Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy

Abstract

The examination of antibody responses in human immunodeficiency virus (HIV)-1-infected individuals in the setting of antiretroviral treatment (ART) interruption can provide insight into the evolution of antibody responses during viral rebound. In this study, we assessed antibody responses in 20 subjects in AIDS Clinical Trials Group A5187, wherein subjects were treated with antiretroviral therapy during acute/early HIV-1 infection, underwent analytic treatment interruption, and subsequently demonstrated viral rebound. Our data suggest that early initiation of ART arrests the maturation of HIV-1-specific antibody responses, preventing epitope diversification of antibody binding and the development of functional neutralizing capacity. Antibody responses do not appear permanently blunted, however, because viral rebound triggered the resumption of antibody maturation in our study. We also found that antibody responses measured by these assays did not predict imminent viral rebound. These data have important implications for the HIV-1 vaccine and eradication fields.

Keywords: HIV eradication; HIV vaccine; antibody; microarray; treatment interruption.

Figure 1.

Immunoglobulin G (IgG) binding titers to a cross-clade panel of human immunodeficiency virus (HIV)-1 envelope proteins by enzyme-linked immunosorbent assay (ELISA) in HIV-infected subjects treated with antiretroviral therapy (ART) at baseline (BL), 4 weeks post-analytic treatment interruption (ATI) and 20 weeks post-ATI. (A) Immunoglobulin G binding titers are plotted over time for subjects that had undetectable (Group 1, left) and detectable (Group 2, right) viral load at week 4 post-ATI. Mean viral load for each group is plotted over time in gray in the background. Average all-clade IgG titers at week 4 and 20 were compared with BL in both groups. (B) Immunoglobulin G titers are plotted by viral load for both groups at 4 weeks post-ATI. (C) Immunoglobulin G titers are plotted by viral load for both groups at 20 weeks post-ATI. **P < .01; ****P < .0001. Abbreviation: NS, not significant.

Figure 2.

Neutralizing antibody (NAb) responses in human immunodeficiency virus (HIV)-infected subjects treated with antiretroviral therapy (ART) at baseline (BL), 4 weeks post-analytic treatment interruption (ATI) and 20 weeks post-ATI. (A) Neutralizing antibody titers against a panel of tier 1 HIV isolates are plotted over time for subjects that had undetectable (Group 1, left) and detectable (Group 2, right) viral load at week 4 post-ATI. Mean viral load for each group is plotted over time in gray in the background. (B) Average tier 1A NAb titers are plotted by viral load for both groups at 4 weeks post-ATI. (C) Average tier 1A NAb titers are plotted by viral load for both groups at 20 weeks post-ATI. Abbreviation: NS, not significant.

Figure 3.

Immunoglobulin G (IgG) responses to linear human immunodeficiency virus (HIV)-1 peptides in HIV-infected subjects treated with antiretroviral therapy (ART) at baseline (BL), 4 weeks post-analytic treatment interruption (ATI) and 20 weeks post-ATI. Mean fluorescent intensity (MFI) of IgG binding is plotted over time in (A–C) for subjects that had undetectable (Group 1, left) and detectable (Group 2, right) viral load at week 4 post-ATI. Mean viral load for each group is plotted over time in gray in the background. The average MFI per protein or protein subregion is depicted for complete HIV proteins (A), envelope (Env) gp120 subregions (B), and glycoprotein (gp)41 regions (C). For all figures, average group MFI at week 4 and 20 was compared with BL: *P < .05; **P < .01; ***P < .001.

Figure 4.

Detailed immunoglobulin G (IgG) responses to linear human immunodeficiency virus (HIV)-1 peptides in HIV-infected subjects treated with antiretroviral therapy (ART) at baseline (BL), 4 weeks post-analytic treatment interruption (ATI), and 20 weeks post-ATI. Mean fluorescent intensity (MFI) of IgG binding to glycoprotein (gp)120, gp41, and Gag peptides is plotted by peptide start position (ie, peptide location on HXB2 reference strain). At 4 weeks post-ATI, Group 1 (G1) and Group 2 (G2) responses are compared to each other; *P < .05; **P < .01.

Figure 5.

The association between immunoglobulin G (IgG) epitope specificity and glycoprotein (gp)140 enzyme-linked immunosorbent assay (ELISA) titer and/or tier 1A neutralizing antibody (NAb) responses in human immunodeficiency virus (HIV)-infected subjects treated with antiretroviral therapy (ART) at 4 weeks post-analytic treatment interruption (ATI) and 20 weeks post-ATI. Average mean fluorescent intensity (MFI) of IgG binding to third hypervariable loop (V3), CC loop, and cytoplasmic tail peptides is plotted against (A) gp140 ELISA titer at 4 weeks post-ATI, (B) gp140 ELISA titer at 20 weeks post-ATI, and (C) tier 1A NAb titer at 20 weeks post-ATI. Abbreviation: NS, not significant.