Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens

Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

Section: Discussionmentioning

confidence: 74%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

“…We make this speculation on our recent vaccine studies in rhesus macaques (epostersonline. com/aidsvax2013/?q=node/639 and http:// epostersonline.com/aidsvax2013/?q=node/ 645&posterview=true) using a conformationally constrained gp120 subunit immunogen (82,83). Taken together, the three ineffective Ad5-HIV trials strongly suggest the presence of CD4 + CCR5 + T cells at the area of transmission.…”

Section: Strategies To Elicit Continuous Protection Against Hiv By Vamentioning

confidence: 76%

“…The emergence of high ADCC titers in low to intermediate anti-C1 IgA responders as a correlate of decreased infection risk is one such example (25). Similarly, post hoc analyses of SHIV/SIV challenge studies using our conformationally constrained gp120 vaccine (82,83) in nonhuman primates revealed that humoral responses being equal, protection from acquisition was lowest or abrogated in rhesus macaques with the highest vaccine-elicited anti-Env T-cell responses (epostersonline. com/aidsvax2013/?q=node/639 and http:// epostersonline.com/aidsvax2013/?q=node/ 645&posterview=true).…”

Section: Approach To Solving the Antibody Persistence And T-cell Balamentioning

confidence: 99%

“…Passive immunization studies using neutralizing mAbs in nonhuman primates have established unequivocally that antibodies can block infection with simian human immunodeficiency viruses (SHIVs) (100)(101)(102)(103). Surprisingly, aside from homologous challenges where Env vaccines and SHIV Env proteins are matched (104,105), it has been difficult to correlate comparable vaccine-elicited neutralizing antibody titers with protection against SHIV where the Env protein is heterologous to the vaccine (82,106). The principal difference between the two approaches is that passive immunization is carried out against a "clean" background, devoid of ongoing host responses elicited by vaccination.…”

Section: Strategies To Elicit Continuous Protection Against Hiv By Vamentioning

confidence: 99%

See 1 more Smart Citation

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Lewis

DeVico

Gallo

2014

Self Cite

The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibodymediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4 + T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Envbased AIDS vaccines regardless of the mechanism of antibody-mediated protection.

“…ELISAs were performed using an antigen-capture format (78) as described previously (68,79). ADCC Assays.…”

Section: Methodsmentioning

confidence: 99%

Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Guan

Pazgier

Sajadi

et al. 2012

Self Cite

139

341

The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virionsensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. Thus, Fcmediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.