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. 2016 Jun 10;13:40. doi: 10.1186/s12977-016-0272-y

Perinatal HIV-1 transmission: Fc gamma receptor variability associates with maternal infectiousness and infant susceptibility

Ria Lassaunière 1,2, Alfred Musekiwa 3, Glenda E Gray 4, Louise Kuhn 5,6, Caroline T Tiemessen 1,2,✉
PMCID: PMC4902924  PMID: 27287460

Abstract

Background

Accumulating data suggest that immune effector functions mediated through the Fc portion of HIV-1-specific immunoglobulin G (IgG) are a key component of HIV-1 protective immunity, affecting both disease progression and HIV-1 acquisition. Through studying Fc gamma receptor (FcγR) variants known to alter IgG Fc-mediated immune responses, we indirectly assessed the role of FcγR-mediated effector functions in modulating perinatal HIV-1 transmission risk. In this study, genotypic data from 79 HIV-1 infected mothers and 78 HIV-1 infected infants (transmitting cases) were compared to 234 HIV-1 infected mothers and 235 HIV-1 exposed-uninfected infants (non-transmitting controls). Associations, unadjusted and adjusted for multiple comparisons, were assessed for overall transmission and according to mode of transmission—intrapartum (n = 31), in utero (n = 20), in utero-enriched (n = 48).

Results

The maternal FcγRIIIa-158V allele that confers enhanced antibody binding affinity and antibody-dependent cellular cytotoxicity capacity significantly associated with reduced HIV-1 transmission [odds ratio (OR) 0.47, 95 % confidence interval (CI) 0.28–0.79, P = 0.004; PBonf > 0.05]. In particular, the FcγRIIIa-158V allele was underrepresented in the in utero transmitting group (P = 0.048; PBonf > 0.05) and in utero-enriched transmitting groups (P = 0.0001; PBonf < 0.01). In both mother and infant, possession of an FcγRIIIb-HNA1b allotype that reduces neutrophil-mediated effector functions associated with increased transmission (OR 1.87, 95 % CI 1.08–3.21, P = 0.025; PBonf > 0.05) and acquisition (OR 1.91, 95 % CI 1.11–3.30, P = 0.020; PBonf > 0.05), respectively. Conversely, the infant FcγRIIIb-HNA1a|1a genotype was significantly protective of perinatal HIV-1 acquisition (OR 0.42, 95 % CI 0.18–0.96, P = 0.040; PBonf > 0.05).

Conclusions

The findings of this study suggest a potential role for FcγR-mediated effector functions in perinatal HIV-1 transmission. However, future studies are required to validate the findings of this study, in particular associations that did not retain significance after adjustment for multiple comparisons.

Electronic supplementary material

The online version of this article (doi:10.1186/s12977-016-0272-y) contains supplementary material, which is available to authorized users.

Keywords: HIV-1, Vertical infectious disease transmission, Risk factors, IgG receptors, Alleles, Antibody-dependent cell cytotoxicity, Phagocytosis

Background

Beyond neutralization, immunoglobulin G (IgG) has the capacity to recruit potent effector functions of the innate immune system through engagement with Fc gamma receptors (FcγRs), which are widely expressed throughout the haematopoietic system. Directly or indirectly, FcγRs mediate antiviral processes that include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), respiratory burst, antigen display, antibody production, cell activation, and release of inflammatory mediators [1].

FcγR-mediated effector functions are increasingly recognized as a component of HIV-1 protective immunity [2]. However, the role of these effector functions in modulating perinatal HIV-1 transmission risk is currently undefined. Given the contribution of FcγR-mediated effector functions to eliminating cell-free and cell-associated virus, these processes may modify the infectiousness of an HIV-1 infected mother. In addition, transplacental transferred anti-HIV-1 IgG may recruit innate immune effector functions in the foetus/infant through engaging FcγRs expressed on foetal/infant immune cells, and in this manner modify the infant’s susceptibility to HIV-1 acquisition.

In vivo, FcγR-mediated effector functions are governed by a balance between activating and inhibitory FcγRs [3]. This balance is perturbed by functionally significant genotypic variants that modulate cellular activation and ultimately effector function capability. These include gene duplication/deletion that affects FcγR surface density [4, 5] and amino acid changes that alter the receptor’s binding affinity for antibody subclasses (FcγRIIa-H131R and FcγRIIIa-F158V) [6, 7], subcellular localization (FcγRIIb-I232T) [8], glycosylation patterns (FcγRIIIb-HNA1a|b|c) [9, 10], and the expression of a functional molecule (FcγRIIc-X57Q and c.798+1A>G) [11, 12].

Using these variants as a proxy for functional capability, this study indirectly assessed the potential role of FcγR-mediated effector functions in mother-to-child transmission of HIV-1. Due to the exploratory nature of the study, associations are reported unadjusted for multiple comparisons. However, adjusted associations were also considered. Our findings highlight a potential role for the FcγRIIIa-F158V variant in modulating maternal infectiousness, while in both mother and infant the FcγRIIIb-HNA1a|b|c variant associated with HIV-1 transmission.

Results

Cohort

A nested case–control study was undertaken to investigate FCGR variability in HIV-1 infected mothers and their infants recruited as part of four perinatal cohorts at two hospitals in Johannesburg, South Africa [13]. Overall, the four cohorts comprised 849 HIV-1 infected mothers and their infants, of whom 83 (10 %) acquired HIV-1 perinatally. In the present study, FCGR genotypic data from 79 HIV-1 infected mothers and 78 HIV-1 infected infants (transmitting cases) were compared with 234 HIV-1 infected mothers and 235 uninfected infants (non-transmitting controls). Mode of transmission was defined according to the presence/absence of detectable HIV-1 DNA in the infant at birth and 6 weeks of age. Infants that tested HIV-1 positive at 6 weeks of age, but who were negative at birth, were considered to be infected intrapartum (during labour and delivery), while infants that tested HIV-1 positive at birth were considered infected in utero. Infants that were HIV-1 positive at 6 weeks, but had no birth sample, were categorized as ‘undetermined’. Since 25/28 (89.2 %) mothers in the ‘undetermined’ category received drug interventions known to reduce intrapartum transmission [14–16], it was concluded that the majority of infants in this group were likely infected in utero and was thus combined with the in utero group to form an in utero-enriched group.

Transmitting mothers had significantly higher HIV-1 plasma viral loads and lower CD4+ T cell counts compared to non-transmitting mothers (Table 1). In addition, infants infected in utero had a significantly lower mean birth weight compared to exposed-uninfected infants. Maternal age, parity, mode of delivery, gestation, child sex, and reported breast feeding did not differ significantly between transmitting mothers (total, intrapartum or in utero) and non-transmitting mothers.

Table 1.

Demographic and clinical characteristics of mothers and infants

Maternal viral load (log10 copies/ml) Non-transmitting (N = 234)a Total transmitting (N = 79) Intrapartum transmitting (N = 31) In utero transmitting (N = 20)b In utero-enriched transmitting (N = 48)
Nc Nc Nc Nc Nc
Median (IQR) 218 4.08 (3.20–4.67) 71 4.77 (3.77–5.34)*** 27 4.77 (3.77–5.26)** 18 4.89 (4.20–5.47)*** 44 4.81 (3.78–5.44)***
Maternal CD4+ T cell count
 Mean (std) 217 520 (275) 70 418 (222)** 27 402 (179)* 15 409 (276) 43 428 (247)*
Maternal age (years)
 Mean (std) 232 26.9 (5.1) 78 27.6 (5.2) 30 26.7 (5.0) 20 27.5 (5.5) 48 28.2 (5.2)
Parity
 Mean (std) 231 2.1 (1.0) 77 2.3 (1.2) 29 2.3 (1.2) 20 2.2 (1.2) 48 2.3 (1.2)
Mode of delivery [N (%)]
 Caesarean section 232 17 (7.3) 77 10 (13.0) 29 2 (6.9) 20 3 (15.0) 48 8 (16.7)
Gestation [N (%)]
 Preterm <37 weeks 215 27 (12.6) 70 12 (17.1) 25 7 (28.0) 19 4 (21.1) 45 5 (11.1)
Child sex [N (%)]
 Male 234 101 (43.1) 79 39 (49.4) 31 18 (58.0) 20 8 (40.0) 48 21 (43.8)
Birth weight (g)
 Mean (std) 231 2980 (453) 78 2889 (442) 30 2943 (400) 20 2784 (320)* 48 2856 (468)
Breast fed N (%)
 >3 days 233 34 (14.6) 78 10 (12.8) 30 5 (16.7) 20 2 (10.0) 48 5 (10.4)
Antiretrovirals
 Nevirapine 234 114 (48.7) 79 47 (59.5) 31 11 (35.5) 20 13 (65.0) 48 36 (75.0)**
 Triple drug therapy 234 6 (2.6) 79 2 (2.5) 31 0 20 0 48 2 (4.2)
 Other drugsd 234 11 (4.7) 79 6 (7.6) 31 3 (9.7) 20 1 (5.0) 48 3 (6.3)
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For comparisons with non-transmitting mothers: * P < 0.05; ** P < 0.01; *** P < 0.001

aFive unmatched mothers

bOne unmatched mother

cNumber of participants for whom data were available

dDifferent regimens of zidovudine (AZT) and lamivudine (3TC)

Variants not detected in the study cohort

The FcγRIIb 2B.4 promoter haplotype (c.-386C/c.-120A) and expression of functional FcγRIIc are rare to absent in Black South African individuals [17]. Accordingly, in the present cohort of Black South African mothers and infants, none possessed the FcγRIIb 2B.4 promoter haplotype. Furthermore, despite 84/313 (25.3 %) mothers and 81/313 (25.9 %) infants bearing an FcγRIIc-Q57 allele, only one non-transmitting mother expressed functional FcγRIIc as predicted by the FCGR2C c.798+1A>G splice-site variant [12].

