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  • Open Access

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

  • 1, 2,
  • 3,
  • 4,
  • 5, 6 and
  • 1, 2Email author
Retrovirology201613:40

https://doi.org/10.1186/s12977-016-0272-y

  • Received: 22 September 2015
  • Accepted: 1 June 2016
  • Published:

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.

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 [1416], 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)

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

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

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

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

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

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

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

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, 2426]. 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).

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

Declarations

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.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Centre for HIV and STIs, National Institute for Communicable Diseases (NHLS), Johannesburg, South Africa
(2)
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
(3)
International Emerging Infections Programme, South Africa Global Disease Detection Centre, Centers for Disease Control and Prevention (CDC), Pretoria, South Africa
(4)
Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa
(5)
Gertrude H. Sergievsky Centre, College of Physicians and Surgeons, Columbia University, New York, NY, USA
(6)
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

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