Background: To investigate gender differences in susceptibility to infection and clinical, immunological, and virological disease progression in children.

Methods: The European Collaborative Study is a prospective cohort study, in which infected and uninfected children born to HIV-infected mothers are followed from birth in centers in 9 European countries. Mixed linear effects natural cubic spline models (allowing for repeated measures) to assess patterns of RNA viral load, CD4⁺, CD8⁺ and absolute lymphocytes (AL) up to age 12 years by HIV infection status, gender, and race.

Results: In this non-breastfeeding population in Europe, the vertical transmission rate (VTR) has decreased significantly to below 1%. In multivariate analysis, VTR was significantly associated with exposure to ART (Adjusted odds ratio (AOR) 0.3 for incomplete monotherapy regimen to AOR 0.09 for combination therapy), elective caesarean section before labor and before membrane rupture (AOR 0.45), maternal CD4 count (1.82 for counts < 200 cells) and gender (AOR 1.44 for girls). There were pronounced early peaks in all CD4, CD8 and AL in the 1,488 uninfected children (9,789 measurements) which declined to adult levels by around 8 years. Uninfected boys and uninfected black children had significantly reduced CD4⁺ and absolute lymphocyte counts; the gender difference was especially pronounced in black children. Patterns and levels were substantially different for the 183 infected children (3,414 measurements); for instance, by age 6 months CD4⁺ cell counts were nearly 1,200 per mm³ less. Levels also significantly differed by gender and race, although infected girls had lower counts than boys. The CD4⁺ differences were not due to general lymphocytosis. RNA viral load peaked around three months of age, and gradually declined thereafter. Viral load peaked higher for girls than boys, but after 4 years RNA load was consistently 0.25 to 0.5 log₁₀ lower for girls than boys (sex by age interaction = 19.7, p < 0.001). Effects of gender and treatment on viral load vary over age (= 6.31, p = 0.043) and gender differences in RNA viral load relating to measurement without treatment were more pronounced than those under treatment. The overall rate of progression to serious disease or death did not differ by gender.

Conclusions: These findings suggest an underlying important genetic component in immune response to HIV-1 and may have implications for therapy decisions.