Delivery of anti-HIV bNAbs by viral vectors

In The Lancet HIV, Frances Priddy and colleagues1Priddy FH Lewis DJM Gelderblom HC et al.Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial.Lancet HIV. 2019; (published online March 15.)http://dx.doi.org/10.1016/S2352-3018(19)30003-7Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar report the results of a phase 1 clinical trial of a recombinant adeno-associated virus (rAAV) vector for antibody gene delivery in healthy adults for immune prophylaxis against HIV-1. The construct assessed in this study encodes the gene for PG9, an anti-HIV-1 antibody that shows broad and potent neutralising activity against viruses from multiple clades.2Klein F Mouquet H Dosenovic P Scheid JF Scharf L Nussenzweig MC Antibodies in HIV-1 vaccine development and therapy.Science. 2013; 341: 1199-1204Crossref PubMed Scopus (356) Google Scholar This trial is the first clinical report of anti-HIV-1 antibody gene delivery and shows that antibody gene delivery can be safely achieved in healthy adults when given intramuscularly. Unfortunately, the rAAV vector construct tested in this study led to low circulating antibody levels, while inducing anti-vector and neutralising anti-PG9 antibody responses. However, the results do suggest successful antibody expression locally and provide indirect evidence of preserved in-vivo serum activity of the expressed protein. Overall, the study provides supportive data for the further development of viral vectors for antibody gene delivery, but it also highlights the challenges of achieving sufficient protein expression while avoiding or limiting anti-vector or anti-antibody immune responses that abrogate antibody production or function. Despite the success of combination antiretroviral therapy (ART) in suppressing viral replication and preventing disease progression, worldwide HIV-1 incidence has declined slowly. Extensive data from animal studies show that neutralising antibodies can induce sterilising protection.3Escolano A Dosenovic P Nussenzweig MC Progress toward active or passive HIV-1 vaccination.J Exp Med. 2017; 214: 3-16Crossref PubMed Scopus (88) Google Scholar As a result, ongoing efforts are directed towards the development of vaccine strategies that reliably induce broad, potent, and long-lasting humoral neutralising immune responses against HIV-1. However, an effective HIV-1 vaccine remains an elusive goal at this point. A new generation of highly potent broadly neutralising antibodies (bNAbs) might be a novel strategy to combat HIV-1 infection.2Klein F Mouquet H Dosenovic P Scheid JF Scharf L Nussenzweig MC Antibodies in HIV-1 vaccine development and therapy.Science. 2013; 341: 1199-1204Crossref PubMed Scopus (356) Google Scholar Antibodies are uniquely attractive molecules because of their dual functionality. In addition to targeting a specific epitope with their variable domains, antibodies harness host effector functions by their constant domains, which engage host Fc receptors.4Bournazos S Wang TT Dahan R Maamary J Ravetch JV Signaling by antibodies: recent progress.Annu Rev Immunol. 2017; 35: 285-311Crossref PubMed Scopus (124) Google Scholar Such interactions can lead to direct clearance of infected cells as well as enhancement of host immune responses to better control or suppress HIV-1 replication. Therefore, antibodies might have roles not only in prevention and treatment, but in HIV-1 cure efforts aimed at long-term virological control or eradication. Clinical studies of newer generation bNAbs have shown their therapeutic potential during HIV-1 infection and two large phase 2b studies are assessing their role in prevention.5Cohen YZ Caskey M Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection.Curr Opin HIV AIDS. 2018; 13: 366-373Crossref PubMed Scopus (55) Google Scholar, 6Mendoza P Gruell H Nogueira L et al.Combination therapy with anti-HIV-1 antibodies maintains viral suppression.Nature. 2018; 561: 479-484Crossref PubMed Scopus (280) Google Scholar, 7Bar-On Y Gruell H Schoofs T et al.Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals.Nat Med. 2018; 24: 1701-1707Crossref PubMed Scopus (149) Google Scholar However, antibodies are expensive to produce and require repeated parenteral dosing. Long-term delivery of bNAbs through antibody gene transfer is a promising new strategy to prevent and potentially treat HIV-1 infection. rAAVs are attractive and safe vectors for several reasons. AAVs have no apparent pathogenicity in humans, recombinant vectors do not encode viral genes, and their genomes persist in the cell in episomal form, such that rAAV transgene products can be transduced for the lifetime of the cell. Clinical studies have shown successful and safe application of rAAVs for the treatment of genetic diseases. In fact, two rAAV gene therapy products have obtained licensure and others are undergoing clinical evaluation.8Lin A Balazs AB Adeno-associated virus gene delivery of broadly neutralizing antibodies as prevention and therapy against HIV-1.Retrovirology. 2018; 15: 66Crossref PubMed Scopus (27) Google Scholar, 9Fuchs SP Desrosiers RC Promise and problems associated with the use of recombinant AAV for the delivery of anti-HIV antibodies.Mol Ther Methods Clin Dev. 2016; 3: 16068Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar In HIV-1, preclinical studies in both humanised mouse and non-human primate models have shown that different rAAV constructs can lead to systemic production of anti-HIV-1 antibody or antibody-like molecules, at levels sufficient to protect against viral challenges.10Johnson PR Schnepp BC Zhang J et al.Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys.Nat Med. 2009; 15: 901-906Crossref PubMed Scopus (264) Google Scholar, 11Fuchs SP Martinez-Navio JM Piatak Jr, M Lifson JD Gao G Desrosiers RC AAV-delivered antibody mediates significant protective effects against SIVmac239 challenge in the absence of neutralizing activity.PLoS Pathog. 2015; 11: e1005090Crossref PubMed Scopus (69) Google Scholar, 12Saunders KO Wang L Joyce MG et al.Broadly neutralizing human immunodeficiency virus type 1 antibody gene transfer protects nonhuman primates from mucosal simian-human immunodeficiency virus infection.J Virol. 2015; 89: 8334-8345Crossref PubMed Scopus (89) Google Scholar However, these studies also demonstrated challenges to the long-term efficacy of this strategy. Even though AAVs are not pathogenic in humans, rAAVs might be recognised as foreign by the host innate immune system. Additionally, pre-existing host immune responses against wild-type AAV can substantially limit infection of long-lived cells and therefore diminish or prevent effective transduction of transgene products. Prevalence of pre-existing immunity varies across different AAV serotypes and can range from about 30% to 70%, as demonstrated during screening in the rAAV1-PG9DP trial.1Priddy FH Lewis DJM Gelderblom HC et al.Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial.Lancet HIV. 2019; (published online March 15.)http://dx.doi.org/10.1016/S2352-3018(19)30003-7Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar Notably, immune responses to the transgene antibody product appears to occur quite consistently in non-human primate studies, even when so-called simianised gene inserts are used. Such responses can be neutralising in nature and limit antibody levels or their neutralising activity in-vivo.1Priddy FH Lewis DJM Gelderblom HC et al.Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial.Lancet HIV. 2019; (published online March 15.)http://dx.doi.org/10.1016/S2352-3018(19)30003-7Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar Whether the likelihood of eliciting anti-antibody responses relates to the specific antibody gene insert or to the level of antibody expression is unclear. bNAbs typically have unusual structural features and might therefore be more immunogenic than other proteins, although anti-antibody responses have not been reported after passive transfer of bNAbs to date.5Cohen YZ Caskey M Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection.Curr Opin HIV AIDS. 2018; 13: 366-373Crossref PubMed Scopus (55) Google Scholar An ongoing phase 1 study is assessing a rAAV8 vector expressing the anti-HIV-1 CD4 binding site antibody VRC07 and results are expected soon (NCT03374202). The clinical usefulness of rAAV antibody gene delivery for HIV-1 prevention or therapy remains to be seen. Areas that could be explored in future studies include delivery of higher rAAV doses, alternative AAV serotypes or gene expression cassettes, and delivery of other bNAbs, including bNAb combinations. I declare no competing interests. Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trialFuture studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralising HIV antibodies. Full-Text PDF Open Access