Multiple Vaccine-Elicited Nonneutralizing Antienvelope Antibody Activities Contribute to Protective Efficacy by Reducing both Acute and Chronic Viremia following Simian/Human Immunodeficiency Virus SHIV_89.6PChallenge in Rhesus Macaques

Abstract

We have shown that following priming with replicating adenovirus type 5 host range mutant (Ad5hr)-human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) recombinants, boosting with gp140 envelope protein enhances acute-phase protection against intravenous simian/human immunodeficiency virus (SHIV) 89.6P challenge compared to results with priming and no boosting or boosting with an HIV polypeptide representing the CD4 binding site of gp120. We retrospectively analyzed antibodies in sera and rectal secretions from these same macaques, investigating the hypothesis that vaccine-elicited nonneutralizing antibodies contributed to the better protection. Compared to other immunized groups or controls, the gp140-boosted group exhibited significantly greater antibody activities mediating antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated viral inhibition (ADCVI) in sera and transcytosis inhibition in rectal secretions. ADCC and ADCVI activities were directly correlated with antibody avidity, suggesting the importance of antibody maturation for functionality. Both ADCVI and percent ADCC killing prechallenge were significantly correlated with reduced acute viremia. The latter, as well as postchallenge ADCVI and ADCC, was also significantly correlated with reduced chronic viremia. We have previously demonstrated induction by the prime/boost regimen of mucosal antibodies that inhibit transcytosis of SIV across an intact epithelial cell layer. Here, antibody in rectal secretions was significantly correlated with transcytosis inhibition. Importantly, the transcytosis specific activity (percent inhibition/total secretory IgA and IgG) was strongly correlated with reduced chronic viremia, suggesting that mucosal antibody may help control cell-to-cell viral spread during the course of infection. Overall, the replicating Ad5hr-HIV/SIV priming/gp140 protein boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities associated with control of both acute and chronic viremia.

The gp41 epitope, QARVLAVERY, is highly conserved and a potent inducer of IgA that neutralizes HIV-1 and inhibits viral transcytosis

“…23 -27 A recent immunization study in rhesus macaques has demonstrated that HIV-specific Abs could control infection by Ab-dependent cellular cytotoxicity, Ab-dependent cellmediated virus inhibition, and transcytosis-inhibition mechanisms. 74 Indeed, there was a strong correlation between viremic control and inhibition of transcytosis by rectal IgA, whereas the nAb response did not correlate with control of viral load. 74 Furthermore, unlike IgG, high titers of systemic IgA are not as concerning as it is non-inflammatory by nature and does not activate complement by acting through the inhibitory Fc receptor.…”

“…74 Indeed, there was a strong correlation between viremic control and inhibition of transcytosis by rectal IgA, whereas the nAb response did not correlate with control of viral load. 74 Furthermore, unlike IgG, high titers of systemic IgA are not as concerning as it is non-inflammatory by nature and does not activate complement by acting through the inhibitory Fc receptor. 75,76 There is ample evidence implicating the importance of " immune quiescence " in maintaining HIV resistance in highly exposed persistently seronegative individuals, 77 -80 and in fact, systemic or mucosal inflammation as a result of immune activation may increase the risk of HIV transmission and pathogenesis.…”

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

“…First, studies in HIV-1-infected people (8)(9)(10)(11)(12)(13)(14) and in macaques infected with simian immunodeficiency virus (15,16) consistently show an inverse correlation between Fc-mediated effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC) (8,9) or antibody-dependent cell-mediated viral inhibition (ADCVI), and viral loads or decreased disease progression (17). Second, vaccine-elicited protection both in nonhuman primates (18)(19)(20)(21) and in a subset of human subjects in the Vax-004 trial (22) correlates with Fc-mediated effector function often observed in the absence of detectable neutralizing antibodies (18)(19)(20)(21). Similarly, there was an inverse relationship between acquisition of HIV-1 and ADCC in the RV144 trial for a subset of subjects who had low to moderate IgA anti-gp120 titers (23).…”

Cross-Reactive Influenza-Specific Antibody-Dependent Cellular Cytotoxicity Antibodies in the Absence of Neutralizing Antibodies

“…This interaction induces both degranulation to release perforin/granzymes as well as secretion of antiviral cytokines such as IFN-g and TNF-a. Nonneutralizing Abs have been shown to have an important role in several virus infection models (19)(20)(21)(22).…”