FCGR copy number variability

The frequency of FCGR3A gene copy number variability (CNV) was low, occurring in 17/313 (5.4 %) mothers and 14/313 (4.5 %) infants (Fig. 1), and did not associate with perinatal HIV-1 transmission (P > 0.05 for all comparisons; Additional file 1: Table S1). FCGR3B gene CNV was observed more frequently in 92/313 (29.4 %) mothers and 100/313 (31.9 %) infants (Fig. 1). The overall distribution of FCGR3B gene copy number was significantly different between exposed-uninfected infants and intrapartum infected infants (P = 0.029), with the intrapartum infected group having fewer FCGR3B gene duplications and no gene deletions (Additional file 1: Table S1). Maternal FCGR3B gene CNV did not associate with HIV-1 transmission (P > 0.05 for all comparisons; Additional file 1: Table S1).

Fig. 1.

Fig. 1

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The distribution of FCGR3A and FCGR3B gene copy number in HIV-1 infected mothers (a, b, respectively) and their infants (c, d, respectively)

FcγR variants and infectiousness of the transmitter/mother

To determine if FcγR variants were associated with the infectiousness of the mother, HIV-1 transmission was assessed according to maternal genotypes and allele carriage in a univariate and multivariate model (Table 2, 3, respectively). Overall, the maternal FcγRIIIa-F158V variant significantly associated with HIV-1 transmission (P = 0.017), while a trend was observed for the FcγRIIIb-HNA1a|b|c variant (P = 0.058).

Table 2.

FcγR genotypes and allele carriage in HIV-1 non-transmitting and transmitting mothers

Non-transmitting Total transmitting Intrapartum transmitting
N (%) N (%) OR (95 % CI) P value PBonf N (%) OR (95 % CI) P value PBonf
FcγRIIa (rs1801274) Overall association P = 0.379 ns P = 0.688 ns
Genotype
 131HH (ref) 60 (25.6) 15 (19.0) 1 6 (19.4) 1
 131HR 106 (45.3) 36 (45.6) 1.36 (0.69–2.68) P = 0.378 ns 14 (45.2) 1.32 (0.48–3.62) P = 0.558 ns
 131RR 68 (29.1) 28 (35.4) 1.65 (0.80–3.37) P = 0.172 ns 11 (35.5) 1.62 (0.56–4.64) P = 0.371 ns
Allele carriage
 ≥1 131H allele 166 (70.9) 51 (64.6) 0.75 (0.43–1.28) P = 0.288 ns 20 (64.5) 0.74 (0.34–1.64) P = 0.464 ns
 ≥1 131R allele 174 (74.4) 64 (81.0) 1.47 (0.78–2.77) P = 0.233 ns 25 (80.6) 1.44 (0.56–3.67) P = 0.449 ns
FcγRIIb (rs1050501) Overall association P = 0.194 ns P = 0.397 ns
Genotype
 232II (ref) 113 (48.3) 32 (40.5) 1 12 (38.7) 1
 232IT 103 (44.0) 36 (45.6) 1.23 (0.71–2.13) P = 0.450 ns 15 (48.4) 1.37 (0.61–3.07) P = 0.442 ns
 232TT 18 (7.7) 11 (13.9) 2.16 (0.93–5.03) P = 0.075 ns 4 (12.9) 2.09 (0.61–7.20) P = 0.242 ns
Allele carriage
 ≥1 232I allele 216 (92.3) 68 (86.3) 0.52 (0.23–1.14) P = 0.103 ns 27 (87.1) 0.56 (0.18–1.79) P = 0.239 ns
 ≥1 232T allele 121 (51.7) 47 (59.5) 1.37 (0.82–2.30) P = 0.231 ns 19 (61.3) 1.48 (0.69–3.18) P = 0.317 ns
FcγRIIIa (rs396991) Overall association P = 0.017 ns P = 0.380 ns
Genotype
 158F/FF/FF (ref) 76 (32.5) 40 (50.6) 1 10 (32.3) 1
 158FV/FFV/FVV 121 (51.7) 31 (39.2) 0.49 (0.28–0.84) P = 0.010 ns 19 (61.3) 1.19 (0.53–2.70) P = 0.672 ns
 158V/VV 36 (15.4) 8 (10.1) 0.41 (0.17–0.97) P = 0.041 ns 2 (6.5) 0.41 (0.09–1.97) P = 0.266 ns
Allele carriage
 ≥1 158F allele 197 (84.2) 71 (89.9) 1.67 (0.74–3.75) P = 0.217 ns 29 (93.5) 2.72 (0.62–11.91) P = 0.183 ns
 ≥1 158V allele 157 (67.1) 39 (49.4) 0.47(0.28–0.79) P = 0.004 ns 21 (67.7) 1.01 (0.45–2.25) P = 0.980 ns
FcγRIIIb Overall association P = 0.058 ns P = 0.647 ns
Genotype
 HNA1a+/1b−/1c− 51 (21.8) 13 (16.5) 0.68 (0.32–1.44) P = 0.315 ns 4 (12.9) 0.51 (0.15–1.70) P = 0.276 ns
 HNA1a−/1b+/1c− 23 (9.8) 7 (8.9) 0.81 (0.31–2.11) P = 0.668 ns 4 (12.9) 1.14 (0.33–3.92) P = 0.837 ns
 HNA1a−/1b−/1c+ 13 (5.6) 0 (0) – 0 (0) –
 HNA1a+/1b+/1c− (ref) 72 (30.8) 27 (34.2) 1 11 (35.5) 1
 HNA1a+/1b−/1c+ 40 (17.1) 11 (13.9) 0.73 (0.33–1.63) P = 0.448 ns 5 (16.1) 0.82 (0.27–2.52) P = 0.727 ns
 HNA1a−/1b+/1c+ 22 (9.4) 17 (21.5) 2.06 (0.95–4.46) P = 0.066 ns 5 (16.1) 1.49 (0.47–4.75) P = 0.502 ns
 HNA1a+/1b+/1c+ 12 (5.1) 4 (5.1) 0.89 (0.26–3.00) P = 0.849 ns 2 (6.5) 1.09 (0.21–5.54) P = 0.916 ns
Allele carriage
 ≥1 HNA1a allotype 175 (74.8) 55 (69.6) 0.77 (0.44–1.36) P = 0.369 ns 22 (71.0) 0.82 (0.36–1.89) P = 0.648 ns
 ≥1 HNA1b allotype 129 (55.1) 55 (69.6) 1.87 (1.08–3.21) P = 0.025 ns 22 (71.0) 1.99 (0.88–4.50) P = 0.099 ns
 ≥1 HNA1c allotype 87 (37.2) 32 (40.5) 1.15 (0.68–1.94) P = 0.599 ns 12 (38.7) 1.07 (0.49–2.30) P = 0.869 ns
In utero transmitting In utero-enriched transmitting
N (%) OR (95 % CI) P value PBonf N (%) OR (95 % CI) P value PBonf
FcγRIIa (rs1801274) P = 0.182 ns P = 0.545 ns
Genotype
 131HH (ref) 2 (10.0) 1 9 (18.8) 1
 131HR 9 (45.0) 2.55 (0.53–12.17) P = 0.241 ns 22 (45.8) 1.38 (0.60–3.20) P = 0.447 ns
 131RR 9 (45.0) 3.97 (0.83–19.10) P = 0.085 ns 17 (35.4) 1.67 (0.69–4.02) P = 0.225 ns
Allele carriage
 ≥1 131H allele 11 (55.0) 0.50 (0.20–1.26) P = 0.143 ns 31 (64.6) 0.75 (0.39–1.44) P = 0.383 ns
 ≥1 131R allele 18 (90.0) 3.10 (0.70–13.77) P = 0.136 ns 39 (81.3) 1.49 (0.68–3.27) P = 0.314 ns
FcγRIIb (rs1050501) P = 0.125 ns P = 0.274 ns
Genotype
 232II (ref) 10 (50.0) 1 20 (41.7) 1
 232IT 6 (30.0) 0.66 (0.23–1.87) P = 0.434 ns 21 (43.8) 1.15 (0.59–2.25) P = 0.678 ns
 232TT 4 (20.0) 2.51 (0.71–8.87) P = 0.153 ns 7 (14.6) 2.20 (0.81–5.94) P = 0.121 ns
Allele carriage
 ≥1 232I allele 16 (80.0) 0.33 (0.10–1.10) P = 0.072 ns 41 (85.4) 0.49 (0.19–1.24) P = 0.133 ns
 ≥1 232T allele 10 (50.0) 0.93 (0.37–2.33) P = 0.883 ns 28 (58.3) 1.31 (0.70–2.45) P = 0.403 ns
FcγRIIIa (rs396991) P = 0.137 ns P = 0.0004 0.017
Genotype
 158F/FF/FF (ref) 11 (55.0) 1 30 (62.5) 1
 158FV/FFV/FVV 8 (40.0) 0.46 (0.18–1.19) P = 0.108 ns 12 (25.0) 0.25 (0.12–0.52) P = 0.0001 0.004
 158V/VV 1 (5.0) 0.19 (0.02–1.50) P = 0.115 ns 6 (12.5) 0.41 (0.16–1.07) P = 0.069 ns
Allele carriage
 ≥1 158F allele 19 (95.0) 3.57 (0.46–27.48) P = 0.222 ns 42 (87.5) 1.31 (0.52–3.31) P = 0.562 ns
 ≥1 158V allele 9 (45.0) 0.39 (0.16–0.99) P = 0.048 ns 18 (37.5) 0.29 (0.15–0.55) P = 0.0001 0.004
FcγRIIIb P = 0.320 ns P = 0.123 ns
Genotype
 HNA1a+/1b−/1c− 6 (30.0) 2.82 (0.67–11.82) P = 0.155 ns 9 (18.8) 0.79 (0.33–1.94) P = 0.612 ns
 HNA1a−/1b+/1c− 1 (5.0) 1.04 (0.10–10.53) P = 0.971 ns 3 (6.3) 0.59 (0.16–2.20) P = 0.429 ns
 HNA1a−/1b−/1c+ 0 (0) – 0 (0) –
 HNA1a+/1b+/1c− (ref) 3 (15.0) 1 16 (33.3) 1
 HNA1a+/1b−/1c+ 4 (20.0) 2.40 (0.51–11.26) P = 0.267 ns 6 (12.5) 0.68 (0.24–1.86) P = 0.448 ns
 HNA1a−/1b+/1c+ 5 (25.0) 5.45 (1.21–24.66) P = 0.028 ns 12 (25.0) 2.45 (1.01–5.96) P = 0.047 ns
 HNA1a+/1b+/1c+ 1 (5.0) 2.00 (0.19–20.85) P = 0.562 ns 2 (4.2) 0.75 (0.15–3.68) P = 0.723 ns
Allele carriage
 ≥1 HNA1a allotype 14 (70.0) 0.79 (0.29–2.14) P = 0.638 ns 33 (68.8) 0.74 (0.38–1.46) P = 0.388 ns
 ≥1 HNA1b allotype 10 (50.0) 0.81 (0.33–2.03) P = 0.659 ns 33 (68.8) 1.79 (0.92–3.47) P = 0.085 ns
 ≥1 HNA1c allotype 10 (50.0) 1.69 (0.68–4.22) P = 0.262 ns 20 (41.7) 1.21 (0.64–2.27) P = 0.560 ns
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P values less than 0.05 are indicated in italics

