Failure of Neutralizing gp120 Monoclonal Antibodies to Prevent HIV Infection of Choriocarcinoma-Derived Trophoblasts

Abstract

Although placental trophoblasts, the only fetal cells in direct contact with infectious maternal blood, can be infected with HIV, the precise cause for the low transmission rate of virus across the placental barrier is unknown. One of the most common conjectures is that maternal anti- HIV antibodies (Abs) contribute to the protection of the fetus. This hypothesis has been tested in vitro by infecting the CD4-negative placental trophoblast line, BeWo, with HIV-1 mg in the presence of serial dilutions of neutralizing monoclonal Abs against the V3 loop (No. 694) or CD4-bindmg conformational domain (No. 588). The results, based on measurement of p24 production from virus-exposed cells, reveal that the titers of Abs, adequate in preventing the infection of control MT-4 T lymphocytes, were less effective in protecting trophoblasts. Furthermore, PCR analysis of HIV DNA formed after a single round of infection has shown no significant decrease in the number of viral copies in Ab-protected BeWo cells. An anti-HIV serum from a pregnant woman did also have no effect. Although our in vitro observations do not necessarily apply to the in vivo situation, the results suggest that the humoral immune response sustained by neutralizing Abs may be able to protect T lymphocytes, but not placental trophoblasts. The findings are consistent with recent clinical studies demonstrating a lack of correlation between the presence of neutralizing anti-HIV Abs in pregnant women and HIV transmission in utero.

HIV‐1 Infection of Trophoblasts Is Independent of gp120/CD4 Interactions but Relies on Heparan Sulfate Proteoglycans

“…Hence, the role played by CD4 and coreceptors in HIV-1 entry into trophoblastic cells is still unclear, but it is reasonable to assume that CD4, CXCR4, and CCR5 are unlikely to play a significant role, because they are expressed at such low levels if present. In agreement with this, several groups have shown recently that CD4 is not required for HIV-1 infection in trophoblasts [27][28][29][30]. In this context, we developed 2 hypotheses.…”

Mucosal AIDS Vaccines

“…The phenomenon of enhancement of HIV infection by HIVspecific antibodies surfaced as early as 1988 and has been regularly reported by reputable investigators in dozens of labs around the world (53,66,133). Our own experience has shown that, depending on the assay conditions and type of target cells, even the most potent neutralizing antibodies can behave like infectionenhancing antibodies (19). For this reason, standard assays with cell-free virus and T cells as targets, commonly used for evaluating the neutralizing titers in AIDS vaccine trials, can be misleading and do not represent a real-life situation.…”

“…This led us to propose that both HIV and HTLV-I may affect mucosal immunity (23,26). A series of subsequent studies using an in vitro model of sexual and transplacental HIV transmission has shown that although target epithelial cells, whether of intestinal or placental origin, seemed to lack a CD4 receptor, they, nevertheless, were susceptible to HIV if the virus was delivered by cell-cell contact (19,25,129). Studies from several labs around the world have confirmed these findings (153).…”

“…While this last prophecy of Sabin (he passed away shortly after his last publication in Nature) was immediately contested (1), he was the first to indicate an inherent flaw in the antibody-based strategy. Furthermore, even when epithelial cells were exposed to large doses of cell-free virus, an artificial condition that allowed productive infection, the neutralizing IgG antibodies or polyclonal antisera were still ineffective in preventing infection (19,129).…”