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HIV-specific antibodies capable of ADCC are common in breastmilk and are associated with reduced risk of transmission in women with high viral loads.

Mabuka J, Nduati R, Odem-Davis K, Peterson D, Overbaugh J - PLoS Pathog. (2012)

Bottom Line: Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58).BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001) and BMS ADCC activity (p = 0.014).Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039).

View Article: PubMed Central - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

ABSTRACT
There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman's autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS)--only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log(10) lower (compared to 0.59 log(10) lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001) and BMS ADCC activity (p = 0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk.

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ADCC activity in BMS and plasma.Percent ADCC activity in BMS(A) and plasma (B). BMS was tested at a 1∶100 dilution and plasma at a 1∶1000 dilution. The subject ID for the corresponding ADCC measure is shown below each bar. The results are from duplicate testing and are an average of at least two independent experiments each done using effector cells from a single donor. nd indicates not done.
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ppat-1002739-g005: ADCC activity in BMS and plasma.Percent ADCC activity in BMS(A) and plasma (B). BMS was tested at a 1∶100 dilution and plasma at a 1∶1000 dilution. The subject ID for the corresponding ADCC measure is shown below each bar. The results are from duplicate testing and are an average of at least two independent experiments each done using effector cells from a single donor. nd indicates not done.

Mentions: We determined the capacity of BMS binding antibodies and their matched plasma to mediate ADCC. The appropriate BMS and plasma dilution for the ADCC assay was determined by testing serial 10-fold dilutions of 4 representative BMS and plasma in the ADCC assay. The dilution that permitted detection of HIV-specific ADCC activity above background levels, but did not yield inhibition of ADCC activity that can occur with more concentrated samples [72] was chosen for testing (1∶100 for BMS and 1∶1000 for plasma). Using a single dilution also allowed us to test all 19 BMS and plasma samples with effector cells obtained from a single PBMC donor, which is critical for avoiding bias due to differences in effector cell activity observed from donor to donor. Overall, ADCC activity was detected in all BMS and plasma samples tested (Figures 5 A and B). BMS ADCC mediated killing ranged from 1–27% (median,15%) while that of plasma ranged from 16–36% (median, 24%). BMS ADCC activity was correlated with gp140 env specific IgG titers (r = 0.56, p = 0.014) (Figure 6). A log10 increase in gp140 titers was associated with an absolute increase of 9.3 in % ADCC mediated killing by BMS (95% CI: 2.18, 16.41; p = 0.013).


HIV-specific antibodies capable of ADCC are common in breastmilk and are associated with reduced risk of transmission in women with high viral loads.

Mabuka J, Nduati R, Odem-Davis K, Peterson D, Overbaugh J - PLoS Pathog. (2012)

ADCC activity in BMS and plasma.Percent ADCC activity in BMS(A) and plasma (B). BMS was tested at a 1∶100 dilution and plasma at a 1∶1000 dilution. The subject ID for the corresponding ADCC measure is shown below each bar. The results are from duplicate testing and are an average of at least two independent experiments each done using effector cells from a single donor. nd indicates not done.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375288&req=5

ppat-1002739-g005: ADCC activity in BMS and plasma.Percent ADCC activity in BMS(A) and plasma (B). BMS was tested at a 1∶100 dilution and plasma at a 1∶1000 dilution. The subject ID for the corresponding ADCC measure is shown below each bar. The results are from duplicate testing and are an average of at least two independent experiments each done using effector cells from a single donor. nd indicates not done.
Mentions: We determined the capacity of BMS binding antibodies and their matched plasma to mediate ADCC. The appropriate BMS and plasma dilution for the ADCC assay was determined by testing serial 10-fold dilutions of 4 representative BMS and plasma in the ADCC assay. The dilution that permitted detection of HIV-specific ADCC activity above background levels, but did not yield inhibition of ADCC activity that can occur with more concentrated samples [72] was chosen for testing (1∶100 for BMS and 1∶1000 for plasma). Using a single dilution also allowed us to test all 19 BMS and plasma samples with effector cells obtained from a single PBMC donor, which is critical for avoiding bias due to differences in effector cell activity observed from donor to donor. Overall, ADCC activity was detected in all BMS and plasma samples tested (Figures 5 A and B). BMS ADCC mediated killing ranged from 1–27% (median,15%) while that of plasma ranged from 16–36% (median, 24%). BMS ADCC activity was correlated with gp140 env specific IgG titers (r = 0.56, p = 0.014) (Figure 6). A log10 increase in gp140 titers was associated with an absolute increase of 9.3 in % ADCC mediated killing by BMS (95% CI: 2.18, 16.41; p = 0.013).

Bottom Line: Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58).BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001) and BMS ADCC activity (p = 0.014).Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039).

View Article: PubMed Central - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

ABSTRACT
There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman's autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS)--only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log(10) lower (compared to 0.59 log(10) lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001) and BMS ADCC activity (p = 0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk.

Show MeSH
Related in: MedlinePlus