Role of placental cytokines and inflammation in vertical transmission of HIV infection.

In light of new evidence suggesting that maternal human immunodeficiency virus (HIV) infection produces at least a three-fold increase in the number of early spontaneous abortions, it is important to search for factors that may predispose to fetal wastage. Immunological factors are thought to play an important role in permitting the HLA-disparate fetus to continue to term, despite powerful maternal immune forces capable of rejection. In the context of a heightened incidence of spontaneous abortion in HIV infection, evidence is now accumulating that implicates an imbalance in immune factors in contributing to this fetal loss. Soluble immune factors, such as cytokines, have been suggested as contributing agents to recurrent spontaneous abortions. Inflammatory cytokines-interleukin 1beta, interleukin 6 and tumor necrosis factor alpha-have been measured in isolated placental trophoblastic cells in HIV-infected and non-infected pregnant women in an attempt to explore this hypothesis. These inflammatory cytokines and their messenger RNAs were significantly elevated before and after stimulation in HIV-infected women, supporting the belief that HIV-infected women present their fetuses a milieu of imbalanced immune factors capable of contributing to immunological rejection. In addition, these elevated inflammatory cytokine levels may contribute to HIV disease progression in fetuses by virtue of activation of HIV gene transcription factors similar to what has been demonstrated in in vitro systems. We therefore propose that HIV infection in pregnant women produces an altered state of certain soluble immune factors, which in concert with other immune factor abnormalities, such as loss of immune selection in the fetal thymus, predisposes the fetus to advanced HIV infection and possible spontaneous abortion.

Early spontaneous abortions and fetal thymic abnormalities in maternal-to-fetal HIV infection.

The thymus is thought to play a major role in the immunopathogenesis of human immunodeficiency virus (HIV) infection, particularly in maternal-to-fetal HIV transmission. Characteristic lesions of the HIV-infected thymus include a prominent CD4+ CD8+ T lymphocyte depletion at the corticomedullary junction, the region of the thymus where immune selection occurs. At least threefold excess early spontaneous abortions were noted in a cohort of 124 HIV-infected pregnant women. In these 13 abortuses a very high rate (54%) of HIV vertical transmission was documented, with the thymus gland particularly affected. It is possible that the thymic insult in HIV-infected fetuses contributes to immune rejection of the fetus, possibly by an imbalance of maternal and fetal T1- and T2-type cytokines, known to be important in HIV disease progression. We propose, therefore, that the early spontaneous abortions occurring in HIV-infected pregnant women are due, at least in part, to abnormal immune forces created by HIV infection of the thymus.