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. 2016 Apr 24;30(7):1005-14.
doi: 10.1097/QAD.0000000000001038.

Broadly neutralizing antibody specificities detected in the genital tract of HIV-1 infected women

Nonhlanhla N Mkhize  1 , Raveshni Durgiah, Vicki Ashley, Derseree Archary, Nigel J Garrett, Quarraisha Abdool Karim, Salim S Abdool Karim, Penny L Moore, Nicole Yates, Jo-Ann S Passmore, Georgia D Tomaras, Lynn Morris
Affiliations

Broadly neutralizing antibody specificities detected in the genital tract of HIV-1 infected women

Nonhlanhla N Mkhize et al. AIDS. .

Abstract

Background: Broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the HIV envelope glycoprotein have been identified in blood from HIV-1 infected women. We investigated whether antibodies in the genital tract from these women share similar epitope specificities and functional profiles as those in blood.

Methods: Immunoglobulin (Ig)G and IgA antibodies were isolated from cervicovaginal lavages or Softcups from 13 HIV-infected women in the CAPRISA cohort using Protein G and Peptide M, respectively. Binding antibodies to envelope antigens were quantified by ELISA and binding antibody multiplex assay. Neutralizing antibody titers and epitope targets were measured using the TZM-bl assay with Env-pseudotyped wild-type and mutated viruses.

Results: HIV-specific IgG, but not IgA, was detected in genital secretions and the ratio of total IgG to HIV-specific IgG was similar to plasma. HIV-specific IgG reacted with multiple envelope antigens, including V1V2, gp120, gp140 and gp41. Two women had high plasma titers of HIV-specific IgG3 which was also detected in their genital tract samples. IgG from the genital tract had neutralizing activity against both Tier 1 and Tier 2 primary HIV-isolates. Antibodies targeting well known glycan epitopes and the membrane proximal region of gp41 were detected in genital secretions, and matched specificities in plasma.

Conclusions: Women with plasma bNAbs have overlapping specificities in their genital secretions, indicating that these predominantly IgG isotype antibodies may transudate from blood to the genital tract. These data provide evidence that induction of systemic HIV-specific bNAbs can lead to antiviral immunity at the portal of entry.

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Figures

Figure 1
Figure 1. Total and HIV-specific immunoglobulins in the female genital tract and plasma are predominantly of the IgG isotype
(A) Quantification of IgG and IgA concentrations in CVL and plasma of the 7 CAPRISA 002 women with broadly cross neutralizing activity. (B) gp120-specific binding of IgG and IgA antibodies purified from CVL and plasma from the same women. (C) Ratio of total IgG to HIV-specific IgG concentrations in CVL and plasma from the 7 CAPRISA 002 women, based on 17b mAb standard curve for gp120 IgG. (D) Comparison of total IgG yields from CVL original data (from CAPRISA 002) and genital secretions collected using Softcup from 10 women in the CAPRISA 002 and 004 cohorts.
Figure 2
Figure 2. HIV-specific activity of IgG antibodies in CVL and plasma
IgG binding antibodies were measured in CVL and plasma from the 7 CAPRISA 002 women who developed broadly cross neutralizing antibodies. Dots represent CVL and plasma samples from 1 year (red), 2 years (green) and 3 years (blue) post HIV infection. Reactivity to 8 antigens was evaluated via a customized binding antibody multiplex assay (BAMA). The median fluorescence intensity (MFI) values were normalized to total IgG concentration (specific activity). Samples that had MF1<100 were considered non-responders therefore the points are not reflected on the plots. Responders had a specific activity >0.01 for all antigens.
Figure 3
Figure 3. IgG3 binding to HIV-specific antigens
IgG3 responses were measured against Env antigens at 1, 2 and 3 years post HIV-infection. Responses were detected in CAP256 (A) and CAP177 (B), represented as specific activity for CVL (left panel) and MFI for plasma samples (right panel). Full data is presented in supplementary Table 1.
Figure 4
Figure 4. Neutralization of HIV by purified IgG from the genital tract
SF162 (Tier 1) and ConC (Tier 2) viruses were tested in a TZM-bl neutralization assay using IgG isolated from CVL supernatant (A) and Softcup (B) from women in the CAPRISA 002 and 004 cohorts. The dotted line represents the IC50.
Figure 5
Figure 5. Epitope mapping of antibody specificities by ELISA (A) and neutralization (B)
CVL and plasma IgG antibody specificities in CAP177 at 3 years post infection were tested by binding to wild-type and N332A mutant gp120 while MPER IgG activity in CAP206 was detected at 3 years post infection in both genital tract and plasma (A). Plasma and genital tract IgG antibody from CAP8, CAP256 and CAP255 were mapped by measuring neutralization of wild-type virus and mutant viruses. The dotted lines represent IC50 values (B).
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