Article

Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression

Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2006; 103(31):11701-6. DOI: 10.1073/pnas.0602185103
Source: PubMed

ABSTRACT The majority of HIV-1-infected neonates and infants have a higher level of viremia and develop AIDS more rapidly than infected adults, including differences seen in clinical manifestations. To determine the mechanisms of HIV-1 infection in neonates vs. adults, we compared the replication kinetics of HIV-1 in neonatal (cord) and adult blood T lymphocytes and monocyte-derived macrophages (MDM) from seven different donors. We found that HIV-1 replicated 3-fold better in cord blood T lymphocytes compared with adult blood T lymphocytes and 9-fold better in cord MDM than adult MDM. We also show that this differential HIV-1 replication did not depend on differences in cell proliferative capabilities, cell surface expression of CD4, CXCR4, and CCR5, or in the amount of PCR products of reverse transcription, DNA synthesis, and translocation of preintegration complex into the nucleus in cord and adult T lymphocytes and MDM. Furthermore, using a single-cycle replication competent HIV-1-NL4-3-Env(-) luciferase amphotropic virus, which measures HIV-1 transcriptional activity independent of receptor and coreceptor expression, we found there was a 3-fold increase of HIV-1 LTR-driven luciferase expression in cord T lymphocytes compared with adult T lymphocytes and 10-fold in cord MDM than in adult MDM. The HIV-1 LTR-driven luciferase expression correlated with HIV-1 LTR transcription, as measured by ribonuclease protection assay. These data suggest that the increased replication of HIV-1 in cord blood compared with adult blood mononuclear cells is regulated at the level of HIV-1 gene expression, resulting in a higher level of viremia and faster disease progression in neonates than adults.

Download full-text

Full-text

Available from: Rajesh Ramakrishnan, Aug 25, 2015
0 Followers
 · 
86 Views
  • Source
    • "The prevalence of the dementia is eventually increasing as AIDS patients are now surviving more. HIV-1 replicates in monocyte and macrophage but not as severe as in infected T cells and blood mononuclear cells (Sundaravaradan et al., 2006). These cells differentiate and travel to several organs, henceforth acting as a source of infectious virus and secret‐ ed viral proteins to cause pathological issues and alternating several signalling pathways and distorting many cellular transcription factors, ultimately resulting in HIV-1 pathogen‐ esis. "
    Current Perspectives in HIV Infection, 04/2013: chapter NeuroAIDS: Mechanisms, Causes, Prevalence, Diagnostics and Social Issues: pages 109-124; InTech.
  • Source
    • "They have also required pre-activation to allow HIV infection in vitro. Interestingly, these studies demonstrated enhanced HIV replication in monocytes/macrophages and total T lymphocytes, as well as more specifically in both CD4 + CD45RA + naïve T cell and CD4 + CD45RO + memory T cell subsets from CBMC compared to PBMC (Ahmad et al., 2011; Sundaravaradan et al., 2006). This is in contrast to our observations in which HIV –ssDNA is only detected in CD3 + CD4 + T cells twenty-four hours after virus exposure and further only CD4 + CD45RO + memory cells exhibit productive viral replication as determined by flow cytometic detection of p24. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In utero priming to malaria antigens renders cord blood mononuclear cells (CBMC) more susceptible to productive HIV infection in vitro in the absence of exogenous stimulation. This provides a unique model to better understand mechanisms affecting lymphocyte susceptibility to HIV infection in vivo. Effector memory CD3(+)CD4(+) T cells (T(EM)) were the exclusive initial targets of HIV with rapid spread to central memory cells. HIV susceptibility correlated with increased expression of CD25 and HLA-DR on T(EM). Virus entered all samples equally, however gag/pol RNA was only detected in HIV susceptible samples, suggesting regulation of proviral gene transcription. Targeted analysis of human genes in memory T cells showed greater expression of IFNG, NFATc1, IRF1, FOS, and PPIA and decreased expression YY1 and TFCP2 in HIV susceptible samples. Thus fetal priming to exogenous antigens enhances specific proviral gene transcription pathways in effector memory cells that may increase risk of vertical transmission of HIV.
    Virology 03/2012; 425(1):23-30. DOI:10.1016/j.virol.2012.01.003 · 3.28 Impact Factor
  • Source
    • "), that measures HIV-1 LTR mediated gene expression via luciferase, we found a higher level of HIV-1 gene expression in both cord CD45RA + and CD45RO + CD4 + T-lymphocytes compared with adult cells (Fig. 6). This data correlates with the increased level of HIV-1 replication seen in CD45RA + and CD45RO + Tlymphocytes (Figs. 4 and 5), and is also consistent with the our previous study on increased HIV-1 replication and gene expression in Tlymphocytes and monocytes/macrophages (Sundaravaradan et al., 2006). We conclude that a higher level of HIV-1 replication in cord CD45RA + and CD45RO + T-lymphocytes compared with adult cells is influenced at the level of HIV-1 gene expression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our previous study has shown that HIV-1 replicated at higher levels in neonatal (cord) blood monocytes/macrophages and T-lymphocytes compared with adult blood cells. However, it is not known whether this differential HIV-1 replication also occurs in naive and/or memory T-lymphocytes. We, therefore, compared HIV-1 replication in CD3(+) and CD4(+) naive (CD45RA(+)) and memory (CD45RO(+)) T-lymphocytes isolated from five cord and adult blood donors. We found that HIV-1 replicated at higher levels in both CD3(+) and CD4(+) CD45RA(+) and CD45RO(+) T-lymphocytes isolated from cord blood compared with adult blood. In addition, there was no difference in the cell surface expression of CD4, CXCR4 and CCR5 on cord blood CD45RA(+) and CD45RO(+) T-lymphocytes compared with adult blood cells. Furthermore, we found that there was an increase in HIV-1 gene expression in cord blood CD45RA(+) and CD45RO(+) T-lymphocytes compared with adult blood cells by using a single-cycle replication competent HIV-1-NL4-3-Env(-)R(+) luciferase amphotropic virus, which measures HIV-1 transcriptional activity independent of CD4 and CXCR4 or CCR5 expression. In summary, HIV-1 replicated at higher levels in cord blood CD45RA(+) and CD45RO(+) T-lymphocytes compared with adult blood cells and this differential replication is influenced at the level of HIV-1 gene expression.
    Virology 02/2011; 413(1):39-46. DOI:10.1016/j.virol.2011.01.033 · 3.28 Impact Factor
Show more