ABSTRACT
HIV-1-induced cytopathicity of thymocytes is a major cause of reduced peripheral T cells and rapid disease progression observed in HIV-1-infected infants. Understanding the virulence factors responsible for thymocyte depletion has paramount importance in addressing the pathogenesis of disease progression in children. In this study, thymocyte depletion was analyzed following infection with two primary CXCR4-tropic HIV-1 pediatric isolates (PI), PI-2 and PI-2.1, which were serially derived from an in utero-infected infant. Although highly similar to each other, PI-2 showed markedly decreased thymocyte depletion in vitro compared with PI-2.1. Further analysis showed a novel deletion in the Nef protein (NefΔK7S) of PI-2, which was absent in PI-2.1. This deletion inhibited Nef-mediated major histocompatibility complex class I (MHC-I) downregulation in infected thymocytes in vitro and in vivo; in contrast, the mutated Nef continued to downregulate CD4 surface expression in vitro. These results suggest that HIV-1 Nef contributes to thymic damage in infants through selective functions.
Subject(s)
HIV Infections/genetics , Histocompatibility Antigens Class I/genetics , Thymocytes/virology , nef Gene Products, Human Immunodeficiency Virus/genetics , Animals , Cells, Cultured , Child, Preschool , Cytopathogenic Effect, Viral , Down-Regulation , Gene Deletion , HIV Infections/virology , HIV-1/genetics , Humans , Infant, Newborn , Mice , Mice, SCID , Mutation , Thymocytes/pathologyABSTRACT
As interferon-gamma (IFN-gamma) is produced at lower levels by neonatal than adult T cells, we determined whether IFN-gamma influences HIV-1 replication in thymocytes. IFN-gamma significantly decreased replication of R5 but not X4 viruses, and reduced depletion of CD3(hi)CD27 (mature) thymocytes, the preferential targets for R5 HIV-1. Thus infection and depletion of functionally mature thymocytes that can produce endogenous IFN-gamma may mutually contribute to HIV-1 replication in the thymus and to reduced T-cell output.
Subject(s)
HIV Infections/virology , HIV-1/drug effects , Interferon-gamma/pharmacology , T-Lymphocyte Subsets/virology , Thymus Gland/virology , Cells, Cultured , Child , HIV Infections/immunology , HIV-1/physiology , Humans , Virus Replication/drug effectsABSTRACT
In October 2007, a joint ANRS-NIH workshop was held on "Mucosal immunity and HIV/AIDS vaccines" in Veyrier-du-Lac, France. Goal of the meeting was to discuss recent developments in the understanding of viral entry and dissemination at mucosal surfaces, rationale for designing vaccines to elicit mucosal immune responses by various routes of immunization, and the types of immune responses elicited. Lessons were drawn from existing vaccines against viral mucosal infections, from the recent failure of the Merck Ad5/HIV vaccine and from attempts at mucosal immunization against SIV. This report summarizes the main concepts and conclusions that came out of the meeting.
Subject(s)
AIDS Vaccines/immunology , HIV Infections/immunology , HIV Infections/prevention & control , HIV/immunology , Animals , Drug Evaluation, Preclinical , HIV Antibodies , HIV Infections/virology , Humans , Immunity, MucosalABSTRACT
Early infection of the thymus with the human immunodeficiency virus (HIV) may explain the more rapid disease progression among children infected in utero than in children infected intrapartum. Therefore, we analyzed infection of thymocytes in vitro by HIV type 1 primary isolates, obtained at or near birth, from 10 children with different disease outcomes. HIV isolates able to replicate in the thymus and impact thymopoiesis were present in all infants, regardless of the timing of viral transmission and the rate of disease progression. Isolates from newborns utilized CCR5, CXCR4, or both chemokine receptors to enter thymocytes. Viral expression was observed in discrete thymocyte subsets postinfection with HIV isolates using CXCR4 (X4) and isolates using CCR5 (R5), despite the wider distribution of CXCR4 in the thymus. In contrast to previous findings, the X4 primary isolates were not more cytopathic for thymocytes than were the R5 isolates. The cytokines interleukin-2 (IL-2), IL-4, and IL-7 increased HIV replication in the thymus by inducing differentiation and expansion of mature CD27(+) thymocytes expressing CXCR4 or CCR5. IL-2 and IL-4 together increased expression of CXCR4 and CCR5 in this population, whereas IL-4 and IL-7 increased CXCR4 but not CCR5 expression. IL-2 plus IL-4 increased the viral production of all pediatric isolates, but IL-4 and IL-7 had a significantly higher impact on the replication of X4 isolates compared to R5 isolates. Our studies suggest that coreceptor use by HIV primary isolates is important but is not the sole determinant of HIV pathogenesis in the thymus.