Strong HIV-1-Specific T Cell Responses in HIV-1-Exposed Uninfected Infants and Neonates Revealed after Regulatory T Cell Removal

Abstract

Background In utero transmission of HIV-1 occurs on average in only 3%–15% of HIV-1-exposed neonates born to mothers not on antiretroviral drug therapy. Thus, despite potential exposure, the majority of infants remain uninfected. Weak HIV-1-specific T-cell responses have been detected in children exposed to HIV-1, and potentially contribute to protection against infection. We, and others, have recently shown that the removal of CD4+CD25+ T-regulatory (Treg) cells can reveal strong HIV-1 specific T-cell responses in some HIV-1 infected adults. Here, we hypothesized that Treg cells could suppress HIV-1-specific immune responses in young children.Methodology/Principal FindingsWe studied two cohorts of children. The first group included HIV-1-exposed-uninfected (EU) as well as unexposed (UNEX) neonates. The second group comprised HIV-1-infected and HIV-1-EU children. We quantified the frequency of Treg cells, T-cell activation, and cell-mediated immune responses. We detected high levels of CD4+CD25+CD127− Treg cells and low levels of CD4+ and CD8+ T cell activation in the cord blood of the EU neonates. We observed HIV-1-specific T cell immune responses in all of the children exposed to the virus. These T-cell responses were not seen in the cord blood of control HIV-1 unexposed neonates. Moreover, the depletion of CD4+CD25+ Treg cells from the cord blood of EU newborns strikingly augmented both CD4+ and CD8+ HIV-1-specific immune responses.Conclusions/SignificanceThis study provides new evidence that EU infants can mount strong HIV-1-specific T cell responses, and that in utero CD4+CD25+ T-regulatory cells may be contributing to the lack of vertical transmission by reducing T cell activation.

Imbalance of naive and memory T lymphocytes with sustained high cellular activation during the first year of life from uninfected children born to HIV-1-infected mothers on HAART

“…Previous studies by our group and others in perinatal HIV-exposed infants have reported evidence of HIV-specific immune response (4,(18)(19)(20)(21)(22)(23)(24)(25). HIV-specific immune response has also been observed in exposed noninfected adults (26)(27)(28)(29).…”

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

“…A systematic review of these studies suggests that natural resistance to HIV infection in highly exposed individuals is mediated by multiple mechanisms, conferring on them an ''immunologic advantage'' that may be related to innate and/or adaptive immune systems. 66,67 Although offering only a partial explanation to the natural resistance to HIV infection, 68 observations in female sex workers in Nairobi with frequent HIV exposure, [69][70][71] in exposed uninfected infants with strong HIV-1-specific T cell responses, 72 and more recently in discordant couples 73 suggest that recurrent viral exposure may lead to priming of HIV-specific systemic and mucosal immune responses. These findings suggest that persons receiving PrEP who are exposed to HIV may generate HIV-specific T cell responses, potentially contributing to protection against the establishment of HIV infection.…”

Immunological and hematological effects of perinatal exposure to antiretroviral drugs in HIV-exposed, non-infected children

“…HIV-1 specific immune responses have been reported in children who have been exposed to the virus yet remained uninfected leading to a state of immune activation [6]. CD8+ immune responses to HIV-1 Env, Gag, and Nef proteins have been shown in the peripheral blood of these infants early after birth [7].…”

“…However, these studies were prior to use of maternal HAART and is likely that these children were exposed to high levels of maternal HIV viremia [7,8]. Even in children exposed perinatally to HAART, HIV-1 specific immune responses even in the setting of low maternal viremia leads to low level of immune activation which is highest in the cord blood and lower in the peripheral blood [6]. This may be either due to infected maternal lymphocytes or activated antigen presenting cells which may have microtransfused across the placenta stimulating the fetal immune system [6].…”

“…Even in children exposed perinatally to HAART, HIV-1 specific immune responses even in the setting of low maternal viremia leads to low level of immune activation which is highest in the cord blood and lower in the peripheral blood [6]. This may be either due to infected maternal lymphocytes or activated antigen presenting cells which may have microtransfused across the placenta stimulating the fetal immune system [6]. Another immunological phenomenon observed is an increase in B lymphocytes especially the CD19/CD5+ in cord blood of HIV exposed newborns [2] with increased B cell apoptosis in later life [6].…”