Table 2.

Immune complex (IC) vaccines against HIV-1.

Strategy	IC Components	Species Used in Study	Immunomodulatory Effects	Additional Notes	References
Targeting V3	gp120 JRFL or LAI (both clade B) + anti-CD4bs mAb 654	BALB/c mice	Both ICs elicited greater titers of antibody responses to V3 Anti-V3 antibodies generated by JRFL IC had limited neutralizing activity but were more cross-reactive than those by LAI IC	Enhanced V3 immunogenicity of ICs correlated with greater antigenicity	[44,49]
Targeting V3	gp120 JRFL (clade B) + anti-CD4bs mAb 654, anti-V2i mAb 2158, or anti-C2 mAb 1006-30	BALB/c mice	ICs with CD4bs mAb 654 or V2i mAb 2158 (to a lesser extent) enhanced V3 antibody responses IC with C2 mAb 1006-30 reduced V3 antibody responses	ICs with F(ab)2 654 were sufficient in enhancing V3 antibody responses, highlighting the key role of Fab	[48]
Targeting V3 Masking V3 Targeting V1V2	gp120 JRFL (clade B) + anti-CD4bs mAb 654, anti-V2i mAb 2158 gp120 A244 (CRF_01.AE) + anti-V2i mAb 2158	BALB/c mice	JRFL ICs elicited V3 antibody responses of greater titers and breadth, and with more tier 1 virus neutralizing activity A244 ICs induced higher levels of V1V2 antibodies with some cross-reactivity	JRFL ICs with C2 or V3 mAbs reduced V3 antibody response JRFL and A244 ICs modulated antibody responses to V1V2 and V3 without affecting the overall antibody responses to HIV-1 Env	[43]
Stabilizing CD4i (chemokine receptor binding site)	gp120 BaL or 89.6 (clade B) + mAb A32	Outbred Harley guinea pigs	IC enhanced exposure and antigenicity of CD4i in vitro IC caused no change in CD4i immunogenicity and neutralizing antibody responses in vivo	Enhanced CD4i antigenicity in vitro did not translate to enhanced immunogenicity in vivo	[67]
Masking CD4i Targeting CD4bs bNAb (VRC01 lineage)	gp120 core + anti-CD4i mAb 17b	New Zealand White rabbits	IC suppressed antibodies against the CD4i bridging sheet, elicited tier 1 neutralization, transiently induced antibody response with similar binding profile to VRC01-class CD4bs bnAbs No enhanced and long-term induction of VRC01-like Abs	17b mAb blocked CD4i bridging sheet and non-neutralizing CD4bs while exposing CD4bs for VRC01 approach from an alternate angle	[70]
Masking glycan hole	BG505 SOSIP.664 gp140 trimer (clade A) + mAbs that target strain-specific glycan hole	New Zealand White rabbits	ICs elicited lower levels of strain-specific antibody responses, indicating successful blockage of immunodominant glycan-hole region ICs stimulated binding antibodies with a lower rate of decay	Diversion away from glycan hole did not improve antibody responses against cross-reactive neutralizing epitopes	[68]