P Bonf Bonferroni corrected P value, OR odds ratio, CI confidence interval, ns not statistically significant, –, the variable of interest was not detected in any of the cases and thus could not be analysed

Table 3.

Maternal FcγR variants associated with perinatal HIV-1 transmission after adjusting for confounding variables

Total transmitting Intrapartum transmitting
Univariate Adjusted for VLa PBonf Univariate Adjusted for VL PBonf
AOR (95 % CI) P value AOR (95 % CI) P value
FcγRIIa (rs1801274)
Genotype
 131HH (ref) 1 1
 131HR P = 0.378 1.81 (0.82–3.99) P = 0.141 ns P = 0.558 1.43 (0.46–4.46) P = 0.539 ns
 131RR P = 0.172 2.59 (1.14–5.87) P = 0.023 ns P = 0.371 2.57 (0.80–8.26) P = 0.113 ns
Allele carriage
 ≥1 131H allele P = 0.288 0.58 (0.33–1.05) P = 0.071 ns P = 0.464 0.49 (0.21–1.16) P = 0.106 ns
 ≥1 131R allele P = 0.233 2.11 (1.00–4.42) P = 0.049 ns P = 0.449 1.82 (0.64–5.23) P = 0.263 ns
FcγRIIb (rs1050501)
Genotype
 232II (ref) 1 1
 232IT P = 0.450 1.29 (0.71–2.35) P = 0.408 ns P = 0.442 1.60 (0.65–3.93) P = 0.309 ns
 232TT P = 0.075 2.80 (1.11–7.10) P = 0.030 ns P = 0.242 3.25 (0.87–12.17) P = 0.080 ns
Allele carriage
 ≥1 232I allele P = 0.103 0.41 (0.17–0.97) P = 0.043 ns P = 0.239 0.40 (0.12–1.33) P = 0.133 ns
 ≥1 232T allele P = 0.231 1.49 (0.84–2.62) P = 0.171 ns P = 0.317 1.81 (0.77–4.28) P = 0.175 ns
FcγRIIIa (rs396991)
Genotype
 158F/FF/FF (ref) 1 1
 158FV/FFV/FVV P = 0.010 0.51 (0.28–0.92) P = 0.026 ns P = 0.672 1.09 (0.45–2.64) P = 0.850 ns
 158V/VV P = 0.041 0.30 (0.11–082) P = 0.018 ns P = 0.266 0.20 (0.02–1.70) P = 0.141 ns
Allele carriage
 ≥1 158F allele P = 0.217 2.29 (0.89–5.88) P = 0.084 ns P = 0.183 5.22 (0.67–40.41) P = 0.114 ns
 ≥1 158V allele P = 0.004 0.46 (0.26–0.82) P = 0.008 ns P = 0.980 0.89 (0.37–2.12) P = 0.786 ns
FcγRIIIb
Genotype
 HNA1a+/1b−/1c− P = 0.315 0.47 (0.20–1.10) P = 0.083 ns P = 0.276 0.45 (0.12–1.61) P = 0.218 ns
 HNA1a−/1b+/1c− P = 0.668 0.90 (0.33–2.46) P = 0.839 ns P = 0.837 1.31 (0.35–4.87) P = 0.683 ns
 HNA1a−/1b−/1c+ – – – –
 HNA1a+/1b+/1c− (ref) 1 1
 HNA1a+/1b−/1c+ P = 0.448 0.63 (0.26–1.51) P = 0.300 ns P = 0.727 0.68 (0.19–2.42) P = 0.547 ns
 HNA1a−/1b+/1c+ P = 0.066 1.37 (0.59–3.19) P = 0.466 ns P = 0.502 1.20 (0.35–4.15) P = 0.777 ns
 HNA1a+/1b+/1c+ P = 0.849 0.42 (0.10–1.71) P = 0.226 ns P = 0.916 0.42 (0.05–3.72) P = 0.433 ns
Allele carriage
 ≥1 HNA1a allotype P = 0.369 0.78 (0.43–1.44) P = 0.433 ns P = 0.648 0.73 (0.30–1.75) P = 0.481 ns
 ≥1 HNA1b allotype P = 0.025 2.11 (1.16–3.85) P = 0.014 ns P = 0.099 2.18 (0.90–5.33) P = 0.086 ns
 ≥1 HNA1c allotype P = 0.599 0.95 (0.54–1.68) P = 0.865 ns P = 0.869 0.88 (0.38–2.04) P = 0.759 ns
In utero transmitting In utero-enriched transmitting
Univariate Adjusted for VL + bwt PBonf Univariate Adjusted for VL PBonf
AOR (95 % CI) P value AOR (95 % CI) P value
FcγRIIa (rs1801274)
Genotype
 131HH (ref) 1 1
 131HR P = 0.241 5.74 (0.66–49.93) P = 0.113 ns P = 0.447 2.28 (0.84–6.17) P = 0.105 ns
 131RR P = 0.085 11.46 (1.29–101.86) P = 0.029 ns P = 0.225 2.82 (1.01–7.89) P = 0.048 ns
Allele carriage
 ≥1 131H allele P = 0.143 0.34 (0.12–0.97) P = 0.045 ns P = 0.383 0.63 (0.32–1.27) P = 0.200 ns
 ≥1 131R allele P = 0.136 7.65 (0.94–62.32) P = 0.057 ns P = 0.314 2.50 (0.97–6.40) P = 0.057 ns
FcγRIIb (rs1050501)
Genotype
 232II (ref) 1
 232IT P = 0.434 0.67 (0.22–2.06) P = 0.487 ns P = 0.678 1.15 (0.56–2.35) P = 0.707 ns
 232TT P = 0.153 3.38 (0.73–15.61) P = 0.119 ns P = 0.121 2.57 (0.85–7.74) P = 0.094 ns
Allele carriage
 ≥1 232I allele P = 0.072 0.25 (0.06–1.07) P = 0.062 ns P = 0.133 0.42 (0.15–1.18) P = 0.100 ns
 ≥1 232T allele P = 0.883 0.93 (0.34–2.54) P = 0.891 ns P = 0.403 1.33 (0.67–2.61) P = 0.412 ns
FcγRIIIa (rs396991)
Genotype
 158F/FF/FF (ref) 1 1
 158FV/FFV/FVV P = 0.108 0.60 (0.21–1.71) P = 0.341 ns P = 0.0001 0.29 (0.14–0.63) P = 0.002 ns
 158V/VV P = 0.115 0.19 (0.02–1.68) P = 0.135 ns P = 0.069 0.34 (0.11–0.98) P = 0.046 ns
Allele carriage
 ≥1 158F allele P = 0.222 4.01 (0.48–33.16) P = 0.198 ns P = 0.562 1.71 (0.61–4.80) P = 0.305 ns
 ≥1 158V allele P = 0.048 0.50 (0.18–1.36) P = 0.174 ns P = 0.0001 0.31 (0.15–0.62) P = 0.001 0.042
FcγRIIIb
Genotype
 HNA1a+/1b−/1c− P = 0.155 1.44 (0.30–6.85) P = 0.644 ns P = 0.612 0.45 (0.16–1.24) P = 0.124 ns
 HNA1a−/1b+/1c− P = 0.971 1.26 (0.12–13.63) P = 0.851 ns P = 0.429 0.66 (0.17–2.56) P = 0.544 ns
 HNA1a−/1b−/1c+ – – – –
 HNA1a+/1b+/1c− (ref) 1 1
 HNA1a+/1b−/1c+ P = 0.267 1.88 (0.37–9.46) P = 0.442 ns P = 0.448 0.59 (0.20–1.68) P = 0.321 ns
 HNA1a−/1b+/1c+ P = 0.028 3.10 (0.60–15.95) P = 0.177 ns P = 0.047 1.53 (0.58–4.02) P = 0.388 ns
 HNA1a+/1b+/1c+ P = 0.562 1.10 (0.10–12.45) P = 0.939 ns P = 0.723 0.44 (0.08–2.28) P = 0.326 ns
Allele carriage
 ≥1 HNA1a allotype P = 0.638 0.85 (0.28–2.63) P = 0.783 ns P = 0.388 0.79 (0.38–1.64) P = 0.523 ns
 ≥1 HNA1b allotype P = 0.659 1.09 (0.39–3.02) P = 0.868 ns P = 0.085 2.23 (1.08–4.62) P = 0.031 ns
 ≥1 HNA1c allotype P = 0.262 1.51 (0.55–4.14) P = 0.420 ns P = 0.560 1.04 (0.53–2.06) P = 0.904 ns
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aThe multivariate analysis adjusted for demographic and clinical variables that independently associated with transmission. Due to high correlation with viral load, CD4 T cell counts were not included in the multivariate model

