In utero activation of fetal memory T cells alters host regulatory gene expression and affects HIV susceptibility

Abstract

In utero priming to malaria antigens renders cord blood mononuclear cells (CBMC) more susceptible to productive HIV infection in vitro in the absence of exogenous stimulation. This provides a unique model to better understand mechanisms affecting lymphocyte susceptibility to HIV infection in vivo. Effector memory CD3+CD4+ T cells (TEM) were the exclusive initial targets of HIV with rapid spread to central memory cells. HIV susceptibility correlated with increased expression of CD25 and HLA-DR on TEM. 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 YY1 and TFCP2 in HIV susceptible samples. Thus fetal priming to exogenous antigens enhances specific proviral gene transcription pathways in effector memory cells that may increase risk of vertical transmission of HIV.

Effect of helminth-induced immunity on infections with microbial pathogens

“…That increased risk was attributed to the in utero priming of T cells by soluble parasite antigens 75 . The finding that there is enhanced activation of proviral gene-transcription pathways in cord-blood T cells from infants primed in utero is consistent with enhancement of the susceptibility of T cells to HIV infection by in utero activation of the immune system 76 .…”

Cytomegalovirus Upregulates Expression of CCR5 in Central Memory Cord Blood Mononuclear Cells, Which May Facilitate In Utero HIV Type 1 Transmission

“…Other studies have noted that stimulated CD4 + CD45RO + CBMCs showed increased HIV-1 replication and gene expression, compared with adult PBMCs [37]. CD3 + CD4 + CBMCs are the only cellular compartment that HIV-1 BaL enters, and while T CM cells are capable of sustaining detectable viral replication following exposure, naive CD4 + T cells do not exhibit similar characteristics [11]. Interestingly, even though CD45RO + T cells are minimal in neonates and infants, in cases where MTCT of HIV-1 has occurred, the majority of HIV-1-infected CD4 + T cells in infants and children are of the CD45RO + phenotype [38].…”

“…In neonates, we investigated this further by first comparing the percentage of naive (T N ), T CM , and effector memory (T EM ) subsets among CD3 + CD4 + T cells in cord blood samples derived from HIV-1-uninfected newborns and peripheral blood samples from HIV-1-uninfected healthy adults. Cell surface markers were used to divide the CD3 + CD4 + T-cell populations into memory (CD45RA − CD45RO + ), T N (CD45RO − CD27 + ), T CM (CD45RO + CD27 + ), and T EM (CD45RO + CD27 − ) subsets, as previously described [11][12][13]. The majority of cord blood lymphocytes have a naive phenotype and express minimal levels of CD45RO ( Figure 2A).…”

Maternal HIV infection alters the immune balance in the mother and fetus; implications for pregnancy outcome and infant health

“…In the infant, congenital CMV infection leads to activation of fetal CD4 þ T cells and increases the number of target cells for HIV, facilitating MTCT of HIV [74,75 && ]. Similarly, malaria antigen-specific T cells in infant cord blood are unlike nonantigen-specific CD4 þ T cells susceptible to HIV without prior mitogenic stimulation [76]. Therefore, the proinflammatory effects of HIV and coinfections play a role in MTCT of HIV at the level of the placenta and the fetus [54,75 && ,77-79].…”

“…This was irrespective of maternal CD4 þ T-cell count, viral load, or use of cART [102 && ]. How all of these events, separately or together can have a long-term effect on the infants immune system requires further studies for example into epigenetic modifications in hematopoietic stem cells, thymic cells, or in immune memory stem cells [76]. Although not the focus of the review, cART is also known to impact the infant's immune system, in particular a reduction of neutrophils in the circulation is reported [16].…”