A Blueprint for HIV Vaccine Discovery
2012; Cell Press; Volume: 12; Issue: 4 Linguagem: Inglês
10.1016/j.chom.2012.09.008
ISSN1934-6069
AutoresDennis R. Burton, Rafi Ahmed, Dan H. Barouch, Salvatore T. Butera, Shane Crotty, Adam Godzik, Daniel E. Kaufmann, M. Juliana McElrath, Michel C. Nussenzweig, Bali Pulendran, Chris Scanlan, William R. Schief, Guido Silvestri, Hendrik Streeck, Bruce D. Walker, Laura M. Walker, Andrew B. Ward, Ian A. Wilson, Richard T. Wyatt,
Tópico(s)Immune Cell Function and Interaction
ResumoDespite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine. Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine. It is nearly 30 years since HIV was identified as the causative agent of AIDS, and yet no vaccine is approaching licensure. This is intensely disappointing. It is due partly to the fact that the process of vaccine development typically takes a long time period, partly to the failure of classical viral vaccination strategies when applied to HIV, and partly to the many barriers to immune recognition evolved by the virus. For acute viruses such as smallpox and polio, natural infection leads to a large fraction of individuals who are immune to reinfection. Hence, vaccination strategies to mimic natural infection without adverse sequelae can be designed. For persistent viruses, immunity to reinfection cannot be readily determined, but nevertheless, in some cases such as human papillomavirus (HPV), a relatively straightforward approach in which vaccines elicit neutralizing IgG is effective (Day et al., 2010Day P.M. Kines R.C. Thompson C.D. Jagu S. Roden R.B. Lowy D.R. Schiller J.T. In vivo mechanisms of vaccine-induced protection against HPV infection.Cell Host Microbe. 2010; 8: 260-270Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). However, for the highly variable retrovirus HIV, the classical vaccination strategies have failed, and it is worth considering why this is the case. As for other viruses, animal model studies, including the macaque, provide an abundance of evidence for protection against HIV or SHIV (chimeric HIV/SIV with envelope (Env) of HIV) challenge by neutralizing antibodies. However, to protect against the huge diversity of global circulating HIVs, the neutralizing antibody response should be broad, and traditional vaccine approaches have failed to induce such a response. We note that although there are reports of some degree of antibody protection in the absence of serum-neutralizing antibodies, including the RV144 trial, the protection is generally not particularly strong, and so we focus here on neutralizing antibodies. Many highly successful vaccines rely on direct mimicry of the pathogen. Live-attenuated viruses (e.g., measles, mumps, yellow fever), inactivated viruses (e.g., poliovirus), or virus-like particles (e.g., HPV) have been used to imitate natural infection and imprint immunological memory. However, for many reasons these approaches have been unsuccessful for HIV vaccine development (Burton et al., 2005Burton D.R. Stanfield R.L. Wilson I.A. Antibody vs. HIV in a clash of evolutionary titans.Proc. Natl. Acad. Sci. 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Second, the extraordinary variability in antigenic regions of the Env spike means that the number of circulating HIV strains is extremely high and that conventional concepts of viral serotypes are rendered irrelevant. Third, because of the instability of the HIV spike, most viral particle-based vaccines tend to express immunodominant, nonfunctional forms of Env on the virion surface (Poignard et al., 2003Poignard P. Moulard M. Golez E. Vivona V. Franti M. Venturini S. Wang M. Parren P.W. Burton D.R. Heterogeneity of envelope molecules expressed on primary human immunodeficiency virus type 1 particles as probed by the binding of neutralizing and nonneutralizing antibodies.J. Virol. 2003; 77: 353-365Crossref PubMed Scopus (110) Google Scholar), which favor the induction of nonneutralizing antibodies (Crooks et al., 2007Crooks E.T. Moore P.L. Franti M. Cayanan C.S. Zhu P. Jiang P. de Vries R.P. Wiley C. Zharkikh I. 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Schülke N. et al.A comparative immunogenicity study of HIV-1 virus-like particles bearing various forms of envelope proteins, particles bearing no envelope and soluble monomeric gp120.Virology. 2007; 366: 245-262Crossref PubMed Scopus (73) Google Scholar), none of these approaches have yet induced potent heterologous antibody responses in nonhuman primate (NHP) models. Finally, it should be noted that, because of the risk of mutation and reversion to a pathogenic form, the use of live attenuated HIV vaccines in humans raises formidable safety and liability issues. Using the same paradigm that formed the basis for successful development of a vaccine against hepatitis B, initial attempts to generate a protective vaccine against HIV focused on the elicitation of Env-specific humoral immune responses using gp120 subunit immunogens. Unfortunately, the results of clinical trials indicated that the antibodies elicited by monomeric gp120 failed to neutralize HIV primary isolates, prevent HIV infection, reduce viral loads, or delay disease progression (Flynn et al., 2005Flynn N.M. Forthal D.N. Harro C.D. Judson F.N. Mayer K.H. Para M.F. rgp120 HIV Vaccine Study GroupPlacebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection.J. Infect. Dis. 2005; 191: 654-665Crossref PubMed Scopus (368) Google Scholar; Pitisuttithum et al., 2006Pitisuttithum P. Gilbert P. Gurwith M. Heyward W. Martin M. van Griensven F. Hu D. Tappero J.W. Choopanya K. Bangkok Vaccine Evaluation GroupRandomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand.J. Infect. Dis. 2006; 194: 1661-1671Crossref PubMed Scopus (318) Google Scholar). 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In addition, MPER antibodies have been associated with autoreactivity (Haynes et al., 2005aHaynes B.F. Fleming J. St Clair E.W. Katinger H. Stiegler G. Kunert R. Robinson J. Scearce R.M. Plonk K. Staats H.F. et al.Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies.Science. 2005; 308: 1906-1908Crossref PubMed Scopus (356) Google Scholar, Haynes et al., 2005bHaynes B.F. Moody M.A. Verkoczy L. Kelsoe G. Alam S.M. Antibody polyspecificity and neutralization of HIV-1: a hypothesis.Hum. Antibodies. 2005; 14: 59-67PubMed Google Scholar), and this argued to be a problem in inducing such antibodies. However, the recent description of a potent MPER bnMAb that shows no autoreactivity (Huang et al., 2012Huang J. Ofek G. Laub L. Louder M.K. Doria-Rose N.A. Longo N.S. Imamichi H. Bailer R.T. Chakrabarti B. Sharma S.K. et al.Broad and potent neutralization of HIV-1 by a gp41-specific human antibody.Nature. 2012; (Published online September 18, 2012)https://doi.org/10.1038/nature11544Crossref Scopus (71) Google Scholar) suggests that autoreactivity may not be the overarching problem envisaged earlier. In summary, the challenge for epitope-based vaccine design is that only broadly conserved and exposed epitopes are suitable for vaccine targeting, but these epitopes, in their natural context, tend to elicit poor antibody responses. When bnAb responses are elicited, the corresponding bnMAbs tend to have unusual features such as high levels of somatic mutations, insertions/deletions, long CDRH3 loops, posttranslational modifications, polyreactivity, and rare stru
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