A Mutation In The CCR5 Coreceptor Slows HIV Disease Progression In Children Born To Seropositive Mothers

Some people remain uninfected by HIV despite frequent exposure. In 1996 a mutation (delta 32) in the CCR5 co-receptor for HIV was found to protect from the infection in homozygotes, i.e. people in whom the CCR5 gene copies on both chromosomes bear the mutation. About 1% of Caucasians are homozygous for the mutation, while about 10% of Europeans are heterozygous (only one gene copy bears the mutation). Heterozygotes can be infected by HIV, but contradictory results had been reported on the possible influence of the mutation on disease progression in adult cohorts. Up to now no study had been perfomed in children.

INSERM (The French National Institute of Health and Medical Research) and hospital research teams led by Marie-Jeanne Mayaux (INSERM Unit 292, Paris), Stéphane Blanche (INSERM Unit 429, Necker Hospital, Paris), Micheline Misrahi, Molecular Biology Laboratory, and Jean-François Delfraissy at Bicetre Hospital, have now reported in the January 28 issue of the Journal of the American Medical Association that heterozygosity for the delta 32 mutation significantly slows HIV disease progression in children born to seropositive mothers. Their work was supported by the French AIDS research organization ANRS.

The main problems encountered when investigating the influence of delta 32 heterozygosity on HIV disease progression in adults are that it is usually difficult to determine the precise date of infection and to rule out multiple infections. The French researchers examined maternofetal HIV-1 transmission in children enrolled in the French Pediatric Cohort. The timing of the infection is known in children and other modes of infection can be ruled out.

512 children born to HIV-1-seropositive mothers of European origin₁ were studied ₂. The delta 32 mutation was screened in both infected (n=276) and uninfected children (n=236). The proportion of heterozygotes was found to be similar in the two groups. This showed that, like in adults, children heterozygous for the delta 32 mutation are not protected against HIV-1 infection.

Disease progression was then compared in 152 infected children, of whom 126 did not have the mutation while the remaining 26 were heterozygotes. Severe clinical manifestations together with the onset of severe immunodeficiency (judged by the circulating CD4+ cell count) occurred significantly later in the heterozygous children.

These findings provide important arguments in the debate over the beneficial effect of delta 32 heterozygosity on HIV disease progression. The CCR5 genotype should also give a prognostic information for children born to HIV-1-infected mothers. In addition, these findings should encourage the development of therapeutic agents acting on drugs targeting HIV coreceptors.

The French Pediatric Cohort :
Founded in 1986 and coordinated by Stéphane Blanche (INSERM 429, Necker Hospital), Marie-Jeanne Mayaux (INSERM 292), and Christine Rouzioux (Necker Hospital), the French Pediatric Cohort enrolls neonates born to HIV-1- or HIV-2-seropositive mothers. As of December 1997, 4200 mother-child pairs had been recruited.

The cohort is mainly used for the following purposes:

• To study immunologic, virologic and obstetric factors influencing the risk of mother-child transmission of HIV-1 and HIV-2.
• To study disease progression and prognostic factors in children.
• To determine the safety and efficacy of antiretroviral drugs prescribed during pregnancy and to the new-born child.

This Cohort is supported by the French AIDS research organization ANRS

For further information :

"CCR5 chemokine receptor mutant allele in HIV-1 mother-to-child transmission and disease progression in children"

M. Misrahi₁, J.P. Teglas₂, N. N'Go₃, M. Burgard₃, M.J. Mayaux₂, C. Rouzioux₃,
J.F. Delfraissy₄, S. Blanche₅

JAMA, vol 279, 4, pp 277-280, 28th January 1998

1Molecular Biology and Hormonology Laboratory, Bicetre Hospital, Le Kremlin Bicetre, France
2 INSERM Unity 292, Bicetre Hospital, Le Kremlin Bicetre, France
3 Virology Laboratory, Necker-Enfants Malades Hospital, Paris, France
4 Internal Medecine Unit, Bicetre Hospital, Le Kremlin Bicetre, France
5 Immunology and Hematology Paediatrics Unit, INSERM 429, Necker-Enfants Malades Hospital, Paris, France

Contacts
Marie-Jeanne Mayaux
INSERM Unit 292, Le Kremlin Bicetre
Tel : 33 1 45 21 23 47
Fax : 33 1 45 21 20 75
E-mail : mayaux@vjf.inserm.fr

Micheline Misrahi
Molecular Biology and Hormonology Laboratory, Bicêtre Hospital
Tel : (INSERM 135) 33 1 45 21 33 29
Fax : 33 1 45 21 38 22