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Therapeutic Efficacy of Vectored PGT121 Gene Delivery in HIV-1-Infected Humanized Mice.

Therapeutic Efficacy of Vectored PGT121 Gene Delivery in HIV-1-Infected Humanized Mice.
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Badamchi-Zadeh A, Tartaglia LJ, Abbink P, Bricault CA, Liu PT, Boyd M, Kirilova M, Mercado NB, Nanayakkara OS, Vrbanac VD, Tager AM, Larocca RA, Seaman MS, Barouch DH,


Badamchi-Zadeh A, Tartaglia LJ, Abbink P, Bricault CA, Liu PT, Boyd M, Kirilova M, Mercado NB, Nanayakkara OS, Vrbanac VD, Tager AM, Larocca RA, Seaman MS, Barouch DH, (click to view)

Badamchi-Zadeh A, Tartaglia LJ, Abbink P, Bricault CA, Liu PT, Boyd M, Kirilova M, Mercado NB, Nanayakkara OS, Vrbanac VD, Tager AM, Larocca RA, Seaman MS, Barouch DH,

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Journal of virology 2018 03 1492(7) pii 10.1128/JVI.01925-17

Abstract

Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies. However, administration of purified bNAbs poses challenges in resource-poor settings, where the HIV-1 disease burden is greatest.vector-based production of bNAbs represents an alternative strategy. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121 in wild-type and immunocompromised C57BL/6 mice as well as in HIV-1-infected bone marrow-liver-thymus (BLT) humanized mice. Ad5.PGT121 and AAV1.PGT121 produced functional antibodyAd5.PGT121 produced PGT121 rapidly within 6 h, whereas AAV1.PGT121 produced detectable PGT121 in serum by 72 h. Serum PGT121 levels were rapidly reduced by the generation of anti-PGT121 antibodies in immunocompetent mice but were durably maintained in immunocompromised mice. In HIV-1-infected BLT humanized mice, Ad5.PGT121 resulted in a greater reduction of viral loads than did AAV1.PGT121. Ad5.PGT121 also led to more-sustained virologic control than purified PGT121 IgG. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice. Further evaluation of vector delivery of HIV-1 bNAbs is warranted, although approaches to prevent the generation of antiantibody responses may also be required.Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies, but delivery of purified antibodies may prove challenging. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice.

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