Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian–human immunodeficiency virus infection

Abstract

Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque model has been developed that mimics the mucosal exposure that can occur during intrapartum HIV-1 transmission. To develop immunoprophylaxis against intrapartum HIV-1 transmission, we used SHIV-vpu+ (refs. 5,6), a chimeric simian-human virus that encodes the env gene of HIV-IIIB. Several combinations of human monoclonal antibodies against HIV-1 have been identified that neutralize SHIV-vpu+ completely in vitro through synergistic interaction. Here, we treated four pregnant macaques with a triple combination of the human IgG1 monoclonal antibodies F105, 2G12 and 2F5. All four macaques were protected against intravenous SHIV-vpu+ challenge after delivery. The infants received monoclonal antibodies after birth and were challenged orally with SHIV-vpu+ shortly thereafter. We found no evidence of infection in any infant during 6 months of follow-up. This demonstrates that IgG1 monoclonal antibodies protect against mucosal lentivirus challenge in neonates. We conclude that epitopes recognized by the three monoclonal antibodies are important determinants for achieving substantial protection, thus providing a rational basis for AIDS vaccine development.

Intranasal HIV-1-gp160-DNA/gp41 Peptide Prime-Boost Immunization Regimen in Mice Results in Long-Term HIV-1 Neutralizing Humoral Mucosal and Systemic Immunity

“…Antiviral and protective activities were detected when neutralizing Abs were i.v. administered passively (14,49,59,60,61). These data clearly suggest that systemic Abs can provide protection against mucosal virus exposure, but because IgG or monomeric IgA in serum and plasma will not be actively transported across mucosa, whereas secretory IgA or IgM will, we believe that mucosal IgA Abs could play an important role and also inhibit epithelial HIV transcytosis (21).…”

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

“…The two NAbs b12 and 2G12 are directed against exterior gp120 protein [7][8][9][10][11], and the three NAbs 2F5, 4E10 and Z13 are directed against the transmembrane gp41 protein [12][13][14]. Passive immunotherapy studies using combinations of some of these mAbs have resulted in protection against intravenous and/or mucosal simianhuman immunodeficiency virus (SHIV) challenge in monkeys [15][16][17][18], In addition, 2F5 and/ or 4E10 plus 2G12 immunotherapy have resulted in reduced viremia in established HIV-1 infection or delay of HIV-1 rebound in individuals undergoing interrupted antiretroviral treatment (ART) [19,20].…”

Live attenuated Listeria monocytogenes expressing HIV Gag: Immunogenicity in rhesus monkeys

“…However, the relative importance of mobilizing each arm of the immune system and the means to induce each type of immunity are unclear. Although several successful passive immunization studies using neutralizing monoclonal antibodies in macaques strongly suggest that inducing broadly reactive neutralizing antibodies as part of any vaccine regimen would be beneficial [1][2][3][4][5], the levels and breadth of neutralizing antibodies induced by active vaccination have thus far proved insufficient to protect against infection [6][7][8]. It appears necessary that a vaccine must activate both cellular and humoral immune mechanisms.…”