389
Views
13
CrossRef citations to date
0
Altmetric
Editorial

Challenges of antibody-mediated protection against HIV-1

Pages 683-687 | Published online: 09 Jan 2014

Enthusiasm for a role of antibodies in protection against HIV-1 has waxed and waned over the 25-year search for an AIDS vaccine. However, it is now clear that antibodies not only contribute to the control of infection once it is established Citation[1,2], as a series of seminal passive immunization studies in nonhuman primates (NHPs) going back almost 20 years show unequivocally that antibodies can prevent infection with model AIDS viruses Citation[3–14]. These latter observations are currently driving an intense effort to identify epitopes recognized by broadly neutralizing monoclonal antibodies (mAbs) to serve as templates for AIDS vaccine design. To this end, a handful of broadly neutralizing mAbs have been successfully vetted in passive immunization studies in NHPs using SHIVs that are model simian immunodeficiency viruses (SIV) in which the SIV envelope glycoprotein (Env) is replaced by a HIV-1 Env glycoprotein. The Env glycoprotein is the only HIV-1 protein known to be recognized by neutralizing antibodies. These studies show that SHIV infection can be blocked by individual mAbs specific for epitopes associated with distinct regions of the HIV-1 Env protein. These include the CD4-binding site Citation[9,15] and high-mannose oligosaccharides Citation[7,16] of gp120, as well as the membrane proximal region of gp41 Citation[17]. It should be noted that while individual mAbs can be effective, mAb mixtures Citation[7,18] or neutralizing sera Citation[19,20] might be more potent. Collectively, these studies strongly argue that the correct antibodies can mediate sterilizing (i.e., transmission-blocking) immunity to HIV-1 and that an AIDS vaccine must elicit such antibodies to be effective. There are three key challenges to the development of an ‘antibody-based’ vaccine that are potentially solvable with the experimental tools currently in hand.

Identification of epitopes recognized by broadly neutralizing antibodies

Extreme genetic diversity is a hallmark of retroviral infections, including HIV-1, which surfaces as a significant and long-recognized antigenic diversity problem in AIDS vaccine development Citation[21–25]. For example, there are 12 distinct clades (genetic subtypes) of HIV-1 Citation[26,27] whose Env proteins are only approximately 70% homologous, showing only slightly less variation within a clade. While clade diversity is not congruent with epitope diversity, no single broadly neutralizing mAb or broadly neutralizing antiserum blocks infectivity of all isolates (reviewed in Citation[24]). Fortunately, recent technological developments in the isolation of human mAbs from circulating B cells in HIV-infected individuals Citation[28–32] are starting to yield new mAbs of significant neutralization breadth. Most recently, two mAbs, PG9 and PG16, were isolated from the memory B cells of a HIV-1-infected individual that neutralize over 70% of a diverse cross-clade reference panel of HIV-1 isolates Citation[31]. These mAbs recognize a new epitope (or epitopes) that is (are) dependent upon the V2 and V3 regions of gp120 in addition to its glycan structures. It is important to note that these two mAbs hold the current record for neutralization breadth. The ability to isolate such mAbs using new high-throughput methods augurs well for the prospect of identifying new epitopes associated with neutralization breadth to serve as templates for vaccine design. However, there is a caveat of this approach that is not widely recognized outside the field.

Owing to the high-throughput requirement of screening, standardized cell line-based neutralization assays must be employed that might not faithfully recapitulate the neutralization potencies of mAbs (or immune sera) when they are evaluated on assays using peripheral blood mononuclear cells as targets Citation[33–35]. Thus, potentially important neutralizing antibodies might be missed when focusing only on cell line-based assays. This is not an indictment of cell line-based assays as it is clear that no single assay format detects all activities Citation[36] and there are insufficient data correlating protection in vivo with neutralization measured in the different assay formats to decide which is superior. Indeed, several NHP vaccination studies have demonstrated correlations between protection and antibody responses that do not score well in conventional neutralization assays Citation[37–39]. This issue is subject to intense study across many laboratories and the boundary conditions for the interpretation of neutralization assays should emerge over the next few years. This information will be essential in the refinement of immunogens to elicit broadly neutralizing antibodies.