P values less than 0.05 are indicated in italics

P Bonf Bonferroni corrected P value, AOR adjusted odds ratio, CI confidence interval, VL viral load, bwt birth weight, ns not statistically significant, –, the variable of interest was not detected in any of the cases and thus could not be analysed

Carriage of at least one maternal FcγRIIIa-158V allele (confers enhanced antibody binding affinity) associated with a reduced odds of perinatal HIV-1 transmission (OR 0.47, 95 % CI 0.28–0.79, P = 0.004). When analysed according to mode of transmission, a similar association was observed for the in utero transmitting group (OR 0.39, 95 % CI 0.16–0.99, P = 0.048) and in utero-enriched transmitting group (OR 0.29, 95 % CI 0.15–0.55, P = 0.0001), but not for the intrapartum transmitting group (OR 1.01, 95 % CI 0.45–2.25, P = 0.980). These associations remained significant for the total transmitting group and in utero-enriched group in the multivariate analysis (P = 0.008 and P = 0.001, respectively) and for the in utero-enriched group after adjustment for multiple comparisons (univariate: PBonf = 0.004; multivariate: PBonf = 0.042).

Possession of an FcγRIIIb-HNA1b allele (modulates neutrophil function) significantly associated with an increased odds of HIV-1 transmission in both the univariate analysis (OR 1.87, 95 % CI 1.08–3.21, P = 0.025) and multivariate analysis (P = 0.014). A similar association was observed for the FcγRIIIb-HNA1b|1c genotype in the in utero transmitting group (OR 5.45, 95 % CI 1.21–24.66, P = 0.028) and in utero-enriched transmitting group (OR 2.45, 95 % CI 1.01–5.96, P = 0.047). However, these associations were not significant in the multivariate analysis.

The FcγRIIa-H131R and FcγRIIb-I232T variants did not associate with perinatal HIV-1 transmission in the univariate analysis. However, after adjustment for confounding variables, the FcγRIIa-131RR genotype (receptor has reduced affinity for IgG2) and FcγRIIb-232TT genotype (confers reduced inhibitory capacity) associated with increased odds of HIV-1 transmission (Table 3).

FcγR variants and susceptibility of the recipient/infant

In addition to an association observed in the mother, the infant FcγRIIIb-HNA1a|b|c variant also associated with susceptibility to HIV-1 acquisition in the infant (P = 0.046). In particular, carriage of least one FcγRIIIb-HNA1b allotype significantly associated with increased susceptibility to HIV-1 acquisition in the univariate analysis (OR 1.91, 95 % CI 1.11–3.30, P = 0.020; Table 4) and multivariate analysis (P = 0.019; Table 5). Conversely, homozygosity for the FcγRIIIb-HNA1a allotype associated with reduced odds of HIV-1 acquisition in the total infected group (OR 0.42, 95 % CI 0.18–0.96, P = 0.040) and intrapartum infected group (OR 0.19, 95 % CI 0.04–0.89, P = 0.035). The protective effect of FcγRIIIb-HNA1a homozygosity was also observed when compared to other allotype combinations, however not all comparisons remained significant in the multivariate analysis (Additional file 2: Table S2).

Table 4.

FcγR genotypes and allele carriage in HIV-1 exposed-uninfected and infected infants

