Influence of Human Immunodeficiency Virus–Infected Maternal Environment on Development of Infant Interleukin‐12 Production

Abstract

Monocyte-derived cytokine production by cord blood mononuclear cells (CBMC) from infants born to human immunodeficiency virus (HIV)-positive and -negative women was measured to determine whether monocyte dysfunction could contribute to the accelerated HIV disease of pediatric patients. Production of interleukin (IL)-12, but not that of tumor necrosis factor-alpha and IL-10, was reduced, compared with adult peripheral blood mononuclear cells (PBMC). This deficiency was more pronounced in infants of HIV-positive women, whose IL-12 production was also deficient. CBMC IL-12 levels were increased by interferon-gamma and CD40 ligand but remained deficient, compared with PBMC. IL-12 production was undetectable in 7 of 8 HIV-positive infants, in contrast to 21 of 26 uninfected infants. Uninfected infants of infected women exhibited an intermediate profile. These findings suggest that the maternal environment and/or exposure in utero to HIV products influence the newborn's immune response and that the differences between infants born to HIV-positive and -negative women may persist.

Failure of HIV-exposed CD4+ T cells to activate dendritic cells is reversed by restoration of CD40/CD154 interactions

“…[19][20][21] Consistent with this hypothesis, we and others have shown that providing exogenous recombinant CD154 increases interleukin 12 (IL-12) production by peripheral mononuclear cells (PBMCs) from HIVinfected donors. [22][23][24] In addition, our recent data indicate that levels of IL-12 p70 production correlate with CD154 expression. 16 Importantly, the CD154 dysregulation described in HIV-infected donors can also be modeled in vitro, following engagement of the CD4 receptor by noninfectious viruses having functional envelope glycoproteins or by native HIV gp120 itself prior to T-cell activation, as we and others have previously shown.…”

Defective antigen-presenting cell function in human neonates

“…Decreased production of IL-12 by CBMC stimulated by Staphylococcus aureus Cowan (SAC) has also been described [25,17]. Since monocytes are the main producers of IL-12 in SACstimulated PBMC, these results also point towards defective activation of neonatal monocytes.…”

“…A progressive decrease in the absolute number of pDCs occurs in the first year of life, but adult levels are reached only around 5 years of age [83]. An age-related increase in the capacity of PBMC to synthesize IL-12 in response to LPS or SAC stimulation has also been reported, but levels of production of such cytokine in 12 month-old children remain low [17,25]. A complex picture is emerging from different studies concerning the capacity of APC from young children to stimulate T cells, depending on the functional readout.…”

Gamma Interferon Production in Response toMycobacterium bovisBCG andMycobacterium tuberculosisAntigens in Infants Born to Human Immunodeficiency Virus-Infected Mothers

“…HIV-specific cellular immune responses can be elicited among a proportion of these infants (11). Reduced interleukin-12 and interleukin-2 production in response to Staphylococcus aureus Cowan and phytohemagglutinin (PHA) stimulation suggests immunosuppressive effects of in utero HIV exposure (3,16). An increase in activated (CD4 ϩ HLA-DR ϩ CD38 ϩ ) and memory (CD4 ϩ CD45RA Ϫ RO ϩ ) lymphocytes suggests in utero antigenic stimulation of CD4 ϩ lymphocytes related to HIV products or antigens associated with opportunistic pathogens (16).…”

“…These naive cells are, compared to memory T cells, deficient in producing gamma interferon (IFN-␥) (5). Furthermore, neonatal T cells respond weakly to antigen-presenting cells, resulting in further decreased IFN-␥ production (3,19,20). This low IFN-␥ production may result in increased susceptibility to intracellular pathogens, including Mycobacterium tuberculosis (15).…”