Vaccine-induced V1V2-specific antibodies control and or protect against infection with HIV, SIV and SHIV—Zolla-Pazner 2019
Review: In humans, only a strong antibody (Ab) response to the V1V2 domain of the gp120 envelope (Env) protein reduces HIV infection risk. Recently, V1V2-specific Abs have also been linked to SIV and SHIV protection. We examine V1V2 Abs' immunologic and antiviral properties and their many in-vivo protective studies here.
Recent findings: Structural and immunologic studies have defined four epitope families in the V1V2 domain: one, V2q, preferentially presents as a quaternary structure of the Env trimer, and another, V2qt, requires the trimeric Env structure. Two families of monoclonal Abs (mAbs)—V2q-specific and V2qt-specific—have broad and potent neutralizing activity. V2 peptides have a fourth epitope family, V2p, and a discontinuous conformational structure, V2i, that overlays the α4β7 integrin binding motif. Antibodies specific for V2i and V2p epitopes show weak neutralizing efficacy but mediate other antiviral effects and have been linked to HIV, SIV, and SHIV control. Vaccines can induce V2p and V2i Abs in nonhuman primates and humans, but not V2q or V2qt Abs.
Summary: Vaccine-induced V2p and V2i Abs protect against HIV, SIV, and SHIV, suggesting they are crucial to induce with preventive vaccinations.
Antibody-mediated protective immunity increasingly include non-neutralizing, Fc-mediated antibody activities. Non-neutralizing antibodies protect against influenza, herpes, alphaviruses, flaviviruses, respiratory syncytial virus, and CMV [12–15]. When IgA HIV-specific antibodies were low, RV144 had significant levels of specific antibodies and antibody-dependent cell-mediated cytotoxicity [3,16,17]. Other non-neutralizing antibody-dependent functions prevent and control HIV in humans and SIV and SHIV in non-human primates [3,16–27].
Immunogens that elicit non-neutralizing antibodies may protect in this AIDS issue. In macaques infected intravenously with SIVmac239-nef, plasma cells in the submucosa and ectopic tertiary lymphoid follicles of the ectocervix and vagina produced IgG antibodies reactive with gp41 trimers (gp41t) that were concentrated in the path of virus entry by neonatal Fc receptors (FcRn) in the vaginal epithelium [28,29]. Voss et al.[30] created and tested SIV gp41t immunogens. Rhesus macaques were immunized and developed serum gp41t-specific antibodies that complexed with FcRn+ cervical vaginal epithelium. These findings support recent findings that non-neutralizing antibodies [27,31,32] and gp41-specific antibodies [33–36] can mediate Fc-dependent biologic processes that protect against viruses. Two of the mAbs employed in the latter tests of Fc-mediated effects, 240-D and 246-D, were Cluster I anti-gp41 mAbs, which target the immunodominant region of the ectodomain and react with trimeric gp41 [37–39].
gp41 Abs may have protected against SIV challenge in an early vaccine candidate, live, attenuated SIVmac239-nef. This issue's data may suggest a new HIV vaccination strategy. This approach does not rule out a role for neutralizing antibodies, but it adds to the many studies cited above showing that the exceptional bnAbs that have been the Holy Grail of HIV vaccine research may not be necessary for protection and that other "conventional" antibodies, which are easier to induce, may be sufficient to protect against HIV. To prove that non-neutralizing antibodies like those in Voss et al.[30] can defend is still difficult. This demonstration would need to explain why non-neutralizing antibodies like the gp41t Abs disclosed in this issue (found in most HIV-infected people) do not protect HIV+ people from superinfection.
Zolla-Pazner, S., Alvarez, R., Kong, X. P., & Weiss, S. (2019). Vaccine-induced V1V2-specific antibodies control and or protect against infection with HIV, SIV and SHIV. Current opinion in HIV and AIDS, 14(4), 309–317. https://doi.org/10.1097/COH.0000000000000551
