Contribution of nonneutralizing vaccine-elicited antibody activities to improved protective efficacy in rhesus macaques immunized with Tat/Env compared with multigenic vaccines.
Previously, chronic-phase protection against SHIV(89.6P) challenge was significantly greater in macaques primed with replicating adenovirus type 5 host range mutant (Ad5hr) recombinants encoding HIVtat and env and boosted with Tat and Env protein compared with macaques primed with multigenic adenovirus recombinants (HIVtat, HIVenv, SIVgag, SIVnef) and boosted with Tat, Env, and Nef proteins. The greater protection was correlated with Tat- and Env-binding Abs. Because the macaques lacked SHIV(89.6P)-neutralizing activity prechallenge, we investigated whether Ab-dependent cellular cytotoxicity (ADCC) and Ab-dependent cell-mediated viral inhibition (ADCVI) might exert a protective effect. We clearly show that Tat can serve as an ADCC target, although the Tat-specific activity elicited did not correlate with better protection. However, Env-specific ADCC activity was consistently higher in the Tat/Env group, with sustained cell killing postchallenge exhibited at higher levels (p < 0.00001) for a longer duration (p = 0.0002) compared with the multigenic group. ADCVI was similarly higher in the Tat/Env group and significantly correlated with reduced acute-phase viremia at wk 2 and 4 postchallenge (p = 0.046 and 0.011, respectively). Viral-specific IgG and IgA Abs in mucosal secretions were elicited but did not influence the outcome of the i.v. SHIV(89.6P) challenge. The higher ADCC and ADCVI activities seen in the Tat/Env group provide a plausible mechanism responsible for the greater chronic-phase protection. Because Tat is known to enhance cell-mediated immunity to coadministered Ags, further studies should explore its impact on Ab induction so that it may be optimally incorporated into HIV vaccine regimens.
Florese
Ruth H
RH
Vaccine Branch and.
Demberg
Thorsten
T
Xiao
Peng
P
Kuller
LaRene
L
Larsen
Kay
K
Summers
L Ebonita
LE
Venzon
David
D
Cafaro
Aurelio
A
Ensoli
Barbara
B
Robert-Guroff
Marjorie
M
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000502:physiology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009500:Neutralization Tests; D018449:SAIDS Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*
D000914:Antibodies, Viral; D000998:Antiviral Agents; D018449:SAIDS Vaccines; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus