Breastfeeding transmission of HIV1: virological aspects

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Breastfeeding transmission of HIV-1 virological
aspects

• Philippe Van de Perre,
• UMR 145, Montpellier, France

Ghent IAS/CTP Working Group, Ghent, December 2002
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Definitions Timing of MTCT
Définition
PCR M6
PCR M3
PCR M1
PCR J1-J2
In utero




Intra-partum / early postnatal



-
Late Postnatal


-
-
Late Postnatal

-
-
-
Non infected
-
-
-
-
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HIV-1 in breast milk
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Three potential compartments with HIV in breast
milk

• Cell-free virions
• Latent (non productive) HIV-infected cells
• Productive HIV-infected cells

• RNA PCR or branched DNA
• DNA PCR
• Cells DNAse RNA PCR

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Cell-free HIV-1 in Breast Milk

• HIV-1 RNA detected in 29 / 75 samples (39)
• In the 29 positive samples
• 16 (55 ) near detection limit (240 copies /mL)
• 6 (21 ) had gt 900 copies / mL
• maximum 8,100 copies / mL

From Lewis P et al., J Infect Dis 1998
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Prevalence of HIV-1 RNA in breast milk
HIV-1 RNA in BM
11/23
50
10/22
8/30
20
0-7 days 8-90 days gt 90 days
Time after delivery
From Lewis P et al., J Infect Dis 1998
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Determinants of postnatal HIV transmission,
multivariate analysis (O. Manigart et al, non
publié)

• Factors Odds ratio CI 95 p-value
• Maternal CD4 count 0.96a 0.72-1.26
  0.76
• Maternal plasma VL 2.32b 0.80-6.27 0.13
• Milk VL at D8 6.31b 1.57-25.36 0.0095
• VL D45-D8 3.88b 1.40-10.76 0.0091
• a For an increase of 100 CD4 cells b for an
  increase of one log10

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The breast milk / mammary compartment
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Tri-iodothyronin, b-oestradiol, prolactin
Macrophages, Infected lymphocytes
Macrophages, lnfected lymphocytes
Mucosal compartment
Free virus

Free virus
Macrophages, Infected lymphocytes
Ductal and alveolar epithelial cells
Mammary compartment
Systemic compartment
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Blood Colostrum
M2 m1
M1
Mother 25
Viral DNA
M2 m1
M2
Viral RNA
m3 m4
Mother 35
M3
Viral DNA
m4
M5
Viral RNA
Mother 65
m6
m7 M8
Viral DNA
M7
M9
Viral RNA
P. Becquart et al Virology 2002
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Portal of entry
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Mucosal lesion
Alternative Receptor (Gal Cer)
Fc receptor
Transcytosis
M cells
Free virus
Lumen
Infected Cells
Cellules infectées

Epithelial cells
Dendritic Cells
Sub mucosa
T Lymphocytes
Monocytes/macrophages
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Polarised HIV-infected cell
Gal Cer
Transcytosis
Macrophages and lymphocytes in the lamina propria
M Bomsel et al, 1997
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Polarised HIV-infected cell
Gal Cer
Inhibition of transcytosis by SIgA and SIgM
Transcytosis
Macrophages and lymphocytes in the lamina propria
M Bomsel et al, 1997
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HIV-infected PBMCs-induced transcytosis (
standard)
IgM anti SC
IgM
dIgA anti SC
dIgA
Non-specific dIgA
Standard
100
50
20
Bomsel M et al. Infection 1998
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Enterocytes-mediated viral selection ?

• Human enterocytes express CCR5 but not CXCR4
• In vitro, human enterocytes are able to transfer
• R5 but not X4 viruses
• This transfer is not inhibited by T20
• 
  (Gang Meng et al. Nature Med 2002)

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Tonsils as a portal of entry for HIV ?

• Tonsil lympho-epithelium contains M cells
• capable of transcytosing HIV in close vicinity of
  
• dendric cells and CD4 lymphocytes
• Thes cells can replicate HIVC

Frankel SS, et al. Science 1996 et Am J Path 1997
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Oral inoculation of macaques with SIV

• Non traumatic inoculation of tonsils with
  cell-free and cell-associated SIV
• No infection of the epithelial cells
• Infection of CD4 close to M cells in the
  tonsil crypts

C Stahl-Henning et al, Science 1999
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Unanswered questions

• What is the impact of viral selection in breast
  milk on the risk of transmission ?
• Is virus producing cells in breast milk a good
  predictor of transmission ?
• What is the portal of entry on HIV-1 in infants ?
• What is the impact of the presence of viral
  ARV-resistant mutants in breast milk ?
• Which cell type is producing HIV in breast milk
  and is a latent reservoir of HIV at the different
  times of lactation ?