In Vivo and In Vitro Escape from Neutralizing Antibodies 2G12, 2F5, and 4E10

Abstract

Recently, passive immunization of human immunodeficiency virus (HIV)-

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design

“…Those studies raised concerns about the in vivo activities of 2F5 and 4E10, since the viral rebound observed in several patients occurred along with the emergence of 2G12-resistant virus, with no resistance to the MPER MAbs emerging. However, a more recent study by Manrique et al showed a different picture when they performed a more in-depth analysis of the virus in vivo and in vitro (135). No mutations in the MPER were found in virus that was obtained from patients at different time points.…”

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

“…[5][6][7]28 Second, methodological approaches for high-throughput screening and recovery of HC and LC genes from individual patient B cells did not exist until more recently, and the previously identified bNAbs were not potent enough to prevent viral escape, even when delivered in combination. [29][30][31][32] Compared with the current crop of bNAbs, first-generation bNAbs have much reduced binding affinities and higher IC 50 values, likely insufficient to be used prophylactically or therapeutically in humans.…”

The good and evil of complement activation in HIV-1 infection

“…[54][55][56][57][58][59][60] Among these nAbs, 2G12, 2F5 and 4E10 are three of the most broadly used Abs cloned from HIV-1-infected patients. 54,55,57,58,[61][62][63][64] 2G12 recognizes a unique mannosedependent epitope within gp120, 55,61,[65][66][67] while binding sites of 2F5 and 4E10 lie within a well-defined region of the membrane-proximal external region of gp41. 54,57,58,60,68 Passive immunization with a cocktail of these three human monoclonal Abs was effective in animal models, i.e., it conferred protection against intravenous, intravaginal or oral challenge with simian human immunodeficiency virus (a monkey HIV-1 analog) in rhesus macaques.…”

“…[69][70][71] However, in a clinical trials with this nAb cocktail in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of HAART, only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization, indicating the limits of these nAbs in controlling HIV-1 infection. 64,72 Why does passive immunization with a cocktail of nAbs provide anti-HIV-1 protection in animal models, but not in humans? Did the HIV-1 viruses mutate under the Ab immune pressure in humans?…”