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

(See the editorial commentary by Emery on pages 169–71, and the major articles by Lichtner et al on pages 178–86.) 10.1093/infdis/jiu419 10.1093/infdis/jiu417 Despite effective administration of combination antiretroviral therapy to human immunodeficiency virus type 1 (HIV-1)–infected pregnant women, mother-to-child transmission (MTCT) of HIV-1 remains a significant global public health concern. Several copathogens that pose threats to the developing fetus during gestation, such as cytomegalovirus (CMV), malaria parasites, and Mycobacterium tuberculosis, may also facilitate in utero transmission of HIV-1 and contribute to the high incidence of MTCT within specific populations [1–3]. These pathogens can promote transmission through increases in proviral load, immune activation, local inflammation, and maternal stimulation of fetal CD4+cells to increase cellular susceptibility to HIV-1 infection. CMV, a highly prevalent beta herpesvirus, infects >90% and 50%–80% of reproductive-age women in developing and developed countries, respectively. HIV-1–infected infants who acquire CMV infection in the first 18 months of life have a significantly higher rate of disease progression than those infected with HIV-1 alone [4, 5]. Studies have shown that CMV induces increases in T-cell activation in peripheral blood mononuclear cells (PBMCs) from HIV-1–infected infants [6] and memory cell differentiation [7]. Strong associations between in utero CMV infection and a higher incidence of MTCT of HIV-1 have been documented [8, 9]; however, the mechanisms that increase neonatal HIV-1 transmission remain unknown. Several in vitro studies demonstrate increased viral transcription and replication in phytohemagglutinin (PHA)/interleukin 2 (IL-2)–activated cord blood mononuclear cells (CBMCs), compared with adult PBMCs. However, these conditions do not mimic the in utero environment, which is normally immunoquiescent and associated with a low risk of HIV-1 transmission (7%) in vivo. In contrast, immune activation may facilitate HIV-1 infection following in utero exposure to CMV antigens. Increased T-cell activation may be associated with CCR5 expression and susceptibility of CBMCs to HIV-1. The goal of the current study is to examine the targets and mechanisms that affect fetal susceptibility to HIV-1 in utero. We demonstrate that the fraction of CD4+CCR5+ and CD4+CD45RO+ T cells in cord blood is significantly lower, compared with adult PBMCs, which may reflect that the low level of in utero HIV-1 transmission is due to a lack of target cells. However, upon in vitro stimulation with CMV antigens or PHA/IL-2, CBMCs undergo increased proliferation and upregulate the fraction of T central memory (TCM) cells and expression of CCR5 among CD4+ T cells. This upregulation of CCR5 was more pronounced in TCM cells, compared with naive CD4+ CBMCs. Unstimulated CD4+ CBMCs that lack CCR5 and CD45RO showed reduced levels of HIV-1 infection and replication in vitro, compared with PBMCs. However, priming CBMCs with CMV antigens influenced the proliferation and activation of CCR5+ TCM cells, rendering these more susceptible to HIV-1 infection in vitro.