Understanding the mechanisms of antibody-mediated protection

It has long been accepted that an antibody that neutralizes HIV-1 potently in an in vitro assay will also protect against a neutralization-sensitive virus in vivo. Indeed, several studies have demonstrated a good correlation between neutralization potency in vitro and the degree of sterilizing protection in vivo using passive immunization models Citation[3,40–44]. This picture was rendered more complex by a seminal study demonstrating the importance of Fc-mediated effector function in the ability of the CD4-binding site mAb, b12, to mediate sterilizing protection against a pathogenic SHIV challenge Citation[45]. In that study, the Fc region of mAb b12 was mutagenized to abrogate Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity Citation[46] and antibody-dependent cell-mediated viral inhibition (ADCVI; reviewed in Citation[47]) while preserving neutralization potency in vitro. Abrogation of Fc-mediated effector function in this mAb compromised its ability to mediate sterilizing protection against SHIV in vivo, although some protective potency was retained Citation[45]. This seminal study and a follow-up study using a more clinically relevant virus challenge model Citation[15] provide the most direct evidence to date that biological mechanisms in addition to neutralization are important in antibody-mediated protection against the transmission of SHIV in vivo.

As already mentioned, several studies have demonstrated correlations between non-neutralizing antibodies (as measured in conventional neutralization assays) and protection against SIV/SHIV transmission in NHPs Citation[37–39,48]. Most interestingly, a similar correlation in the Vax-004 trial using ADCVI as the readout was reported for a subset of HIV-1-resistant subjects defined by Fc-receptor polymorphisms Citation[49], although global efficacy was not found in that study. Taken together, these observations have renewed interest in defining the mechanisms of antibody-mediated protection. In addition to the Fc-mediated effector functions listed earlier, there are data suggesting that protective antibodies might act by aggregating virus in mucosal fluids, blocking transcytosis across epithelial barriers Citation[50] and complement-mediated virolysis Citation[51], although the latter mechanism was not supported by b12 mutagenesis Citation[45].

Solving the ‘persistence’ problem

The poor persistence of ongoing anti-Env antibody responses (serological memory) in the absence of continuous antigenic stimulation is a sleeping giant that confronts the development of an antibody-based AIDS vaccine (Citation[28,52] and reviewed in Citation[24]). Passive immunization studies show that there is approximately a 24-h window for an antibody to mediate protection against virus exposure Citation[53,54]. This suggests that antibody responses elicited by a vaccine must persist at protective levels as long as the recipient is engaging in behavior associated with exposure to HIV-1. Poor serological memory is potentially a major problem in the deployment of antibody-based vaccines. Poor persistence of anti-Env antibody responses was observed in the early days of antibody-based diagnostics development Citation[55] and it has repeatedly surfaced in clinical trials of Env-based subunit vaccines Citation[24]. The poor persistence of anti-Env antibody responses in the absence of continuous antigenic stimulation contrasts with protective antibody responses to common vaccine antigens such as diphtheria and tetanus toxoids (among others) where serological memory can persist for years after immunization Citation[56]. The nature of this problem has not been studied systematically but it is almost certainly an outcome of the unusual structural aspects of the HIV-1 Env glycoprotein that is heavily glycosylated (reviewed in Citation[57]) and conformationally plastic Citation[58,59]. The poor persistence of anti-Env responses without continuous boosting is probably due to the poor ability of Env to elicit antibody responses characterized by the long-lived plasma cells in the bone marrow (reviewed in Citation[60]) that are characteristic of persistent serological memory. Whether this is due to unusual helper T-cell responses to Env, the B-cell subset addressed by Env, or both of these variables remains to be determined, as do the relationships among these variables and Env structure. It is interesting to note that the persistence problem appears to have surfaced recently in the RV144 study where modest efficacy was demonstrated for the first time in an AIDS vaccine trial Citation[61].

That study employed a combination immunization strategy using gp120 expressed by a poxvirus vector in conjunction with a subunit gp120 matched to locally circulating clades of HIV-1 Citation[61]. Modest but significant protection against transmission was observed that waned over time Citation[61], much in the same way as anti-Env antibody responses do to these types of immunogens Citation[24]. While it is currently conjecture that this protection is antibody-based and that it wanes in lock step with anti-Env antibody responses, its temporal dependence is strongly suggestive of the poorly persistent antibody responses typically elicited by Env immunogens. In order to determine whether this is so, further study is required.

