Human immunodeficiency virus (HIV) infection during pregnancy induces CD4 T‐cell differentiation and modulates responses to Bacille Calmette‐Guérin (BCG) vaccine in HIV‐uninfected infants

Abstract

Human immunodeficiency virus (HIV)-negative infants born to HIV-positive mothers frequently exhibit a range of immunological abnormalities. We tested the hypothesis that HIV during pregnancy affects the ability of CD4 T cells of HIV-negative infants to respond to vaccine challenge by recruiting HIV-negative infants born to HIV-negative and HIV-positive mothers and measuring their responses to Bacille Calmette-Guérin (BCG) vaccine given at birth. At 2 weeks, maternal HIV status did not influence CD4 T-cell counts or differentiation, but by 10 weeks CD4 counts of infants born to HIV-positive mothers fell to a level characteristic of HIV-positive infants. Among the CD4 T-cell populations, markers of differentiation (CCR7− CD45RA− CD27−) and senescence (CD57, PD-1) were more common among infants born to HIV-positive mothers than among infants born to HIV-negative mothers. At 2 weeks of age, we assessed the effector response to heat-killed BCG and tuberculin purified protein derivative (PPD) by overnight interferon (IFN)-γ enzyme-linked immunosorbent spot-forming cell assay (ELISpot), but found no measurable effect of maternal HIV status. At 10 weeks, we assessed CD4 T-cell memory by measuring proliferation in response to the same antigens. We observed a bimodal response that allowed infants to be classified as high or low responders and found that fewer infants born to HIV-positive mothers were able to mount a robust proliferative response, suggesting that their reduced CD4 counts and increased differentiation indicated a deficiency in their ability to develop immunological memory.

High rate of Quantiferon positive and tuberculin negative tests in infants born at a large Italian University Hospital in 2011: a cautionary hypothesis

“…The IFN-gamma response to BCG and MTB antigens is increased in HIV negative un-infected and un-exposed newborns compared to newborns from HIV positive mothers. 19 This, in our opinion, confirms that the immune memory of the newborn can be affected in utero by the asset of maternal antigens. In a murine model a higher IFN-gamma response can be obtained from neonatal lymphocytes stimulated in vitro in the offspring of mothers exposed to mycobacterial antigens compared to the offspring of unexposed mothers.…”

In-utero exposure to maternal HIV infection alters T-cell immune responses to vaccination in HIV-uninfected infants

“…Studies in this target population are prone to confounding by the inherent differences between HEU and HIV-unexposed infants, and previous studies have not always accounted for these biases [25,26,38,46–48]. In this study, the higher proliferative responses of HEU infants persisted after adjusting for confounders including breastfeeding, birth weight, and gestational age.…”

“…Likewise, assessing T-cell responses to the superantigen SEB, which is used in many assays as a positive control, revealed important attributes of T-cell functionality in these infants. SEB stimulation results in signaling without the need for co-stimulatory molecules, and through multiple Vβ T-cell receptors (TCRS) [46,47]. When polyclonal stimulation with anti-CD3 and anti-CD28 was assessed in other studies, only HEU infants born to mothers with detectable plasma viral loads had increased proliferation compared to their unexposed counterparts [27].…”

High Prevalence of Tuberculosis Infection in HIV-1 Exposed Kenyan Infants

“…6 HIV-1 exposed children may have higher risk for TB due to increased exposure to active TB, impaired BCG vaccine responses, and alterations in innate and adaptive immunity that may affect TB susceptibility. 4,5,22 The IMPAACT 1041 trial detected latent TB among 2.6% of HIV-1 exposed children below 2 years using TST; however, this study excluded infants with known active TB contacts, had high incidence of active TB prior to 2 years, and did not assess earlier time-points for latent TB. Extrapolating from their observed 4.25% annual rate of active TB and assuming that 20–40% of infants with TB infection develop active TB, we estimate an annual rate of infant TB infection between 11 and 21%, consistent with our findings.…”