OBJECTIVES: Passive immunization for the prevention of HIV-1 infection is 
currently being reenergized. The anti-CD4 monoclonal antibody ibalizumab has 
demonstrated safety and efficacy in phase 1 and 2 clinical trials for treatment 
of HIV-1 infection and is undergoing a phase 1 clinical trial in HIV-1 
uninfected individuals for prevention. Here, we sought to assess ibalizumab 
antiviral breadth and potency and to identify determinants of natural 
preexisting resistance.
METHODS: Ibalizumab breadth and potency was assessed against a large clinically 
relevant panel of HIV-1 pseudoviruses (n = 116) commonly used to assess vaccine 
candidates. Determinants of resistance were assessed by sequence analysis.
RESULTS: Ibalizumab neutralized 92% and 66% of viruses as defined by 50% and 80% 
inhibition, respectively. Median in vitro neutralization potency by IC50 was 
0.03 μg/mL, substantially lower than the broadly neutralizing mAbs, PG9, or 
VRC01. The dominant determinant of resistance was the absence of a potential 
N-linked glycosylation site (PNGS) at the V5 N-terminus (P < 0.001), with the V2 
loop length possibly influencing the degree of resistance afforded by the 
absence of the V5 N-terminal PNGS (P = 0.001). Other significant independent 
correlates of resistance included PNGS at position 386 and the side chain length 
of residue 375. Ibalizumab exhibited complementary resistance to VRC01 (P = 
0.006) and sCD4 (P < 0.001), in part mediated by the V5 PNGS.
CONCLUSIONS: Ibalizumab breadth and potency compared favorably with broadly 
neutralizing anti-HIV-1 monoclonal antibodies, supporting the clinical 
development of ibalizumab, alone or in combination, for HIV-1 prevention.