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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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Levels of total and HIV-1 env specific IgG and IgA in unfractionated BMS and plasma.(A)Total IgG and IgA in unfractionated BMS and plasma. The Y-axis shows the log10 Ab conc (ug/ml) and the X-axis shows the sample type and Ab isotype. Black and grey symbols denote BMS and plasma, respectively. Triangles and circles represent IgG and IgA, respectively. (B) Unfractionated BMS and plasma HIV-1 env specific IgG and IgA titers. The Y-axis shows the log10 HIV-1 env specific titers (reciprocal dilution) and the X-axis shows the sample type and Ab isotype. Symbols are as described for A.
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ppat-1002739-g004: Levels of total and HIV-1 env specific IgG and IgA in unfractionated BMS and plasma.(A)Total IgG and IgA in unfractionated BMS and plasma. The Y-axis shows the log10 Ab conc (ug/ml) and the X-axis shows the sample type and Ab isotype. Black and grey symbols denote BMS and plasma, respectively. Triangles and circles represent IgG and IgA, respectively. (B) Unfractionated BMS and plasma HIV-1 env specific IgG and IgA titers. The Y-axis shows the log10 HIV-1 env specific titers (reciprocal dilution) and the X-axis shows the sample type and Ab isotype. Symbols are as described for A.

Mentions: To determine if low NAbs in BMS reflected lower total BM Ab levels, we measured the levels of total and HIV-1envspecific IgG and IgA Abs in BMS and compared them to plasma (Figure 4). The levels of total BMS IgG were 0.88 log10 lower than BMS IgA(p<0.0001) (Figure 4A, black symbols). This is in contrast to plasma, where the IgG levels were found to be 1.02 log10 higher than IgA (p<0.0001) (Figure 4A, grey symbols). There was a pronounced difference between the magnitude of total IgG in BMS and plasma with BMS total IgG being2.25 log10 lower than plasma IgG (p<0.0001). In contrast, the total IgA levels in plasma were only slightly higher than in BMS, with a modest 0.39log10 difference between BMS and plasma (p = 0.004). We found statistically significant correlation between total BMS IgG and plasma IgG (r = 0.67; p = 0.0034)while the levels of BMS total IgA correlated with total plasma IgA (r = 0.78; p = 0.0003). There was no significant correlation between BMS total IgG and BMS total IgA (r = 0.39; p = 0.10) (Table S2).


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)

Levels of total and HIV-1 env specific IgG and IgA in unfractionated BMS and plasma.(A)Total IgG and IgA in unfractionated BMS and plasma. The Y-axis shows the log10 Ab conc (ug/ml) and the X-axis shows the sample type and Ab isotype. Black and grey symbols denote BMS and plasma, respectively. Triangles and circles represent IgG and IgA, respectively. (B) Unfractionated BMS and plasma HIV-1 env specific IgG and IgA titers. The Y-axis shows the log10 HIV-1 env specific titers (reciprocal dilution) and the X-axis shows the sample type and Ab isotype. Symbols are as described for A.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002739-g004: Levels of total and HIV-1 env specific IgG and IgA in unfractionated BMS and plasma.(A)Total IgG and IgA in unfractionated BMS and plasma. The Y-axis shows the log10 Ab conc (ug/ml) and the X-axis shows the sample type and Ab isotype. Black and grey symbols denote BMS and plasma, respectively. Triangles and circles represent IgG and IgA, respectively. (B) Unfractionated BMS and plasma HIV-1 env specific IgG and IgA titers. The Y-axis shows the log10 HIV-1 env specific titers (reciprocal dilution) and the X-axis shows the sample type and Ab isotype. Symbols are as described for A.
Mentions: To determine if low NAbs in BMS reflected lower total BM Ab levels, we measured the levels of total and HIV-1envspecific IgG and IgA Abs in BMS and compared them to plasma (Figure 4). The levels of total BMS IgG were 0.88 log10 lower than BMS IgA(p<0.0001) (Figure 4A, black symbols). This is in contrast to plasma, where the IgG levels were found to be 1.02 log10 higher than IgA (p<0.0001) (Figure 4A, grey symbols). There was a pronounced difference between the magnitude of total IgG in BMS and plasma with BMS total IgG being2.25 log10 lower than plasma IgG (p<0.0001). In contrast, the total IgA levels in plasma were only slightly higher than in BMS, with a modest 0.39log10 difference between BMS and plasma (p = 0.004). We found statistically significant correlation between total BMS IgG and plasma IgG (r = 0.67; p = 0.0034)while the levels of BMS total IgA correlated with total plasma IgA (r = 0.78; p = 0.0003). There was no significant correlation between BMS total IgG and BMS total IgA (r = 0.39; p = 0.10) (Table S2).

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