Exposed-uninfected Total infected Intrapartum infected
N (%) N (%) OR (95 % CI) P value PBonf N (%) OR (95 % CI) P value PBonf
FcγRIIa (rs1801274) Overall association P = 0.704 ns P = 0.907 ns
Genotype
 131HH (ref) 47 (20.0) 19 (24.4) 1 7 (22.6) 1
 131HR 116 (49.4) 36 (46.2) 0.77 (0.40–1.47) P = 0.426 ns 14 (45.2) 0.81 (0.31–2.13) P = 0.670 ns
 131RR 72 (30.6) 23 (29.5) 0.79 (0.39–1.61) P = 0.516 ns 10 (32.3) 0.93 (0.33–2.62) P = 0.895 ns
Allele carriage
 ≥1 131H allele 163 (69.4) 55 (70.5) 1.06 (0.60–1.85) P = 0.848 ns 21 (67.7) 0.93 (0.42–2.07) P = 0.854 ns
 ≥1 131R allele 188 (80.0) 59 (75.6) 0.76 (0.42–1.43) P = 0.414 ns 24 (77.4) 0.86 (0.35–2.11) P = 0.737 ns
FcγRIIb (rs1050501) Overall association P = 0.278 ns P = 0.773 ns
Genotype
 232II (ref) 116 (49.4) 33 (42.3) 1 14 (45.2) 1
 232IT 90 (38.3) 30 (38.5) 1.17 (0.67–2.06) P = 0.583 ns 12 (38.7) 1.10 (0.49–2.51) P = 0.811 ns
 232TT 29 (12.3) 15 (19.2) 1.82 (0.87–3.79) P = 0.110 ns 5 (16.1) 1.43 (0.48–4.29) P = 0.525 ns
Allele carriage
 ≥1 232I allele 206 (86.8) 63 (78.6) 0.59 (0.30–1.17) P = 0.132 ns 26 (83.9) 0.73 (0.26–2.06) P = 0.554 ns
 ≥1 232T allele 119 (47.2) 45 (55.7) 1.33 (0.79–2.23) P = 0.280 ns 17 (54.8) 1.18 (0.56–2.51) P = 0.660 ns
FcγRIIIa (rs396991) Overall association P = 0.339 ns P = 0.964 ns
Genotype
 158F/FF/FF (ref) 86 (36.6) 34 (43.6) 1 12 (38.7) 1
 158FV/FFV/FVV 118 (50.2) 38 (48.7) 0.81 (0.47–1.40) P = 0.456 ns 15 (48.4) 0.91 (0.41–2.04) P = 0.821 ns
 158V/VV 31 (13.2) 6 (7.7) 0.49 (0.19–1.28) P = 0.145 ns 4 (12.9) 0.92 (0.28–3.08) P = 0.899 ns
Allele carriage
 ≥1 158F allele 194 (82.6) 72 (92.3) 0.75 (0.44–1.26) P = 0.272 ns 27 (87.1) 0.91 (0.42–1.97) P = 0.819 ns
 ≥1 158V allele 149 (63.4) 44 (56.4) 1.82 (0.73–4.55) P = 0.198 ns 19 (61.3) 1.03(0.34–3.13) P = 0.964 ns
FcγRIIIb Overall association P = 0.046 ns P = 0.023 ns
Genotype
 HNA1a+/1b−/1c− 58 (24.7) 9 (11.5) 0.42 (0.18–0.96) P = 0.040 ns 2 (6.5) 0.19(0.04–0.89) P = 0.035 ns
 HNA1a−/1b+/1c− 25 (10.6) 7 (9.0) 0.76 (0.29–1.95) P = 0.565 ns 1 (3.2) 0.22 (0.03–1.81) P = 0.160 ns
 HNA1a−/1b−/1c+ 14 (6.0) 4 (5.1) 0.77 (0.23–2.55) P = 0.672 ns 0 (0) –
 HNA1a+/1b+/1c− (ref) 73 (31.2) 27 (34.6) 1 13 (41.9) 1
 HNA1a+/1b−/1c+ 36 (15.3) 11 (14.1) 0.83 (0.37–1.85) P = 0.643 ns 7 (22.6) 1.09 (0.40–2.97) P = 0.863 ns
 HNA1a−/1b+/1c+ 22 (9.4) 13 (16.7) 1.60 (0.71–3.61) P = 0.260 ns 7 (22.6) 1.79 (0.63–5.03) P = 0.272 ns
 HNA1a+/1b+/1c+ 7 (3.0) 7 (9.0) 2.70 (0.87–8.43) P = 0.086 ns 1 (3.2) 0.80 (0.09–7.07) P = 0.843 ns
Allele carriage
 ≥1 HNA1a allotype 174 (74.0) 54 (69.2) 0.79 (0.45–1.38) P = 0.408 ns 23 (74.2) 1.01 (0.43–2.37) P = 0.986 ns
 ≥1 HNA1b allotype 127 (54.0) 54 (69.2) 1.91 (1.11–3.30) P = 0.020 ns 22 (71.0) 2.08 (0.92–4.70) P = 0.079 ns
 ≥1 HNA1c allotype 79 (33.6) 35 (44.9) 1.61 (0.95–2.71) P = 0.075 ns 15 (48.4) 1.85 (0.87–3.94) P = 0.110 ns
In utero infected In utero-enriched infected
N (%) OR (95 % CI) P value PBonf N (%) OR (95 % CI) P value PBonf
FcγRIIa (rs1801274) P = 0.265 ns P = 0.693 ns
Genotype
 131HH (ref) 4 (21.1) 1 12 (25.5) 1
 131HR 6 (31.6) 0.61 (0.16–2.25) P = 0.456 ns 22 (46.8) 0.74 (0.34–1.62) P = 0.455 ns
 131RR 9 (47.4) 1.47 (0.43–5.04) P = 0.541 ns 13 (27.7) 0.71 (0.30–1.68) P = 0.433 ns
Allele carriage
 ≥1 131H allele 10 (52.6) 0.49 (0.19–1.26) P = 0.139 ns 34 (72.3) 1.16 (0.58–2.32) P = 0.685 ns
 ≥1 131R allele 15 (78.9) 0.94 (0.30–2.96) P = 0.912 ns 35 (74.5) 0.73 (0.35–1.51) P = 0.396 ns
FcγRIIb (rs1050501) P = 0.083 ns P = 0.218 ns
Genotype
 232II (ref) 7 (36.8) 1 19 (40.4) 1
 232IT 6 (31.6) 1.10 (0.36–3.40) P = 0.862 ns 18 (38.3) 1.22 (0.61–2.46) P = 0.577 ns
 232TT 6 (31.6) 3.43 (1.07–10.98) P = 0.038 ns 10 (21.3) 2.11 (0.88–5.01) P = 0.092 ns
Allele carriage
 ≥1 232I allele 13 (68.4) 0.31 (0.11–0.87) P = 0.026 ns 37 (78.7) 0.52 (0.23–1.16) P = 0.110 ns
 ≥1 232T allele 12 (63.2) 1.67 (0.64–4.39) P = 0.298 ns 28 (59.6) 1.44 (0.76–2.71) P = 0.264 ns
FcγRIIIa (rs396991) P = 0.711 ns P = 0.145 ns
Genotype
 158F/FF/FF (ref) 9 (47.4) 1 22 (46.8) 1
 158FV/FFV/FVV 8 (42.1) 0.65 (0.24–1.75) P = 0.391 ns 23 (48.9) 0.76 (0.40–1.46) P = 0.410 ns
 158V/VV 2 (10.5) 0.62 (0.13–3.01) P = 0.550 ns 2 (4.3) 0.25 (0.06–1.14) P = 0.073 ns
Allele carriage
 ≥1 158F allele 17 (89.5) 0.64 (0.25–1.64) P = 0.354 ns 45 (95.7) 0.66 (0.35–1.23) P = 0.190 ns
 ≥1 158V allele 10 (52.6) 1.29 (0.28–5.87) P = 0.740 ns 25 (53.2) 3.42 (0.79–14.81) P = 0.100 ns
FcγRIIIb P = 0.182 ns P = 0.079 ns
Genotype
 HNA1a+/1b−/1c− 3 (15.8) 0.76 (0.17–3.29) P = 0.709 ns 7 (14.9) 0.63 (0.24–1.66) P = 0.350 ns
 HNA1a−/1b+/1c− 1 (5.3) 0.58 (0.07–5.24) P = 0.631 ns 6 (12.8) 1.25 (0.43–3.61) P = 0.678 ns
 HNA1a−/1b−/1c+ 1 (5.3) 1.04 (0.11–9.62) P = 0.970 ns 4 (8.5) 1.49 (0.43–5.20) P = 0.532 ns
 HNA1a+/1b+/1c− (ref) 5 (26.3) 1 14 (29.8) 1
 HNA1a+/1b−/1c+ 2 (10.5) 0.81 (0.15–4.39) P = 0.808 ns 4 (8.5) 0.58 (0.18–1.89) P = 0.365 ns
 HNA1a−/1b+/1c+ 5 (26.3) 3.32 (0.88–12.52) P = 0.077 ns 6 (12.8) 1.42 (0.49–4.14) P = 0.518 ns
 HNA1a+/1b+/1c+ 2 (10.5) 4.17 (0.68–25.59) P = 0.123 ns 6 (12.8) 4.47 (1.30–15.31) P = 0.017 ns
Allele carriage
 ≥1 HNA1a allotype 12 (63.2) 0.60 (0.23–1.60) P = 0.307 ns 31 (66.0) 0.70 (0.35–1.33) P = 0.258 ns
 ≥1 HNA1b allotype 13 (68.4) 1.84 (0.68–5.01) P = 0.231 ns 32 (68.1) 1.81 (0.93–3.53) P = 0.079 ns
 ≥1 HNA1c allotype 10 (52.6) 2.19 (0.86–5.62) P = 0.101 ns 20 (42.6) 1.46 (0.77–2.77) P = 0.243 ns
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P values less than 0.05 are indicated in italics

P Bonf Bonferroni corrected P value, OR odds ratio, CI confidence interval, ns not statistically significant, –, the variable of interest was not detected in any of the cases and thus could not be analysed

Table 5.

Infant FcγR variants associated with perinatal HIV-1 acquisition after adjusting for confounding variables

