Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: outcome depends on IgG dose.
BACKGROUND
A key goal for HIV-1 envelope immunogen design is the induction of cross-reactive neutralizing antibodies (nAbs). As AIDS vaccine recipients will not be exposed to strains exactly matching any immunogens due to multiple HIV-1 quasispecies circulating in the human population worldwide, heterologous SHIV challenges are essential for realistic vaccine efficacy testing in primates. We assessed whether polyclonal IgG, isolated from rhesus monkeys (RMs) with high-titer nAbs (termed SHIVIG), could protect RMs against the R5-tropic tier-2 SHIV-2873Nip, which was heterologous to the viruses or HIV-1 envelopes that had elicited SHIVIG.


RESULTS
SHIVIG demonstrated binding to HIV Gag, Tat, and Env of different clades and competed with the broadly neutralizing antibodies b12, VRC01, 4E10, and 17b. SHIVIG neutralized tier 1 and tier 2 viruses, including SHIV-2873Nip. NK-cell depletion decreased the neutralizing activity of SHIVIG 20-fold in PBMC assays. Although SHIVIG neutralized SHIV-2873Nip in vitro, this polyclonal IgG preparation failed to prevent acquisition after repeated intrarectal low-dose virus challenges, but at a dose of 400 mg/kg, it significantly lowered peak viremia (P = 0.001). Unexpectedly, single-genome analysis revealed a higher number of transmitted variants at the low dose of 25 mg/kg, implying increased acquisition at low SHIVIG levels. In vitro, SHIVIG demonstrated complement-mediated Ab-dependent enhancement of infection (C'-ADE) at concentrations similar to those observed in plasmas of RMs treated with 25 mg/kg of SHIVIG.


CONCLUSIONS
Our primate model data suggest a dual role for polyclonal anti-HIV-1 Abs depending on plasma levels upon virus encounter.
Anton M
AM
Sholukh
Siddappa N
SN
Byrareddy
Vivekanandan
V
Shanmuganathan
Girish
G
Hemashettar
Samir K
SK
Lakhashe
Robert A
RA
Rasmussen
Jennifer D
JD
Watkins
Hemant K
HK
Vyas
Swati
S
Thorat
Tania
T
Brandstoetter
Muhammad M
MM
Mukhtar
John K
JK
Yoon
Francis J
FJ
Novembre
Francois
F
Villinger
Gary
G
Landucci
Donald N
DN
Forthal
Sarah
S
Ratcliffe
Iskra
I
Tuero
Marjorie
M
Robert-Guroff
Victoria R
VR
Polonis
Miroslawa
M
Bilska
David C
DC
Montefiori
Welkin E
WE
Johnson
Hildegund C
HC
Ertl
Department of Virology and Immunology, Texas Biomedical Research Institute, PO Box 760549, San Antonio, TX 78245-0549, USA. rruprecht@txbiomed.org.
Ruth M
RM
Ruprecht
D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000821:virology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D056738:Cross Protection; D004195:Disease Models, Animal; D015483:HIV Antibodies / Q000008:administration & dosage*; D015497:HIV-1 / Q000276:immunology*; D007116:Immunization, Passive / Q000379:methods*; D007074:Immunoglobulin G / Q000008:administration & dosage*; D008253:Macaca mulatta; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D016896:Treatment Outcome
D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007074:Immunoglobulin G