AAV-Mediated Expression of Broadly Neutralizing and Vaccine-like Antibodies Targeting the HIV-1 Envelope V2 Region

Fiona T van den Berg; Nigel A Makoah; Stuart A Ali; Tristan A Scott; Rutendo E Mapengo; Lorraine Z Mutsvunguma; Nonhlanhla N Mkhize; Bronwen E Lambson; Prudence D Kgagudi; Carol Crowther; Salim S Abdool Karim; Alejandro B Balazs; Marc S Weinberg; Abdullah Ely; Patrick B Arbuthnot; Lynn Morris

doi:10.1016/j.omtm.2019.06.002

AAV-Mediated Expression of Broadly Neutralizing and Vaccine-like Antibodies Targeting the HIV-1 Envelope V2 Region

Mol Ther Methods Clin Dev. 2019 Jun 12:14:100-112. doi: 10.1016/j.omtm.2019.06.002. eCollection 2019 Sep 13.

Authors

Fiona T van den Berg^{1

2}, Nigel A Makoah^{3

4}, Stuart A Ali², Tristan A Scott^{1

2}, Rutendo E Mapengo³, Lorraine Z Mutsvunguma², Nonhlanhla N Mkhize³, Bronwen E Lambson³, Prudence D Kgagudi³, Carol Crowther³, Salim S Abdool Karim^{5

6}, Alejandro B Balazs⁷, Marc S Weinberg^{1

2}, Abdullah Ely¹, Patrick B Arbuthnot¹, Lynn Morris^{3

4

5}

Affiliations

¹ Wits-SAMRC Antiviral Gene Therapy Research Unit, Department of Molecular Medicine & Hematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
² HIV Pathogenesis Research Unit, Department of Molecular Medicine & Hematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³ Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa.
⁴ Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁵ Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
⁶ Department of Epidemiology, Columbia University, New York, NY, USA.
⁷ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.

Abstract

HIV-1 infection continues to be a global health challenge and a vaccine is urgently needed. Broadly neutralizing antibodies (bNAbs) are considered essential as they inhibit multiple HIV-1 strains, but they are difficult to elicit by conventional immunization. In contrast, non-neutralizing antibodies that correlated with reduced risk of infection in the RV144 HIV vaccine trial are relatively easy to induce, but responses are not durable. To overcome these obstacles, adeno-associated virus (AAV) vectors were used to provide long-term expression of antibodies targeting the V2 region of the HIV-1 envelope protein, including the potent CAP256-VRC26.25 bNAb, as well as non-neutralizing CAP228 antibodies that resemble those elicited by vaccination. AAVs mediated effective antibody expression in cell culture and immunocompetent mice. Mean concentrations of human immunoglobulin G (IgG) in mouse sera increased rapidly following a single AAV injection, reaching 8-60 μg/mL for CAP256 antibodies and 44-220 μg/mL for CAP228 antibodies over 24 weeks, but antibody concentrations varied for individual mice. Secreted antibodies collected from serum retained the expected binding and neutralizing activity. The vectors generated here are, therefore, suitable for the delivery of V2-targeting HIV antibodies, and they could be used in a vectored immunoprophylaxis (VIP) approach to sustain the level of antibody expression required to prevent HIV infection.

Keywords: AAV; HIV vaccine; V2 apex; broadly neutralizing antibodies; gene transfer; vectored immunoprophylaxis.

Grants and funding

DP2 DA040254/DA/NIDA NIH HHS/United States