Total infected Intrapartum infected
Univariate Adjusted for VLa PBonf Univariate Adjusted for VL PBonf
AOR (95 % CI) P value AOR (95 % CI) P value
FcγRIIa (rs1801274)
Genotype
 131HH (ref) 1 1
 131HR P = 0.426 0.79 (0.38–1.62) P = 0.519 ns P = 0.670 0.80 (0.27–2.32) P = 0.685 ns
 131RR P = 0.516 0.84 (0.39–1.83) P = 0.657 ns P = 0.895 0.97 (0.31–2.97) P = 0.951 ns
Allele carriage
 ≥1 131H allele P = 0.848 1.01 (0.55–1.85) P = 0.970 ns P = 0.854 0.89 (0.37–2.12) P = 0.792 ns
 ≥1 131R allele P = 0.414 0.81 (0.41–1.59) P = 0.536 ns P = 0.737 0.87 (0.32–2.32) P = 0.774 ns
FcγRIIb (rs1050501)
Genotype
 232II (ref) 1 1
 232IT P = 0.583 1.29 (0.70–2.39) P = 0.415 ns P = 0.811 1.40 (0.57–3.44) P = 0.469 ns
 232TT P = 0.110 1.97 (0.89–4.37) P = 0.096 ns P = 0.525 1.82 (0.56–5.90) P = 0.317 ns
Allele carriage
 ≥1 232I allele P = 0.132 0.57 (0.28–1.20) P = 0.140 ns P = 0.554 0.65 (0.22–1.90) P = 0.429 ns
 ≥1 232T allele P = 0.280 1.46 (0.83–2.57) P = 0.195 ns P = 0.660 1.50 (0.65–3.47) P = 0.344 ns
FcγRIIIa (rs396991)
Genotype
 158F/FF/FF (ref) 1 1
 158FV/FFV/FVV P = 0.456 0.87 (0.49–1.56) P = 0.647 ns P = 0.821 1.14 (0.49–2.66) P = 0.764 ns
 158V/VV P = 0.145 0.28 (0.08–1.00) P = 0.051 ns P = 0.899 0.28 (0.03–2.27) P = 0.232 ns
Allele carriage
 ≥1 158F allele P = 0.272 3.34 (0.96–11.57) P = 0.058 ns P = 0.819 3.89 (0.50–30.31) P = 0.194 ns
 ≥1 158V allele P = 0.198 0.75 (0.43–1.31) P = 0.311 ns P = 0.964 0.95 (0.42–2.19) P = 0.910 ns
FcγRIIIb
Genotype
 HNA1a+/1b−/1c− P = 0.040 0.37 (0.15–0.92) P = 0.033 ns P = 0.035 0.20 (0.04–0.96) P = 0.044 ns
 HNA1a−/1b+/1c− P = 0.565 0.69 (0.25–1.86) P = 0.459 ns P = 0.160 0.20 (0.03–1.69) P = 0.139 ns
 HNA1a−/1b−/1c+ P = 0.672 0.70 (0.18–2.78) P = 0.616 ns – – P = 0.970
 HNA1a+/1b+/1c− (ref) 1 1
 HNA1a+/1b−/1c+ P = 0.643 0.73 (0.31–1.72) P = 0.478 ns P = 0.863 0.97 (0.33–2.79) P = 0.949 ns
 HNA1a−/1b+/1c+ P = 0.260 1.57 (0.64–3.88) P = 0.326 ns P = 0.272 1.80 (0.57–5.71) P = 0.316 ns
 HNA1a+/1b+/1c+ P = 0.086 2.36 (0.63–8.75) P = 0.201 ns P = 0.843 – ns P = 0.123
Allele carriage
 ≥1 HNA1a allotype P = 0.408 0.79 (0.43–1.46) P = 0.452 ns P = 0.986 1.01 (0.40–2.56) P = 0.981 ns
 ≥1 HNA1b allotype P = 0.020 2.02 (1.12–3.64) P = 0.019 ns P = 0.079 1.91 (0.81–4.53) P = 0.140 ns
 ≥1 HNA1c allotype P = 0.075 1.52 (0.86–2.69) P = 0.146 ns P = 0.110 1.74 (0.77–3.96) P = 0.185 ns
In utero infected In utero-enriched infected
Univariate Adjusted for VL + bwt PBonf Univariate Adjusted for VL PBonf
AOR (95 % CI) P value AOR (95 % CI) P value
FcγRIIa (rs1801274)
Genotype
 131HH (ref) 1 1
 131HR P = 0.456 0.71 (0.15–3.25) P = 0.657 ns P = 0.455 0.75 (0.32–1.79) P = 0.520 ns
 131RR P = 0.541 1.87 (0.45–7.79) P = 0.390 ns P = 0.433 0.77 (0.30–1.96) P = 0.581 ns
Allele carriage
 ≥1 131H allele P = 0.139 0.42 (0.15–1.21) P = 0.108 ns P = 0.685 1.07 (0.51–2.22) P = 0.858 ns
 ≥1 131R allele P = 0.912 1.17 (0.31–4.58) P = 0.817 ns P = 0.396 0.76 (0.34–1.70) P = 0.503 ns
FcγRIIb (rs1050501)
Genotype
 232II (ref) 1 1
 232IT P = 0.862 0.80 (0.23–2.74) P = 0.724 ns P = 0.577 1.18 (0.56–2.50) P = 0.658 ns
 232TT P = 0.038 3.53 (0.95–13.14) P = 0.060 ns P = 0.092 2.02 (079–5.16) P = 0.144 ns
Allele carriage
 ≥1 232I allele P = 0.026 0.26 (0.08–0.86) P = 0.028 ns P = 0.110 0.54 (0.23–1.28) P = 0.160 ns
 ≥1 232T allele P = 0.298 1.33 (0.47–3.77) P = 0.593 ns P = 0.264 1.38 (0.70–2.74) P = 0.353 ns
FcγRIIIa (rs396991)
Genotype
 158F/FF/FF (ref) 1 1
 158FV/FFV/FVV P = 0.391 0.61 (0.20–1.86) P = 0.385 ns P = 0.410 0.74 (0.37–1.49) P = 0.405 ns
 158V/VV P = 0.550 0.85 (0.16–4.42) P = 0.842 ns P = 0.073 0.29 (0.06–1.36) P = 0.117 ns
Allele carriage
 ≥1 158F allele P = 0.354 0.93 (0.19–4.53) P = 0.931 ns P = 0.190 2.91 (0.66–12.92) P = 0.160 ns
 ≥1 158V allele P = 0.740 0.66 (0.23–1.85) P = 0.425 ns P = 0.100 0.65 (0.33–1.28) P = 0.215 ns
FcγRIIIb
Genotype
 HNA1a+/1b−/1c− P = 0.709 0.77 (0.15–3.86) P = 0.748 ns P = 0.350 0.53 (0.18–1.52) P = 0.234 ns
 HNA1a−/1b+/1c− P = 0.631 0.46 (0.04–4.76) P = 0.513 ns P = 0.678 1.13 (0.37–3.42) P = 0.827 ns
 HNA1a−/1b−/1c+ P = 0.970 1.48 (0.14–15.83) P = 0.744 ns P = 0.532 1.33 (0.32–5.54) P = 0.695 ns
 HNA1a+/1b+/1c− (ref) 1 1
 HNA1a+/1b−/1c+ P = 0.808 0.65 (0.10–4.10) P = 0.645 ns P = 0.365 0.50 (0.15–1.67) P = 0.259 ns
 HNA1a−/1b+/1c+ P = 0.077 4.47 (0.84–23.80) P = 0.080 ns P = 0.518 1.50 (0.46–4.92) P = 0.501 ns
 HNA1a+/1b+/1c+ P = 0.123 3.35 (0.40–27.73) P = 0.262 ns P = 0.017 4.44 (1.14–17.40) P = 0.032 ns
Allele carriage
 ≥1 HNA1a allotype P = 0.307 0.58 (0.19–1.76) P = 0.337 ns P = 0.258 0.66 (0.32–1.37) P = 0.265 ns
 ≥1 HNA1b allotype P = 0.231 1.82 (0.63–5.32) P = 0.271 ns P = 0.079 2.16 (1.05–4.44) P = 0.037 ns
 ≥1 HNA1c allotype P = 0.101 2.16 (0.76–6.14) P = 0.149 ns P = 0.243 1.42 (0.71–2.81) P = 0.321 ns
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P values less than 0.05 are indicated in italics

P Bonf Bonferroni corrected P value, AOR adjusted odds ratio, CI confidence interval, VL viral load, bwt birth weight, –, the variable of interest was not detected in any of the cases and thus could not be analysed

aThe multivariate analysis adjusted for demographic and clinical variables that independently associated with transmission. Due to high correlation with viral load, CD4 T cell counts were not included in the multivariate model

Linkage disequilibrium at the low affinity FCGR gene locus

Linkage disequilibrium (LD) between the different FcγR variants could potentially modulate associations observed for the individual FcγRs. Given the strong association of the maternal FcγRIIIa-F158V variant with perinatal HIV-1 transmission, we determined LD in the study cohort (Fig. 2) and adjusted for its possible confounding effect on the associations observed for FcγRIIIb-HNA1a|b|c, FcγRIIa-H131R and FcγRIIb-I232T in the multivariate analysis (Table 6).

Fig. 2.

Fig. 2

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LD for FcγR variants in the study cohort comprising Black South African HIV-1 infected mothers (left) and their infants (right). Values and colours reflect r2 (× 100) and D′/LOD measures of LD, respectively. The black triangle depicts a haplotype block that is indicative of the relationship between the FcγRIIIb-HNA1b and -HNA1c allotypes. Such that HNA1b and HNA1c are identical at amino acid position 65 (p.65S) and differ only at amino acid position 78 (p.78A1b>D1c)

Table 6.

