HIV-1 autologous antibody neutralization associates with mother to child transmission

Abstract

The HIV-1 characteristics associated with mother to child transmission (MTCT) are still poorly understood and if known would indicate where intervention strategies should be targeted. In contrast to horizontally infected individuals, exposed infants possess inherited antibodies (Abs) from their mother with the potential to protect against infection. We investigated the HIV-1 gp160 envelope proteins from seven transmitting mothers (TM) whose children were infected either during gestation or soon after delivery and from four non-transmitting mothers (NTM) with similar viral loads and CD4 counts. Using pseudo-typed viruses we tested gp160 envelope glycoproteins for TZM-bl infectivity, CD4 and CCR5 interactions, DC-SIGN capture and transfer and neutralization with an array of common neutralizing Abs (NAbs) (2F5, 2G12, 4E10 and b12) as well as mother and infant plasma. We found no viral correlates associated with HIV-1 MTCT nor did we find differences in neutralization with the panel of NAbs. We did, however, find that TM possessed significantly higher plasma neutralization capacities than NTM (P = 0.002). Furthermore, we found that in utero (IU) TM had a higher neutralization capacity than mothers transmitting either peri - partum (PP) or via breastfeeding (BF) (P = 0.002). Plasma from children infected IU neutralized viruses carrying autologous gp160 viral envelopes as well as those from their corresponding mothers whilst plasma from children infected PP and/or BF demonstrated poor neutralizing capacity. Our results demonstrate heightened autologous NAb responses against gp120/gp41 can associate with a greater risk of HIV-1 MTCT and more specifically in those infants infected IU. Although the number of HIV-1 transmitting pairs is low our results indicate that autologous NAb responses in mothers and infants do not protect against MTCT and may in fact be detrimental when considering IU HIV-1 transmissions.

Figure 1. Phylogenetic analysis of the gp160 envelope region.

The analysis was performed using the Neighbor-Joining (N-J) method of MEGA version 4. Positions containing an alignment gap were included for pair-wise sequence analysis. TM depicted by closed circles, IC by open circles and NTM by triangles. The clones selected for further analyses are indicated with an asterix.

Figure 2. Infectivity of TZM-bl cells with Env pseudo-typed viruses.

Viruses were tested from NTM, TM and infected children (IC) with results expressed in relative luciferase units (RLU). *Probability that the groups are similar is <0.05.

Figure 3. Inhibition of Env pseudo-typed viruses from NTM, TM and infected children (IC) expressed as IC₅₀’s.

(A) sCD4, (B) αCD4 Ab OKT4 and (C) CCR5 antagonist Maraviroc. NTM are represented by dots, TM by squares, and IC by triangles. Competition with Maraviroc of subtype A (open diamonds) versus subtype C (open dots) viruses is shown in D. **Probability that the groups are similar is <0.01.

Figure 4. DC-SIGN mediated capture and transfer of Env pseudo-typed viruses from NTM, TM and infected children (IC).

(A) Quantity of Env pseudo-typed virus captured by Raji-DC-SIGN cells as determined by CA-p24. (B) Extent of infection of TZM-bl cells by captured Env pseudo-typed viruses expressed in relative luciferase units (RLU). (C and D) Linear regression analysis of the V1–V5 number of PNGS and virus capture by Raji-DC-SIGN cells, in (C) NTM and TM and (D) in IC. NTM are represented by circles, TM by squares, and IC by triangles.

Figure 5. Plasma neutralization of NTM, TM, infected children (IC) and non-IC.

(A) Neutralization of Env pseudo-typed viruses carrying NTM and TM gp160. (B) Neutralization of Env pseudo-typed viruses carrying the JRFL gp160. Neutralization from NTM is represented by dots, from TM by squares, from NIC by diamonds and from IC by triangles. (C) Autologous neutralization of Env pseudo-typed viruses carrying TM gp160/gp41, divided into IU and PP/BF and (D) neutralization of children’s Env pseudo-typed viruses. Neutralization by plasma from IU TM is represented by closed dots, from PP/BF TM by open dots, from IU IC by closed triangles and from BF IC by open triangles. The dashed line indicates the lowest plasma dilution tested (1→48). *Probability that the groups are similar is <0.05, **Probability that the groups are similar is <0.01.