Prenatal priming to malaria antigens increases susceptibility to HIV infection

Mother-to-child-transmission of HIV (MTCT) remains a significant cause of new HIV infections in many countries. Maternal risk factors such as high viral load, maternal immune status, vaginal delivery and presence of cervicovaginal infections increase the rate of HIV transmission to the newborn. However, all risk factors for MTCT during the in utero and perinatal periods, especially in developing countries, are not fully understood. To examine whether fetal immune activation as a consequence of prenatal exposure to parasitic antigens increases risk of MTCT, cord blood mononuclear cells (CBMC) from Kenyan versus North American newborns were examined for relative susceptibility to HIV infection in vitro. Kenyan CBMC were 3-fold more likely to be infected with HIV compared to North American CBMC (p=0.03). Fetal sensitization to malaria antigens further enhanced susceptibility to HIV when compared to Kenyan CBMC not sensitized to malaria (p=0.03). CD4⁺ T cells from malaria sensitized newborns expressed higher levels of CD25 and HLA-DR ex vivo, consistent with increased immune activation. CD4⁺ T cells were the primary reservoir of infection at day four following virus exposure.

To explore mechanisms for this selective susceptibility, we examined subpopulations of CBMC infected and molecular pathways involved. Effector memory CD3⁺CD4⁺ T cells (T_EM) were the exclusive initial targets of HIV infection with rapid spread to central memory cells (T_CM). HIV susceptibility correlated with increased expression of CD25 and HLA-DR on T_EM. Virus entered all samples equally, however gag/pol RNA was only detected in HIV susceptible samples, suggesting regulation of proviral gene transcription. Targeted analysis of human genes in memory T cells showed greater expression of IFNG, NFATc1, IRF1, FOS, and PPIA and decreased expression of YY1 and TFCP2 in HIV susceptible samples.

Thus prenatal exposure and in utero priming to malaria increases the susceptibility of fetal cells to HIV infection by activating cellular pathways in effector memory T cells that enhance HIV proviral gene transcription. Prevention of parasitic coinfections in HIV positive women during pregnancy to prevent prenatal sensitization may reduce the risk of MTCT.