Nov. 25, 2003 In the largest study ever of HIV-infected children, researchers at the University of California, San Diego (UCSD) School of Medicine have demonstrated that a child's individual genetic factors are an important determinant of disease progression and cognitive impairment associated with HIV.
Published in the November 15, 2003 issue of the Journal of Infectious Diseases, the study in 1,049 HIV-infected children showed that even slight genetic alternations can affect how the virus enters a cell or how the immune system responds to the virus, making some children more susceptible to worsening HIV symptoms, and others less susceptible.
The U.S. Centers for Disease Control and Prevention estimates that 9,300 children under age 13 in the United States have AIDS. The United Nations notes that 3.2 million children under age 15 in the world are HIV positive.
"Perhaps the greatest potential for our research findings is to help guide treatment for HIV-infected individuals," said the study's senior author, Stephen Spector, M.D., chair of the executive committee of the national Pediatric AIDS Clinic Trial Group, chief of the UCSD Division of Pediatric Infectious Diseases, and director of UCSD's Mother, Child & Adolescent HIV Program. "Instead of taking the approach that one size fits all, we potentially can individualize HIV treatment based on each person's genetic makeup."
The UCSD team identified several genetic changes, called polymorphisms. One involves a protein molecule called CCR5, which the HIV virus uses to gain entry into macrophages, one of the cells that provide the body's defense against infection.
While past studies have shown that mutant forms of CCR5 appear to confer protection against HIV in adults, the UCSD team focused on gene mutations in the large group of children. They determined that HIV-infected children with a specific polymorphism called CCR5-delta32 had half the rate of disease progression (12 percent vs 26 percent) as compared to children with normal CCR5. However, only about 6 percent of the children followed in the study had the CCR5-delta32 polymorphism.
In spite of the clear benefit observed in children with the CCR5-delta32 polymorphism, the disease state of some children with the CCR5 mutant worsened at a faster rate if they also had another gene alteration called SDF1-3'A (14 percent vs 22 percent).
The researchers found that children with CCR5-delta32 also had less neurocognitive impairment and those with the SDF1 mutation had a faster decline in neurocognitive function.
The most rapid progression of HIV symptoms was seen in children with normal CCR5 plus a polymorphism called 59029-A/A (33 percent with the 59029 polymorphism vs 26 percent with normal CCR5). This particular polymorphism was seen in about 25 percent of the HIV-infected children studied, representing the genotype that most often accelerated the rate of disease progression in children with normal CCR5. And, because the beneficial CCR5-delta32 polymorphism is uncommon among Black and Hispanic individuals, gene alterations at the 59029 site had the greatest impact on the largest number of children across race/ethnicity groups.
The study also demonstrated that personal genetic differences do not affect children in the same way they do adults.
"We found that there were some polymorphisms that had an impact in adults but not children, and some that seemed to have an important impact on children but only a modest impact in adults," Spector said.
For example, past studies have shown that the polymorphism CCR2-641 lessons HIV progression in adults. In the current study, however, the UCSD team found no significant association between disease progression or death among children with any of the CCR2 genotypes.
In continuing research, Spector's team hopes to identify those specific individuals who are at the highest risk for having difficulties with their HIV infection. "Those are the children you want to treat immediately," he said. "On the other hand, we might be able to identify another group of children at very low risk of HIV progression. We may not have to treat them for many years, thus avoiding many of the side-effects of HIV drugs."
### The study was supported by the Pediatric AIDS Clinical Trials Group and by grants from the National Institute of Allergy and Infectious Diseases and the University of California Center for AIDS Research.
In addition to Spector, the paper's authors were Kumud K. Singh, Ph.D. and Charlene F. Barroga, Ph.D, UCSD Department of Pediatrics; Michael D. Hughes, Ph.D, Jie Chen, MSc, and Claire Raskino, MSc, the Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston; and Ross E. McKinney Jr., M.D., Duke University Medical Center, Durham, NC.
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