Multivariate analysis adjusted FcγRIIIa-F158V

Multivariate, not adjusted for FcγRIIIa-F158V PBonf Multivariate analysis with adjustment for FcγRIIIa-F158V genotype and allele carriage
F158V genotype PBonf ≥1 158F allele PBonf ≥1 158V allele PBonf
Maternal
FcγRIIa (rs1801274)
131RR genotype
 Total transmitting P = 0.023 ns 1.93 (0.82–4.57), P = 0.133 ns 2.25 (0.97–5.24), P = 0.133 ns 2.08 (0.89–4.86), P = 0.091 ns
 In utero transmitting P = 0.029 ns 9.37 (1.01–87.22), P = 0.049 ns 9.59 (1.05–87.37), P = 0.045 ns 10.26 (1.12–94.28), P = 0.040 ns
 In utero-enriched transmitting P = 0.048 ns 1.94 (0.66–5.70), P = 0.226 ns 2.60 (0.90–7.52), P = 0.077 ns 1.98 (0.67–5.80), P = 0.214 ns
≥1 131H allele
 In utero transmitting P = 0.045 ns 0.42 (0.14–1.29), P = 0.132 ns 0.40 (0.14–1.15), P = 0.088 ns 0.39 (0.13–1.18), P = 0.096 ns
≥1 131R allele
 Total transmitting P = 0.049 ns 1.80 (0.84–3.85), P = 0.128 ns 1.90 (0.89–4.05), P = 0.095 ns 1.91 (0.90–4.06), P = 0.091 ns
FcγRIIb (rs1050501)
232TT genotype
 Total transmitting P = 0.030 ns 2.06 (0.78–5.41), P = 0.144 ns 2.48 (0.96–9.36), P = 0.060 ns 2.17 (0.83–5.67), P = 0.115 ns
≥1 232I allele
 Total transmitting P = 0.043 ns 0.49 (0.20–1.20), P = 0.118 ns 0.43 (0.18–1.05), P = 0.063 ns 0.48 (0.20–1.18), P = 0.110 ns
FcγRIIIb
≥1 HNA1b allotype
 Total transmitting P = 0.014 ns 2.26 (1.22–4.17), P = 0.009 ns 2.19 (1.20–4.02), P = 0.011 ns 2.21 (1.20–4.11), P = 0.011 ns
 In utero-enriched transmitting P = 0.031 ns 2.43 (1.15–5.16), P = 0.020 ns 2.32 (1.11–4.82), P = 0.025 ns 2.40 (1.13–5.10), P = 0.023 ns
Infant
FcγRIIIb
HNA1a+/1b−/1c− genotype
 Total infected P = 0.033 ns 0.37 (0.15–0.93), P = 0.034 ns 0.37 (0.15–0.91), P = 0.031 ns 0.37 (0.15–0.93), P = 0.034 ns
 Intrapartum infected P = 0.044 ns 0.20 (0.04–0.96), P = 0.044 ns 0.19 (0.04–0.95), P = 0.043 ns 0.20 (0.04–0.96), P = 0.044 ns
HNA1a+/1b+/1c+ genotype
 In utero-enriched infected P = 0.032 ns 5.67 (1.39–23.11), P = 0.016 ns 4.47 (1.13–17.64), P = 0.032 ns 5.74 (1.39–23.57), P = 0.015 ns
≥1 HNA1b allotype
 Total infected P = 0.019 ns 2.11 (1.16–3.83), P = 0.014 ns 2.04 (1.12–3.69), P = 0.019 ns 2.08 (1.15–3.77), P = 0.016 ns
 In utero-enriched infected P = 0.037 ns 2.29 (1.10–4.76), P = 0.026 ns 2.22 (1.07–4.58), P = 0.032 ns 2.26 (1.09–4.68), P = 0.028 ns
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P values less than 0.05 are indicated in italics

P Bonf Bonferroni corrected P value, AOR adjusted odds ratio, CI confidence interval, VL viral load, bwt birth weight, ns not statistically significant

–, the variable of interest was not detected in any of the cases and thus could not be analysed

To determine LD for the FcγRIIIb-HNA1a|b|c allotypes, we used, as a tag-variant, one of four amino acid changes that differentiate HNA1a from HNA1b and HNA1c (p.Na65Sbc, rs448740) as well as the variant that differentiates HNA1c from HNA1a and HNA1b (p.Aab78Dc, rs5030738). The maternal FcγRIIIb-Na65Sbc variant was not in LD with FcγRIIIa-F158V (P = 0.057, D′ = 0.189, r2 = 0.020), while the p.Aab78Dc variant was in moderate LD with FcγRIIIa-F158V (P = 0.024, D′ = 0.471, r2 = 0.029) with the FcγRIIIa-158V allele overrepresented in individuals bearing an FcγRIIIb-78A allele (HNA1c individuals) compared to FcγRIIIb-78DD individuals (59 vs. 20 %). Following adjustment for FcγRIIIa-F158V in the multivariate analysis, the associations previously observed for the FcγRIIIb-HNA1b allotype strengthened for both the total and in utero-enriched transmitting groups (Table 6). Similarly, significance was retained in the infants with associations strengthening for the FcγRIIIb-HNA1a+|1b+|1c+ genotype in the in utero-enriched infected group and carriage of an HNA1b allotype in the total infected and in utero-enriched infected groups (Table 6). Overall, this suggests that the observed associations between the FcγRIIIb-HNA1a|b|c variant and perinatal HIV-1 transmission are not only independent of FcγRIIIa-F158V, but also potentially negatively confounded by FcγRIIIa-F158V.

Both maternal FcγRIIa-H131R and FcγRIIb-I232T was in moderate LD with FcγRIIIa-F158V (P < 0.0001, D′ = 0.351, r2 = 0.077 and P = 0.002, D′ = 0.448, r2 = 0.052, respectively), with the FcγRIIIa-158V allele overrepresented in individuals bearing an FcγRIIa-131H allele compared to FcγRIIa-131RR individuals (66 vs. 39 %) and in individuals bearing an FcγRIIb-232I allele compared to FcγRIIb-232TT individuals (59 vs. 39 %). When adjusted for FcγRIIIa-F158V in the multivariate analysis, all associations for the FcγRIIa-H131R and FcγRIIb-I232T weakened with the majority losing significance (Table 6). This suggests that the associations observed for FcγRIIa-H131R and FcγRIIb-I232T potentially resulted from LD with FcγRIIIa-F158V.

Discussion

The extent to which FcγR-mediated effector mechanisms contribute to the risk of HIV-1 transmission and acquisition is currently undefined. Through the study of FcγR functional variants we indirectly demonstrated a role for FcγR-mediated effector functions in modulating perinatal HIV-1 transmission and acquisition. Our findings indicate that the FcγRIIIa-F158V variant that alters antibody binding affinity and functional capacity is associated with infectiousness of an HIV-1 infected mother, while the FcγRIIIb-HNA1a|b|c variant that affects neutrophil effector function is associated with both maternal infectiousness and infant susceptibility.

The significance of FcγR-mediated effector functions in maintaining immune homeostasis is validated by the association of functionally significant FcγR variants with immune disorders [18]. Here we describe an association between the high binding FcγRIIIa allele and reduced maternal infectiousness in perinatal transmission of HIV-1. In particular, carriage of the FcγRIIIa-158V allele by the mother was associated with ~50 % reduction in the odds of HIV-1 transmission. The significant association in the in utero-enriched transmission group, but not in the intrapartum group, suggests that the underlying mechanism may be more pronounced at the maternofoetal interface. FcγRIIIa-bearing leukocytes, including natural killer cells, macrophages and γδ T lymphocytes, are readily recruited to the decidua where they likely contribute to eliminating cell-associated HIV-1 through ADCC [19, 20]. While decidual natural killer cells are primarily FcγRIIIa negative during a healthy pregnancy, they likely upregulate FcγRIIIa expression in the presence of HIV-1 as demonstrated for other perinatally transmitted viruses—human cytomegalovirus and hepatitis C virus [21, 22]. Since cell-associated HIV-1 is thought to be more infectious in utero compared to cell-free virus [23], ADCC-mediated killing of HIV-1 infected cells may contribute to protective immunity at the maternofoetal interface. Of consequence, the FcγRIIIa-F158V variant impacts on ADCC capacity, such that the FcγRIIIa-158V allele exhibits enhanced IgG binding and ADCC capacity compared to the FcγRIIIa-158F allele [7, 24]. The decreased in utero transmission risk associated with the FcγRIIIa-158V allele suggests that the enhanced ADCC capacity conferred by this variant may potentiate elimination of cell-associated HIV-1 and reduce the odds of HIV-1 crossing the placenta through cell–cell interactions. However, the role of ADCC and other potential FcγRIIIa-mediated immune mechanisms—systemic or localized—in perinatal HIV-1 transmission needs to be further elucidated.

In contrast to that observed for the FcγRIIIa-F158V variant, an association between the FcγRIIIb-HNA1a|b|c allotype and perinatal HIV-1 transmission was observed in both the mother and infant. The different FcγRIIIb allotypes arise from multiple amino acid substitutions that do not alter antibody binding affinity, but affect the glycosylation and tertiary structure of the receptor [9, 24–26]. Neutrophils from FcγRIIIb-HNA1a homozygous donors have an enhanced phagocytic and respiratory burst capacity compared to neutrophils from FcγRIIIb-HNA1b homozygous donors [27, 28]. In the present study, homozygosity for the FcγRIIIb-HNA1a allotype in the infant was associated with reduced odds of HIV-1 acquisition compared to other allotype combinations. In both mother and infant, carriage of at least one FcγRIIIb-HNA1b allotype was associated with increased odds of HIV-1 acquisition. Since expression of FcγRIIIb is largely restricted to neutrophils, these findings suggest a potential role for neutrophil-mediated FcγR effector functions in modulating perinatal HIV-1 transmission and acquisition. The underlying mechanism may also involve basophils as FcγRIIIb is detected at low levels on a subset of this cell population, although its function here is unknown.

