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.

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In a continuing effort to develop safe and efficacious vaccine and immunotherapeutic vectors, we constructed recombinant vaccinia virus (rVV) vaccines lacking either the B13R (SPI-2) or the B22R (SPI-1) immune-modulating gene and coexpressing IFN-␥. B13R and B22R are nonessential VV immune-modulating genes that have antiapoptotic and antiinflammatory properties with sequence homology to serine protease inhibitors (serpins). IFN-␥ is a cytokine with potent immunoregulatory, antineoplastic, and antiviral properties. We observed that these rVVs with a deletion in a serpin gene and expressing IFN-␥ replicated to high titers in tissue culture yet were avirulent in both immunocompromised and immunocompetent mice with no detectable viral replication in these animals. A single immunization elicited potent humoral, T helper, and cytotoxic T cell immune responses in mice despite the absence of any detectable virus replication in vivo. IFN-␥ coexpression and the inactivation of one or more VV immune-modulating genes provide an optimized method for increasing the safety while maintaining the efficacy of rVV vaccines. This strategy provides a method for developing highly safe and efficacious vaccines for smallpox and other diseases and immunotherapeutic vectors.vaccines ͉ safety ͉ efficacy ͉ immune-modulating genes ͉ smallpox V accinia virus (VV), the orthopoxvirus used in the global eradication of smallpox, also has served as an effective vector for eukaryotic protein expression, vaccine development, and immunotherapeutic treatments for cancer (1). The emerging threat of smallpox bioterrorism has once again brought VV vaccines to the forefront. Currently, vaccination of military and emergency response personnel with VV is recommended, and vaccination is being considered for the general public (2). Although VV has not been directly associated with any specific disease, complications have been observed in immunocompromised and immunosuppressed individuals (3). In light of the current threat of bioterrorism and the ongoing AIDS epidemic, the complications of VV infection in immunocompetent and especially in immunocompromised populations must be thoroughly addressed to circumvent any possible pathogenic effects of mass vaccination. Therefore, increasing safety while maintaining proven efficacy is one of the foremost considerations for the widespread use of VV vaccines.VV has been used extensively as a vector for the development of recombinant live vaccines (1). There are currently two well established effective recombinant VV (rVV) vaccines, one for rabies (4) and the other for rinderpest (5)(6)(7)8).We and others have demonstrated that the cytokine IFN-␥ can be used as both an adjuvant and an attenuating agent for the development of safe and efficacious live VV vaccines (9-11). IFN-␥ is a cytokine that plays an essential role in the regulation of the immune system and host defense against pathogens (12). The effects of IFN-␥ on the immune system are profound. IFN-␥ modulates macrophage tumoricidal and microbicidal activity, na...