Conclusion

Currently, an antibody-based strategy is the only track to a preventative AIDS vaccine that is supported by direct experimental evidence from passive immunization studies. As such, the pace of this strategy is impacted by the three aforementioned developmental challenges and it is difficult to know when (or even if) these problems can be solved. Despite these uncertainties, there is renewed optimism that an effective AIDS vaccine can be developed. This optimism is due to success in the RV144 vaccine trial Citation[61], along with a confluence of new information on the specificity and mechanisms of antibody-mediated protection against HIV-1, the development of new tools to study antibody responses, and the strong ability to translate new findings into clinical trials. It will be interesting to take stock of these three challenges over the next few years as there now appears to be light at the end of the long tunnel to an AIDS vaccine.

Acknowledgements

The author thanks his colleagues Yongjun Guan, Bob Gallo, Tony DeVico and Roberta Kamin-Lewis for discussions leading to the ideas in this editorial.

Financial & competing interests disclosure

George K Lewis is a shareholder in Profectus Biosciences (MD, USA). He is also a co-inventor on pending patents covering methods to isolate monoclonal antibodies cited in this report. Research in the author’s laboratory is supported by grants from the NIH (R01AI087181 and R01AI084830) and the Bill and Melinda Gates Foundation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

References

  • Wei X, Decker JM, Wang S et al. Antibody neutralization and escape by HIV-1. Nature422(6929), 307–312 (2003).
  • Richman DD, Wrin T, Little SJ, Petropoulos CJ. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl Acad. Sci. USA100(7), 4144–4149 (2003).
  • Baba TW, Liska V, Hofmann-Lehmann R et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med.6(2), 200–206 (2000).
  • Putkonen P, Thorstensson R, Ghavamzadeh L et al. Prevention of HIV-2 and SIVsm infection by passive immunization in cynomolgus monkeys. Nature352(6334), 436–438 (1991).
  • Emini EA, Schleif WA, Nunberg JH et al. Prevention of HIV-1 infection in chimpanzees by gp120 V3 domain-specific monoclonal antibody. Nature355(6362), 728–730 (1992).
  • Mascola JR, Lewis MG, Stiegler G et al. Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J. Virol.73(5), 4009–4018 (1999).
  • Mascola JR, Stiegler G, VanCott TC et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med.6(2), 207–210 (2000).
  • Shibata R, Igarashi T, Haigwood N et al. Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nat. Med.5(2), 204–210 (1999).
  • Parren PW, Marx PA, Hessell AJ et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro.J. Virol.75(17), 8340–8347 (2001).
  • Prince AM, Reesink H, Pascual D et al. Prevention of HIV infection by passive immunization with HIV immunoglobulin. AIDS Res. Hum. Retroviruses7(12), 971–973 (1991).
  • Putkonen P, Thorstensson R, Ghavamzadeh L et al. Prevention of HIV-2 and SIVsm infection by passive immunization in cynomolgus monkeys. Nature352, 436–438 (1991).
  • Gardner MB, Rosenthal A, Jennings M, Yee JA, Antipa L, Robinson EJ. Passive immunization of rhesus macques against SIV infection and disease. AIDS Res. Hum. Retroviruses11, 843–854 (1995).
  • Van Rompay KK, Berardi CJ, Dillard-Telm S et al. Passive immunization of newborn rhesus macaques prevents oral simian immunodeficiency virus infection. J. Infect. Dis.177(5), 1247–1259 (1998).
  • Joag SV, Li Z, Wang C et al. Passively administered neutralizing serum that protected macaques against infection with parenterally inoculated pathogenic simian-human immunodeficiency virus failed to protect against mucosally inoculated virus. AIDS Res. Hum. Retroviruses15(4), 391–394 (1999).
  • Hessell AJ, Poignard P, Hunter M et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat. Med.15(8), 951–954 (2009).
