Title: Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy
Abstract: Despite 30 years of effort, there is no effective vaccine for HIV-1. However, antibodies can prevent HIV-1 infection in humanized mice and macaques when passively transferred. New single-cell-based methods have uncovered many broad and potent donor-derived antibodies, and structural studies have revealed the molecular bases for their activities. The new data suggest why such antibodies are difficult to elicit and inform HIV-1 vaccine development efforts. In addition to protecting against infection, the newly identified antibodies can suppress active infections in mice and macaques, suggesting they could be valuable additions to anti-HIV-1 therapies and to strategies to eradicate HIV-1 infection. Despite 30 years of effort, there is no effective vaccine for HIV-1. However, antibodies can prevent HIV-1 infection in humanized mice and macaques when passively transferred. New single-cell-based methods have uncovered many broad and potent donor-derived antibodies, and structural studies have revealed the molecular bases for their activities. The new data suggest why such antibodies are difficult to elicit and inform HIV-1 vaccine development efforts. In addition to protecting against infection, the newly identified antibodies can suppress active infections in mice and macaques, suggesting they could be valuable additions to anti-HIV-1 therapies and to strategies to eradicate HIV-1 infection. The HIV-1 infection cycle begins with host cell recognition and entry mediated by the HIV-1 envelope spike (Env) on the surface of the virion (Figure 1). Each Env is composed of a trimer of identical gp160 protein subunits that are cleaved posttranslationally to yield two associated glycoproteins, gp120 and gp41: gp120 carries the recognition sites for the host receptor (CD4) and coreceptor (primarily CCR5 and CXCR4), and gp41 mediates fusion between the virus and host cell membranes. During acute infection with HIV-1, serum viral loads peak approximately 3 weeks after transmission and then fall 1–2 logs to a set point determined by the host immune system (Cohen et al., 2011Cohen M.S. Shaw G.M. McMichael A.J. Haynes B.F. Acute HIV-1 Infection.N. Engl. J. Med. 2011; 364: 1943-1954Crossref PubMed Scopus (0) Google Scholar, Daar et al., 1991Daar E.S. Moudgil T. Meyer R.D. Ho D.D. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection.N. Engl. J. Med. 1991; 324: 961-964Crossref PubMed Google Scholar). 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In rare individuals who carry specific HLA alleles such as HLA-B∗5701, T cell responses can even reduce viremia to undetectable levels for prolonged periods of time (Migueles et al., 2000Migueles S.A. Sabbaghian M.S. Shupert W.L. Bettinotti M.P. Marincola F.M. Martino L. Hallahan C.W. Selig S.M. Schwartz D. Sullivan J. Connors M. HLA B∗5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors.Proc. Natl. Acad. Sci. USA. 2000; 97: 2709-2714Crossref PubMed Scopus (0) Google Scholar). In contrast, antibodies appear not to contribute significantly to the control of HIV-1 during natural infection. Anti-Env antibodies can be detected several weeks after infection. The initial antibody response is directed against gp41 and has little effect on viral dynamics (Cooper et al., 1987Cooper D.A. Imrie A.A. Penny R. Antibody response to human immunodeficiency virus after primary infection.J. Infect. 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Leavitt S.A. Majeed S. Steenbeke T.D. Venturi M. Chaiken I. Fung M. et al.HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.Nature. 2002; 420: 678-682Crossref PubMed Scopus (0) Google Scholar). For example, the coreceptor binding site is not fully exposed until after the CD4-binding site on gp120 is engaged by CD4. Similarly the fusion machinery in the membrane-proximal external region (MPER) of gp41 is not exposed until after the coreceptor binding site is occupied and the virus begins the fusion process (Frey et al., 2008Frey G. Peng H. Rits-Volloch S. Morelli M. Cheng Y. Chen B. A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies.Proc. Natl. Acad. Sci. USA. 2008; 105: 3739-3744Crossref PubMed Scopus (0) Google Scholar). Thus, conformational masking diminishes the effects of antibodies that target these two relatively conserved regions by restricting access. 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The targets of the new antibodies can be divided into the following major groups: (1) CD4-binding site, (2) N-linked glycan-containing epitopes, and (3) the membrane proximal external region (MPER). In addition, there are yet to be defined conformational epitopes, e.g., antibody 3BC176 (Klein et al., 2012aKlein F. Gaebler C. Mouquet H. Sather D.N. Lehmann C. Scheid J.F. Kraft Z. Liu Y. Pietzsch J. Hurley A. et al.Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein.J. Exp. Med. 2012; 209: 1469-1479Crossref PubMed Scopus (86) Google Scholar) (Figure 1). Since the CD4-binding site on gp120 is the site of initial host receptor interaction it cannot be completely masked by conformational changes or the glycan shield, and therefore it is potentially vulnerable. Moreover, it must be conserved between strains to maintain its function. It is not an easy target, however, because the site is a recessed pocket that accepts the terminal immunoglobulin-like domain of CD4 (Kwong et al., 1998Kwong P.D. Wyatt R. Robinson J. Sweet R.W. Sodroski J. Hendrickson W.A. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody.Nature. 1998; 393: 648-659Crossref PubMed Scopus (2119) Google Scholar). Fitting into the CD4-binding pocket is a challenge for the larger antigen-binding unit of an antibody, which is composed of paired immunoglobulin domains (variable heavy and variable light, VH and VL). Nevertheless, the human immune system has found at least two distinct ways to produce antibodies that can access this site. One way mimics CD4 itself, by positioning the antibody VH domain to bind gp120 using primarily the complementarity determining region (CDR) H2 loop and framework residues (Zhou et al., 2010Zhou T. Georgiev I. Wu X. Yang Z.Y. Dai K. Finzi A. Kwon Y.D. Scheid J.F. Shi W. Xu L. et al.Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.Science. 2010; 329: 811-817Crossref PubMed Scopus (531) Google Scholar) and engaging the CD4-binding loop on gp120 with backbone atoms in the C″ strand of VH (Diskin et al., 2011Diskin R. Scheid J.F. Marcovecchio P.M. West Jr., A.P. Klein F. Gao H. Gnanapragasam P.N. Abadir A. Seaman M.S. Nussenzweig M.C. Bjorkman P.J. Increasing the potency and breadth of an HIV antibody by using structure-based rational design.Science. 2011; 334: 1289-1293Crossref PubMed Scopus (194) Google Scholar, Wu et al., 2011Wu X. Zhou T. Zhu J. Zhang B. Georgiev I. Wang C. Chen X. Longo N.S. Louder M. McKee K. et al.NISC Comparative Sequencing ProgramFocused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.Science. 2011; 333: 1593-1602Crossref PubMed Scopus (426) Google Scholar, Zhou et al., 2010Zhou T. Georgiev I. Wu X. Yang Z.Y. Dai K. Finzi A. Kwon Y.D. Scheid J.F. Shi W. Xu L. et al.Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.Science. 2010; 329: 811-817Crossref PubMed Scopus (531) Google Scholar) (Figure 2A). The antibodies in this class are CD4 mimetics because the VH domain occupies the same position as the terminal immunoglobulin-like domain of CD4 and both use the C″ strand to interact with the CD4-binding loop of gp120 (Zhou et al., 2010Zhou T. Georgiev I. Wu X. Yang Z.Y. Dai K. Finzi A. Kwon Y.D. Schei