As low CD4 counts and large differentiated T-cell subpopulations are associated with reduced immune responses in the context of HIV infection810and aging,11,12it is consistent that seroreverters also show relatively poor interleukin (IL)-26and IL-1213production in response to polyclonal stimuli. Impairment of seroreverters immune systems is of particular concern in Sub-Saharan Africa, which has both a high HIV prevalence and a high burden of infectious disease.14Immune impairment suggests a mechanism for the frequent poor health of seroreverters5,15but no conclusion can be drawn without establishing whether the impairment affects antigen-specific responses and the development of immune memory to natural infectious challenge or vaccination. Chalcone 4 hydrate One of the most widely used vaccines world-wide is the Bacille Calmette-Gurin (BCG) strain ofMycobacterium bovis, which protects against miliary tuberculosis RGS17 and tuberculosis meningitis in child years.16BCG is given at birth in most African countries and induces a strong cellular response, especially in CD4 T cells.17,18Thus BCG represents a strong model for assessing antigen-specific CD4 T-cell responses in infants. We therefore tested the hypothesis that HIV during pregnancy reduces CD4 T-cell responses in healthy infants by comparing the development of immunity to BCG between seroreverters and a control group born to HIV-negative mothers. the effector response to heat-killed BCG and tuberculin purified protein derivative (PPD) by immediately interferon (IFN)- enzyme-linked immunosorbent spot-forming cell assay (ELISpot), but found no measurable effect of maternal HIV status. At 10 weeks, we assessed CD4 T-cell memory by measuring proliferation in response to the same antigens. We observed a bimodal response that allowed infants to be classified as high or low responders and found that fewer infants given birth to to HIV-positive Chalcone 4 hydrate mothers were able Chalcone 4 hydrate to mount a strong proliferative response, suggesting that their reduced CD4 counts and increased differentiation indicated a deficiency in their ability to develop immunological memory. Keywords:Bacille Calmette-Gurin (BCG), CD4+T lymphocytes, human immunodeficiency computer virus (HIV), immunological memory, infant == Introduction == Over 35 million women of childbearing age are infected annually with human immunodeficiency computer virus (HIV) in Sub-Saharan Africa,1and large numbers of children are given birth to to HIV-positive women. Infants infectedin uteroor perinatally have a poor prognosis, with as many as 25% developing acquired immune deficiency syndrome (AIDS) within the first year.2However, even in the absence of interventions such as antiretroviral therapy (ART) or caesarean section, most infants born to HIV-positive women are not infected. The rapidly expanding availability of ART to prevent perinatal Chalcone 4 hydrate transmission throughout Africa makes it likely that this overwhelming majority of infants given birth to to HIV-positive mothers will remain HIV-negative. These seroreverters3are given birth to with maternally derived antibodies to HIV that they later drop. They frequently have lower birth weights than infants given birth to to HIV-negative mothers,4and a low maternal CD4 count was found to be a strong risk factor for infant mortality and hospital admission in this infant populace.5 The implication that seroreverters are physiologically and immunologically disadvantaged is supported by their lower CD4 counts and higher proportions of differentiated T cells3,6,7than infants born to HIV-negative mothers. As low CD4 counts and large differentiated T-cell subpopulations are associated with reduced immune responses in the context of HIV contamination810and aging,11,12it is usually consistent that seroreverters also show relatively poor interleukin (IL)-26and IL-1213production in response to polyclonal stimuli. Impairment of seroreverters immune systems is usually of particular concern in Sub-Saharan Africa, which has both a high HIV prevalence and a high burden of infectious disease.14Immune impairment suggests a mechanism for the frequent poor health of seroreverters5,15but no conclusion can be drawn without establishing whether the impairment affects antigen-specific responses and the development of immune memory to natural infectious challenge or vaccination. One of the most widely used vaccines world-wide is the Bacille Calmette-Gurin (BCG) strain ofMycobacterium bovis, which protects against miliary tuberculosis and tuberculosis meningitis in child years.16BCG is given at birth in most African countries and induces a strong cellular response, especially in CD4 T cells.17,18Thus BCG represents a strong model for assessing antigen-specific CD4 T-cell responses in infants. We therefore tested the hypothesis that HIV during pregnancy reduces CD4 T-cell responses in healthy infants by comparing the development of immunity to BCG between seroreverters and a control group given birth to to HIV-negative mothers. We administered the BCG vaccine at birth and assessed the T-cell effector response at 2 weeks and the T-cell memory response at 10 weeks, while quantifying CD4 T-cell subpopulations at both time-points. At 2 weeks of age, we found no discernable differences in CD4 T-cell subpopulations or the effector response to BCG. However, by 10 weeks, seroreverters experienced lower CD4 counts, higher levels Chalcone 4 hydrate of CD4 T-cell differentiation and reduced proliferative capacity in response to mycobacterial antigens. Together these data show an impaired ability to both induce CD4 T-cell differentiation and activate a pool of memory T cells through vaccination. == Methods == == Recruitment and immunization == Women with known HIV status were asked to provide informed consent and were recruited when they gave birth at Queen Elizabeth.