  • Hessell AJ, Rakasz EG, Poignard P et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog.5(5), e1000433 (2009).
  • Hessell AJ, Rakasz EG, Tehrani DM et al. Broadly neutralizing monoclonal antibodies 2F5 and 4E10, directed against the human immunodeficiency virus type 1 (HIV-1) gp41 membrane proximal external region (MPER), protect against SHIVBa-L mucosal challenge. J. Virol.84(3), 1302–1313 (2010).
  • Hofmann-Lehmann R, Rasmussen RA, Vlasak J et al. Passive immunization against oral AIDS virus transmission: an approach to prevent mother-to-infant HIV-1 transmission? J. Med. Primatol.30(4), 190–196 (2001).
  • Shibata R, Igarashi T, Haigwood N et al. Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nat. Med.5(2), 204–210 (1999).
  • Nishimura Y, Igarashi T, Haigwood N et al. Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies. J. Virol.76(5), 2123–2130 (2002).
  • Zolla-Pazner S. Identifying epitopes of HIV-1 that induce protective antibodies. Nat. Rev. Immunol.4(3), 199–210 (2004).
  • Moore JP, Parren PW, Burton DR. Genetic subtypes, humoral immunity, and human immunodeficiency virus type 1 vaccine development. J. Virol.75(13), 5721–5729. (2001).
  • Burton DR, Desrosiers RC, Doms RW et al. HIV vaccine design and the neutralizing antibody problem. Nat. Immunol.5(3), 233–236 (2004).
  • Mascola JR, Montefiori DC. The role of antibodies in HIV vaccines. Annu. Rev. Immunol.28, 413–444 (2010).
  • Karlsson Hedestam GB, Fouchier RA, Phogat S, Burton DR, Sodroski J, Wyatt RT. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat. Rev. Microbiol.6(2), 143–155 (2008).
  • Korber B, Gaschen B, Yusim K, Thakallapally R, Kesmir C, Detours V. Evolutionary and immunological implications of contemporary HIV-1 variation. Br. Med. Bull.58, 19–42 (2001).
  • Korber B, Gnanakaran S. The implications of patterns in HIV diversity for neutralizing antibody induction and susceptibility. Curr. Opin. HIV AIDS4(5), 408–417 (2009).
  • Guan Y, Sajadi MM, Kamin-Lewis R et al. Discordant memory B cell and circulating anti-Env antibody responses in HIV-1 infection. Proc. Natl Acad. Sci. USA106(10), 3952–3957 (2009).
  • Liao HX, Levesque MC, Nagel A et al. High-throughput isolation of immunoglobulin genes from single human B cells and expression as monoclonal antibodies. J. Virol Methods158(1–2), 171–179 (2009).
  • Scheid JF, Mouquet H, Feldhahn N et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature458(7238), 636–640 (2009).
  • Walker LM, Phogat SK, Chan-Hui PY et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science326(5950), 285–289 (2009).
  • Corti D, Langedijk JP, Hinz A et al. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One5(1), e8805 (2010).
  • Crooks ET, Moore PL, Richman D et al. Characterizing anti-HIV monoclonal antibodies and immune sera by defining the mechanism of neutralization. Hum. Antibodies14(3–4), 101–113 (2005).
  • Polonis VR, Brown BK, Rosa Borges A et al. Recent advances in the characterization of HIV-1 neutralization assays for standardized evaluation of the antibody response to infection and vaccination. Virology375(2), 315–320 (2008).
  • Mann AM, Rusert P, Berlinger L, Kuster H, Gunthard HF, Trkola A. HIV sensitivity to neutralization is determined by target and virus producer cell properties. AIDS23(13), 1659–1667 (2009).
  • Fenyo EM, Heath A, Dispinseri S et al. International network for comparison of HIV neutralization assays: the NeutNet report. PLoS One4(2), e4505 (2009).
  • Gomez-Roman VR, Patterson LJ, Venzon D et al. Vaccine-elicited antibodies mediate antibody-dependent cellular cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with SIVmac251. J. Immunol.174(4), 2185–2189 (2005).
  • DeVico A, Fouts T, Lewis GK et al. Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens. Proc. Natl Acad. Sci. USA104(44), 17477–17482 (2007).
  • Hidajat R, Xiao P, Zhou Q et al. Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 challenge of rhesus macaques. J. Virol.83(2), 791–801 (2009).
