AIDSWEEKLY Plus; Monday, February 9, 1998
Daniel J. DeNoon, Senior Editor
The gene encodes the CCR5 receptor, required for infection with the macrophage-tropic (M-tropic) HIV strains responsible for the vast majority of infections. A 32-nucleotide deletion in the CCCR5 gene (CCR5delta32) protects cells against infection with M-tropic HIV strains.
Adults homozygous for CCR5delta32 - that is, those who inherited the mutant gene from both parents - are protected against HIV infection and, when infected, have slower disease progression. Heterozygous adults - who got the gene from only one parent - tend to have a slower loss of CD4 cells and lower viral burdens resulting in a two-fold lower risk of AIDS (see AIDS Weekly Plus, January 20, 1997).
Heterozygous children in the French study, however, appeared to do even better than adults.
"Heterozygosity for the CCR5delta32 deletion does not protect children from infection by the maternal virus but substantially reduces the progression of the disease in HIV-1 infected children," wrote Micheline Misrahi of France's Institut National de la Sante et de la Recherche Medicale (INSERM) and colleagues.
Misrahi et al. reported their findings in The Journal of the American Medical Association ("CCR5 Chemokine Receptor Variant in HIV- 1 Mother-to-Child Progression in Children," JAMA, 1998;279:277-80).
The researchers enrolled subjects from the 52 medical institutions collaborating in the French Pediatric HIV Cohort study. They studied 512 non-African children born 1983-1996 to mothers with HIV infection.
Transmission in this cohort was relatively high: 276 (54 percent) of the children acquired HIV infection from their mothers.
Only one of the children was homozygous for CCR5delta32. Although this infant was not infected, suggestive of protection, her uniqueness in this study makes meaningful statistical analysis impossible.
However, 49 (9.6 percent) of the children were heterozygous for CCR5delta32. They were divided nearly evenly between the infected and uninfected groups (9.8 versus 9.3 percent, respectively). But a comparison of AIDS progression between the heterozygous children and the children homozygous for the normal gene revealed striking differences.
"The incidence of stage C symptoms in heterozygous infected children was 9 percent at 36 months versus 28 percent in children homozygous for the normal allele (P<0.004)," Misrahi et al. reported.
"The proportion of children at 8 years old with no stage B or C symptoms was 49 percent for heterozygous children and 11 percent for children homozygous for the normal allele (P<0.003). The progression of severe immune deficiency (CD4 <15 percent, CDC stage 3) was also significantly different between the two groups (P<0.001)."
These findings add urgency to the ongoing race to discover drugs or vaccines capable of disabling the CCR5 receptor or the portion of the HIV-1 envelope that interacts with it.
"If this finding is confirmed, such knowledge could lead to further investigation of CCR5 antagonists for possible use in prophylactic strategies," commented JAMA Contributing Editor Jeanette M. Smith in an editorial note.
The corresponding author for this study is Micheline Misrahi, Laboratory of Hormonology and Molecular Biology, Institut National de la Sante et de la Recherche Medicale, Paris, France.
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