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. 2015 Apr 8;17(4):500-6.
doi: 10.1016/j.chom.2015.03.002.

Passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity in HIV-infected infants is associated with reduced mortality

Caitlin Milligan  1 , Barbra A Richardson  2 , Grace John-Stewart  3 , Ruth Nduati  4 , Julie Overbaugh  5
Affiliations

Passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity in HIV-infected infants is associated with reduced mortality

Caitlin Milligan et al. Cell Host Microbe. .

Abstract

In addition to direct effects on virus infectivity, antibodies mediate antibody-dependent cellular cytotoxicity (ADCC), the killing of an antibody-coated virus-infected cell by cytotoxic effector cells. Although ADCC has been suggested to protect against HIV, the relationship between HIV-specific ADCC antibodies at the time of HIV exposure and infection outcome in humans remains to be assessed. We evaluated the ADCC activity of passively acquired antibodies in infants born to HIV-infected mothers. ADCC levels were higher in uninfected than infected infants, although not significantly. Increase in ADCC antibody activity in infected infants was associated with reduced mortality risk. Infant ADCC positively correlated with the magnitude of IgG1 binding, and IgG1 levels were associated with survival in infected infants. Infant IgG3-binding antibodies were not associated with infected infant survival. These data suggest a therapeutic benefit of pre-existing HIV-specific ADCC antibodies and support a role for eliciting ADCC-mediating IgG1 in HIV vaccines.

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Conflict of interest statement

The authors have no conflicts of interest to report.

Figures

Figure 1
Figure 1. Infant ADCC Antibody Responses
(A) Passively acquired infant ADCC responses are shown in relation to infection outcome. Results are normalized to a positive control (HivIg) and data are represented as mean ± SEM. (B) Kaplan-Meier estimates for infected infants with infant ADCC antibody activity ≥ infected infant cohort median ADCC activity (solid line) and infected infants with ADCC antibody activity < median (dashed line).
Figure 2
Figure 2. Maternal ADCC Antibody Responses
(A) Correlation between maternal and infant ADCC antibody responses. (B) maternal ADCC responses are shown in relation to infant infection outcome. Results are normalized to a positive control (HivIg) and data are represented as mean ± SEM. (C) Kaplan-Meier estimates for infected infants with maternal ADCC antibody activity ≥ the maternal transmitter cohort median ADCC activity (solid line) and infected infants with maternal ADCC antibody activity < median (dashed line).
Figure 3
Figure 3. IgG1 and IgG3 HIV-Specific Responses in Infants
Correlation of infant ADCC antibody activity and IgG1 log2MFI responses (A) or IgG3 log2EPT (D). IgG1 (B) or IgG3 (E) responses in relation to infant infection status; mean ± SEM are shown. Kaplan-Meier estimates for infected infants with IgG1 log2MFI ≥ infected infant cohort median (solid line) and infected infants with IgG1 log2MFI < cohort median (dashed line) (C) or IgG3 levels detectable at a 1:50 dilution (solid line) vs. undetectable (dashed line) (F).
Figure 4
Figure 4. Kinetics of ADCC Antibody Responses in HIV-Infected Infants
ADCC antibody activity in plasma in longitudinal samples from 6 HIV-infected infants. Three had passively acquired ADCC activity < infected infant cohort median (A,B,C) and three had activity > median (D,E,F) Black arrow indicates estimated time of infection defined as the midpoint between the last negative and first positive HIV DNA test. Unfilled dot represents first HIV-DNA positive test. Results represent mean ± SD for 2 independent experiments in duplicate. (G) Correlation between the passively acquired ADCC antibody response (measured in the first week of life) and maximum de novo ADCC activity measured after infection, for the six infants.
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