  • Li A, Baba TW, Sodroski J et al. Synergistic neutralization of a chimeric SIV/HIV type 1 virus with combinations of human anti-HIV type 1 envelope monoclonal antibodies or hyperimmune globulins. AIDS Res. Hum. Retroviruses13(8), 647–656 (1997).
  • Mascola JR, Louder MK, VanCott TC et al. Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12. J. Virol.71(10), 7198–7206 (1997).
  • Mascola JR, Lewis MG, Stiegler G et al. Protection of macaques against pathogenic simian/human immunodefiency virus 89.6PD by passive transfer of neutralizing antibodies. J. Virol.73, 4009–4018 (1999).
  • Parren PW, Marx PA, Hessell AJ et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro.J. Virol.75(17), 8340–8347 (2001).
  • Nishimura Y, Igarashi T, Haigwood N et al. Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies. J. Virol.76(5), 2123–2130 (2002).
  • Hessell AJ, Hangartner L, Hunter M et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature449(7158), 101–104 (2007).
  • Hezareh M, Hessell AJ, Jensen RC, van de Winkel JG, Parren PW. Effector function activities of a panel of mutants of a broadly neutralizing antibody against human immunodeficiency virus type 1. J. Virol.75(24), 12161–12168 (2001).
  • Forthal DN, Moog C. Fc receptor-mediated antiviral antibodies. Curr. Opin. HIV AIDS4(5), 388–393 (2009).
  • Xiao P, Zhao J, Patterson LJ et al. Multiple vaccine-elicited non-neutralizing anti-envelope antibody activities contribute to protective efficacy by reducing both acute and chronic viremia following SHIV89.6P challenge in rhesus macaques. J. Virol. DOI: 10.1128/JVI.00410-10 (2010) (Epub ahead of print).
  • Forthal DN, Gilbert PB, Landucci G, Phan T. Recombinant gp120 vaccine-induced antibodies inhibit clinical strains of HIV-1 in the presence of Fc receptor-bearing effector cells and correlate inversely with HIV infection rate. J. Immunol.178(10), 6596–6603 (2007).
  • Shen R, Drelichman ER, Bimczok D et al. GP41-specific antibody blocks cell-free HIV type 1 transcytosis through human rectal mucosa and model colonic epithelium. J. Immunol.184(7), 3648–3655 (2010).
  • Spear GT, Takefman DM, Sullivan BL, Landay AL, Zolla-Pazner S. Complement activation by human monoclonal antibodies to human immunodeficiency virus. J. Virol.67(1), 53–59 (1993).
  • Bonsignori M, Moody MA, Parks RJ et al. HIV-1 envelope induces memory B cell responses that correlate with plasma antibody levels after envelope gp120 protein vaccination or HIV-1 infection. J. Immunol.183(4), 2708–2717 (2009).
  • Nishimura Y, Igarashi T, Haigwood NL et al. Transfer of neutralizing IgG to macaques 6 h but not 24 h after SHIV infection confers sterilizing protection: implications for HIV-1 vaccine development. Proc. Natl Acad. Sci. USA100(25), 15131–15136 (2003).
  • Ferrantelli F, Buckley KA, Rasmussen RA et al. Time dependence of protective post-exposure prophylaxis with human monoclonal antibodies against pathogenic SHIV challenge in newborn macaques. Virology358(1), 69–78 (2007).
  • Manca N, di Marzo Veronese F, Ho DD, Gallo RC, Sarngadharan MG. Sequential changes in antibody levels to the env and gag antigens in human immunodeficiency virus infected subjects. Eur. J. Epidemiol.3(2), 96–102 (1987).
  • Amanna IJ, Carlson NE, Slifka MK. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med.357(19), 1903–1915 (2007).
  • Vigerust DJ, Shepherd VL. Virus glycosylation: role in virulence and immune interactions. Trends Microbiol.15(5), 211–218 (2007).
  • Finzi A, Xiang SH, Pacheco B et al. Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitions. Mol. Cell.37(5), 656–667 (2010).
  • Pancera M, Majeed S, Ban YE et al. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proc. Natl Acad. Sci. USA107(3), 1166–1171 (2010).
  • McHeyzer-Williams MG, Ahmed R. B cell memory and the long-lived plasma cell. Curr. Opin Immunol.11(2), 172–179 (1999).
  • Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med.361(23), 2209–2220 (2009).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.