High-Level Ability of Secretory IgA to Block HIV Type 1 Transcytosis: Contrasting Secretory IgA and IgG Responses to Glycoprotein 160

Abstract

The IgG and secretory IgA (S-IgA) responses to the HIV-1 envelope (gp160 antigen) were analyzed in the colostrum (Col) and in the cervicovaginal fluid (CVF) of HIV-l-infected women. We show IgG antibodies (Abs) to the recombinant gp160 to be predominant as compared with the corresponding S-IgA isotype. The low level of the S-IgA response cannot be related to a general disturbance of the mucosal-associated Iymphoid tissue (MALT) because the level of a current Ab to a caries-associated antigen from Streptococcus sobrinus was in the normal range in these secretions. The major subclass of IgA to gp160 was of the alpha1 isotype both in Col and in CVF. However, the specific activities of S-IgA1 and S-IgA2 were different when expressed as the ratio of the anti-gp160 related to total Ig of each subclass. Indeed, the specific activity of the S-IgA2 was predominant over S-IgA1 in the Col, whereas the reciprocal results were found in CVF, showing a subcompartmentalization of these secretions. The ability of S-IgA and IgG to block one of the pathways involved in the HIV-1 penetration across mucosa, i.e., transcytosis through epithelial cells, was evaluated using a functional in vitro assay. Both S-IgA and IgG Abs impaired virus transcytosis, irrespective of the level of antigp160 specific activities. However, specific S-IgA was more efficient than IgG. These features suggest that mucosal specific S-IgA to HIV-1 could be relevant in decreasing infectivity of HIV-1 in corporal fluids.

Intraepithelial Cell Neutralization of HIV-1 Replication by IgA

“…In addition to the conventional neutralization activity mentioned, human IgA Ab has also been shown to be able to act intracellularly to block HIV transcytosis from the apical to the basolateral side of epithelial cell monolayers, suggesting the potential to inhibit spread of HIV from mucosal epithelium to the lamina propria (16,24,33,35,36). The ability of IgA Ab to act in this manner has been referred to as "intracellular neutralization" (16).…”

“…With respect to HIV, IgA (and IgM) Abs placed at either the apical or basolateral surface have been reported to block transcytosis of virus from the apical to the basolateral side in a tight epithelial cell monolayer (16,24,(33)(34)(35)(36). These findings suggest that in vivo HIV-specific IgA can both exclude HIV from mucosal epithelial cells and prevent transcytosing HIV from spreading to the lamina propria, where abundant T cells and macrophages are potential targets of infection.…”

A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs

“…1) mediates viral interaction with the epithelial cell receptor of HIV-1, GalCer (7,10,11). This interaction may be important for the nonfusion processes that enable HIV-1 to cross simple epithelia and can be blocked by the 2F5 IgG, ELDKWA-specific IgA from infected or highly exposed persistently seronegative individuals (20,21). The ability of anti-ELDKWA Abs to block viral transmission in vivo by passive immunization in the macaque model (17,18) further illuminates the importance of inducing Abs against this region as part of a prophylactic HIV-1 vaccine.…”

“…Similarly, vaginal application of the gp120-directed b12 Ab was highly effective in protecting monkeys from a vaginal challenge (19). Third, anti-HIV-1 secretory IgA, isolated from mucosal secretions of infected individuals, can block transcytosis of HIV-1 and infection of CD4 ϩ cells ex vivo (20,21) and the neutralization potential of these Abs was greater than the paired IgGs (21). Fourth, transcytosis and infection neutralizing secretory IgAs have been detected in highly exposed persistently seronegative individuals.…”

Hiv-specific secretory IgA in breast milk of HIV-positive mothers is not associated with protection against HIV transmission among breast-fed infants

“…5 HIV-specific IgA antibodies are detected in breast milk of a high proportion of HIV-positive, lactating women. [6][7][8] In an in vitro model, sIgA purified from colostrum was able to block one of the pathways involved in HIV penetration across mucosa, that is, transcytosis through epithelial cells, 9 suggesting that sIgA may be related to decreased infectivity of breast milk. Although persistence of HIV-specific IgA and IgM in breast milk was associated with reduced transmission in one study in Rwanda, 10 no protective association was observed in two other studies.…”