Background:  It is not known whether HIV-exposed uninfected children born to mothers submitted to prophylactic interventions currently recommended are born with immunologic abnormalities found before the HAART era.

Methods:  From March 2004 to June 2005, we evaluated 39 HIV-exposed uninfected neonates (ENI) and 53 healthy unexposed neonates (CTL); 97% HIV-infected mothers received some ART and 87% received HAART during pregnancy. Viral load at delivery was <50 copies/mL for 60% mothers; mean viral load among those with detectable levels was 2908 copies/mL; 97% had elective caesarean section. After 12 months, 16 ENI neonates were further evaluated and compared with 16 unexposed healthy age-matched children. Immunophenotyping of lymphocytes and CD34⁺ cells was done by 4-color flow cytometry in cord blood and in peripheral blood.

Results:  ENI neonates had higher natural killer (NK) cells (cells/mm³, ENI 1206, CTL 935; t-test, p = 0.051) and CD34⁺ cells (cells/mm³, ENI 127, CTL 42; t-test, p <0.001). Numbers of CD3⁺ T, CD4⁺ T, CD8⁺ T, and B cells did not differ between groups. ENI neonates had lower percentages of naive CD4⁺ T cells (CD45RA⁺CCR7⁺) than CTL (ENI 75%, CTL 82%; t-test, p = 0.015). Central memory CD4⁺ T cell percentages (CD45RA^­CCR7⁺) were higher in ENI than in CTL (ENI 14%, CTL 10%; t-test, p = 0.007). Maturation subsets of CD8⁺ T cells did not differ between groups. CD38 expression on CD8⁺ T cells was significantly higher in ENI (ENI 93%, CTL 89%; ^t-test, p = 0.024). At 12 months of age, ENI infants persisted with higher NK cell values (cells/mm³:  ENI 1561, CTL 750; t-test, p = 0.02), but not CD34⁺ cells (cells/mm³:  ENI 41, CTL 51; t-test, p = 0.072). By contrast, ENI infants had higher percentages of naive CD4⁺ T and CD8⁺ T cells than CTL infants (CD4:  ENI 66%, CTL 53%, t-test, p = 0.005) (CD8:  ENI 53%, CTL 32%, t-test, p = 0.001), and lower percentages of terminally differentiated (CD45RA⁺CCR7^­) CD4⁺ T and CD8⁺ T cells (CD4:  ENI:9%, CTL 21%, t-test, p = 0.004) (CD8:  ENI 19%, CTL 39%, t-test, p <0.001). Expression of CD38 on CD4⁺ T cells was higher in ENI than in CNT infants (ENI 87%, CTL 75%, t-test, p = 0.001).

Conclusions:  Despite good maternal virologic control, HIV-exposed uninfected children are born with markers of immune activation that persist at least until 12 months of age. NK cells are also elevated at birth and that is maintained after 1 year. That suggests that in utero exposure to HIV but might also be part of the mechanisms that contribute to prevention of vertical infection.