To date, only the FcγRIIa-H131R variant has been studied in perinatal HIV-1 transmission, with an association reported between the FcγRIIa-131HH genotype and increased infant susceptibility [29]. This association was however not observed in the present study. The contrasting findings are likely attributable to study design. In the Brouwer et al. study, infants were considered perinatally infected if PCR positive at or before 4 months of age where in the present study infant infection status was determined up to 6 weeks of age. The implication thereof is that the number of infants that acquired HIV-1 through breastfeeding is likely higher in the Brouwer et al. study compared to the 12.8 % in the present study. If this is the case, the findings of the Brouwer et al. study may be more representative of an association with HIV-1 transmission through breastfeeding, rather than in utero or intrapartum transmission.

Perinatal HIV-1 transmission is an attractive model in which to study the role of antibodies and their effector functions in HIV-1 protective immunity. This represents a natural situation where the individual at risk is passively immunized with HIV-1-specific antibodies through transplacental transfer of IgG [30, 31]. This model also affords the opportunity to study both members of the transmitting dyad, allowing the assessment of factors contributing to the infectiousness of the transmitter (mother) as well as the susceptibility of the recipient (infant). The findings of this study therefore not only highlight additional immunological factors associated with risk of perinatal HIV-1 transmission, but further support a role for FcγR-mediated effector functions in HIV-1 protective immunity. In particular, findings underscore a potential involvement of neutrophils in protection from HIV-1 transmission and a possible role of FcγR-mediated effector functions in modulating the infectiousness of an HIV-1 infected individual. The significance of these findings in the context of sexual transmission will need to be determined.

There are a number of limitations of the current study and areas that require further investigation. Due to the small sample size and number of comparisons performed it is likely that a number of associations are due to chance. However, since the adjustment for multiple comparisons eliminate type I errors at the cost of type 2 errors, we considered it more important to identify potential factors that may play a role in perinatal HIV-1 transmission rather than dismissing these leads as chance variations brought about by multiple comparisons. Nonetheless, when a Bonferroni correction is applied (α = 0.0012), the association with the maternal FcγRIIIa-F158V variant in the in utero-enriched transmitting group remains significant.

Conclusions

The maternal and infant immune mechanisms involved in modulating the risk of perinatal HIV-1 transmission and acquisition are complex and multifactorial. Using the approach of studying FcγR genetic variants as proxy for functional capability, this study has revealed the potential importance of FcγR-mediated immune mechanisms that likely involve FcγRIIIa-bearing immune cells and neutrophils. The findings of this study need to be validated in larger cohorts, in particular associations that did not retain significance following adjustment for multiple comparisons. Moreover, understanding the role of IgG Fc-mediated mechanisms requires an appreciation for the collective contribution of multiple components in addition to FcγR genetic variants. These include factors such as the magnitude and specificity of maternal HIV-1 specific antibodies, the efficiency of antibody transfer across the placenta, immune cell phenotypes at the sites of HIV-1 exposure, and the impact of the overall immune environment and state of activation on maternal and infant immune responses.

Methods

Study populations

All study participants were Black South African individuals. Ethical clearance was obtained from the University of the Witwatersrand Human Research Ethics Committee and the Institutional Review Board of Columbia University. Written informed consent was obtained from all participants.

Cohort HIV-1 infection status

Maternal HIV-1 RNA levels were determined using the Roche Amplicor RNA Monitor assay version 1.5 (Roche Diagnostic Systems, Inc., Branchburg, New Jersey, USA). CD4+ T cell counts were determined using the FACSCount System from Becton–Dickinson (San Jose, CA, USA). Infant samples were tested for HIV-1 DNA using the Roche Amplicor Monitor version 1.5 qualitative PCR assay (Roche Diagnostic Systems).

FCGR gene copy number variability and nucleotide variant detection

Genomic DNA was extracted from EDTA anticoagulated blood samples using the QIAamp DNA Mini Kit (Qiagen, Dusseldorf, Germany). Functional FCGR variants were genotyped using the FCGR-specific multiplex ligation-dependent probe amplification (MLPA) assay (MRC Holland, Amsterdam, The Netherlands) according to manufacturer’s instructions [19, 20]. The assay detects the genomic copy number of the FCGR2C, FCGR3A and FCGR3B genes and known functional allelic variants that include FcγRIIa-H131R; FcγRIIb-I232T, FcγRIIIa-F158V, FcγRIIIb-HNA1a|b|c, FCGR2C expression variants (p.X57Q and c.798+1A>G), and the FCGR2B/C promoter variants (c.-386G>C and c.-120T>A). Genotypes assigned to study participants according to the MLPA assay were confirmed on randomly selected samples with nucleotide sequencing or TaqMan® SNP Genotyping Assays (Thermofisher, Life Technologies, Foster City, USA).

Computational and statistical analysis

Univariate analyses were used to determine the association between FcγR functional variants and perinatal HIV-1 transmission. Multivariate logistic regression was used to adjust for available confounders that were independently significantly associated with HIV-1 transmission i.e. viral load (all groups) and birth weight (in utero transmitting group) (Table 1). Due to high correlation with viral load, CD4 T+ cell count was not included in the multivariate model. The t test was used to compare normally distributed continuous variables and the Fisher’s exact test for categorical data. All analyses were performed in STATA version 10.1 (StataCorp LP, College Station, USA) and a P value of less than 0.05 was considered statistically significant. Adjustment for multiple comparisons was performed using the Bonferroni correction, which considered 42 independent tests—mothers and infants, three unrelated clinical subgroups, and seven loci (FCGR3A gene copy number, FCGR3B gene copy number, FcγRIIa-H131R, FcγRIIb-I232T, FcγRIIIa-F158V, FcγRIIIb-HNA1a|b|c, and overall FcγR variability profiles).

LD between pairs of biallelic loci was tested using an expectation–maximization likelihood-ratio test with 16 000 permutations (significance level <0.05) in Arlequin ver 3.5.2.2 [32]. LD coefficients (D′ and r2) were determined in Haploview [33]. Only individuals bearing two copies of each low affinity FCGR gene were considered. LD with FcγRIIIb-HNA1a|b|c was assessed using two loci: rs448740 (p.N65S; as tag-variant) that differentiates HNA1a (p.65 N) from HNA1b|c (p.65S) and rs5030738 (p.A78D) that differentiates HNA1a|b (p.78A) from HNA1c (p.78D).

Authors’ contributions

RL performed the researched and wrote the paper. AM and RL performed data analysis. GG recruited patients and acquired clinical data. LK contributed to the design of the study. CT designed the study and supervised the research. All co-authors critically revised the manuscript for intellectual content. All authors read and approved the manuscript.

Acknowledgements

The authors thank the study participants and Dorothy Southern for her review of the manuscript. This work is based on the research supported by grants from NICHD (HD 42402), the South African Medical Research Council and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation. Ria Lassauniere is the recipient of bursaries from the South African National Research Foundation, the Poliomyelitis Research Foundation and a University of the Witwatersrand postgraduate merit award.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Competing interests

The authors declare that they have no competing interests.

Abbreviations

ADCC

antibody-dependent cellular cytotoxicity

ADCP

antibody-dependent cellular phagocytosis

AOR

adjusted odds ratio

CI

confidence interval

CNV

copy number variability

DNA

deoxyribonucleic acid

Fc

fragment, crystallisable

FcγR

Fc gamma receptors

HIV

human immunodeficiency virus

HNA

human neutrophil antigen

IgG

immunoglobulin G

MLPA

multiplex ligation-dependent probe amplification

PCR

polymerase chain reaction

RNA

ribonucleic acid

sdNVP

single dose nevirapine

Additional files

12977_2016_272_MOESM1_ESM.docx (25.8KB, docx)

10.1186/s12977-016-0272-y Associations of maternal and infant FCGR3A and FCGR3B gene copy number with perinatal HIV-1 transmission. Univariate and multivariate analysis of associations of maternal and infant FCGR3A and FCGR3B gene copy number with perinatal HIV-1 transmission.

12977_2016_272_MOESM2_ESM.docx (21.7KB, docx)

10.1186/s12977-016-0272-y Association of the FcγRIIIb-HNA1a homozygous genotype with perinatal HIV-1 acquisition when compared to other combinations of FcγRIIIb-HNA allotypes. Univariate and multivariate analysis of associations of the FcγRIIIb-HNA1a homozygous genotype with perinatal HIV-1 acquisition when compared to other combinations of FcγRIIIb-HNA allotypes.

Contributor Information

Ria Lassaunière, Email: rial@nicd.ac.za.

Alfred Musekiwa, Email: ydm4@cdc.gov.

Glenda E. Gray, Email: Glenda.Gray@mrc.ac.za

Louise Kuhn, Email: lk24@cumc.columbia.edu.

Caroline T. Tiemessen, Email: carolinet@nicd.ac.za

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