and 2 (rhCD4-Ig). An I39N mutation in CD4 domain 1, present in human and sooty mangabey CD4 orthologs, largely restored rhCD4-Ig neutralization of SIVmac239 and other SIV isolates. We further observed that SIVmac316, a derivative of SIVmac239, bound to and was neutralized by huCD4-Ig and rhCD4-Ig with nearly identical efficiencies. Introduction of two SIVmac316 CD4-binding site residues (G382R and H442Y) into the SIVmac239 envelope glycoprotein (Env) markedly increased its neutralization sensitivity to rhesus CD4-Ig without altering neutralization by human CD4-Ig, SIV neutralizing antibodies, or sera from SIV-infected macaques. These changes also allowed SIVmac239 Env to bind rhCD4-Ig more efficiently than huCD4-Ig. The variant with G382R and H442Y (G382R/H442Y variant) also infected cells expressing rhesus CD4 with markedly greater efficiency than did unaltered SIVmac239 Env. We propose that infections of rhesus macaques with SIVmac239 G382R/H442Y might better model some aspects of human infections. IMPORTANCE Rhesus macaque infection with simian immunodeficiency virus (SIV)has served as an important model of human HIV-1 infection. However, differences between this model and the human case have complicated the development of vaccines and therapies. Here we report the surprising observation that SIVmac239, a commonly used model virus, more efficiently utilizes human CD4 than the CD4 of rhesus macaques, whereas the closely related virus SIVmac316 uses both CD4 orthologs equally well. We used this insight to generate a form of SIVmac239 envelope glycoprotein (Env) that utilized rhesus CD4 more efficiently, while retaining its resistance to antibodies and sera from infected macaques. This Env can be used to make the rhesus model more similar in some ways to human infection, for example by facilitating infection of cells with low levels of CD4. This property may be especially important to efforts to eradicate latently infected cells.KEYWORDS CD4, SIVmac239, SIVmac316, human immunodeficiency virus, rhesus macaques, simian immunodeficiency virus

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“…Primate protection from SIV challenge has recently been reported with AAV vector expressing the simianized form of the VRC07 bNAb [49]. Recent work has tackled secondary challenges, such as testing harder-to-neutralize SIV strains and strategies to avoid anti-antibody responses, a major obstacle in developing effective vectored antibody therapies [50]. Fuchs et al recently showed that use of a fully simianized, authentic IgG structure does not ameliorate the immunogenicity of a foreign antibody as hoped [51].…”

Section: Vectored Delivery Of Antibodies and Antibody-like Moleculesmentioning

confidence: 99%

Cell and gene therapy strategies to eradicate HIV reservoirs

Spragg

Feelixge

Jerome

2016

Current Opinion in HIV and AIDS

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Purpose of review Highly active antiretroviral treatment has dramatically improved prognosis for people living with HIV by preventing AIDS-related morbidity and mortality through profound suppression of viral replication. However, a long-lived viral reservoir persists in latently infected cells that harbor replication-competent HIV genomes. If therapy is discontinued, latently infected memory cells inevitably reactivate and produce infectious virus, resulting in viral rebound. The reservoir is the biggest obstacle to a cure of HIV. Recent findings This review summarizes significant advances of the past year in the development of cellular and gene therapies for HIV cure. In particular, we highlight work done on suppression or disruption of HIV co-receptors, vectored delivery of antibodies and antibody-like molecules, T cell therapies, and HIV genome disruption. Summary A number of recent advancements in cellular and gene therapies have emerged at the forefront of HIV cure research, potentially having broad implications for the future of HIV treatment.

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Host Anti-antibody Responses Following Adeno-associated Virus–mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys

Cited by 61 publications

References 41 publications

Use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys

Use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys

Simian Immunodeficiency Virus SIVmac239, but Not SIVmac316, Binds and Utilizes Human CD4 More Efficiently than Rhesus CD4

Cell and gene therapy strategies to eradicate HIV reservoirs

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