Leishmania Induces Survival, Proliferation and Elevated Cellular dNTP Levels in Human Monocytes Promoting Acceleration of HIV Co-Infection

Fred Hutchinson Cancer Research Center, United States of America
PLoS Pathogens (Impact Factor: 7.56). 04/2012; 8(4):e1002635. DOI: 10.1371/journal.ppat.1002635
Source: PubMed


Leishmaniasis is a parasitic disease that is widely prevalent in many tropical and sub-tropical regions of the world. Infection with Leishmania has been recognized to induce a striking acceleration of Human Immunodeficiency Virus Type 1 (HIV-1) infection in coinfected individuals through as yet incompletely understood mechanisms. Cells of the monocyte/macrophage lineage are the predominant cell types coinfected by both pathogens. Monocytes and macrophages contain extremely low levels of deoxynucleoside triphosphates (dNTPs) due to their lack of cell cycling and S phase, where dNTP biosynthesis is specifically activated. Lentiviruses, such as HIV-1, are unique among retroviruses in their ability to replicate in these non-dividing cells due, at least in part, to their highly efficient reverse transcriptase (RT). Nonetheless, viral replication progresses more efficiently in the setting of higher intracellular dNTP concentrations related to enhanced enzyme kinetics of the viral RT. In the present study, in vitro infection of CD14+ peripheral blood-derived human monocytes with Leishmania major was found to induce differentiation, marked elevation of cellular p53R2 ribonucleotide reductase subunit and R2 subunit expression. The R2 subunit is restricted to the S phase of the cell cycle. Our dNTP assay demonstrated significant elevation of intracellular monocyte-derived macrophages (MDMs) dNTP concentrations in Leishmania-infected cell populations as compared to control cells. Infection of Leishmania-maturated MDMs with a pseudotyped GFP expressing HIV-1 resulted in increased numbers of GFP+ cells in the Leishmania-maturated MDMs as compared to control cells. Interestingly, a sub-population of Leishmania-maturated MDMs was found to have re-entered the cell cycle, as demonstrated by BrdU labeling. In conclusion, Leishmania infection of primary human monocytes promotes the induction of an S phase environment and elevated dNTP levels with notable elevation of HIV-1 expression in the setting of coinfection.

Download full-text


Available from: Waaqo Daddacha, Sep 29, 2015
1 Follower
19 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: HIV replication is limited by cellular restriction factors, such as APOBEC and tetherin, which themselves are counteracted by viral proteins. SAMHD1 was recently identified as a novel HIV restriction factor in myeloid cells, and was shown to be blocked by the lentiviral protein Vpx. SAMHD1 limits viral replication through an original mechanism: it hydrolyses intracellular dNTPs in non-cycling cells, thus decreasing the amount of these key substrates, which are required for viral DNA synthesis. In this Progress article, we describe how SAMHD1 regulates the pool of intracellular nucleotides to control HIV replication and the innate immune response.
    Nature Reviews Microbiology 08/2012; 10(10):675-80. DOI:10.1038/nrmicro2862 · 23.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose of review: HIV infection profoundly impairs the immune mechanisms needed to control and clear Leishmania infection, and outcomes in patients with HIV-associated visceral leishmaniasis are poor. This review summarizes recent work describing the epidemiology, presentation and outcomes of HIV-associated visceral leishmaniasis and discusses advances in diagnosis and management. Recent findings: Studies have shown that serological tests can effectively diagnose HIV-associated visceral leishmaniasis, with a sensitivity of 98% if direct agglutination test and rK39 assays are used in combination. Few data exist to guide treatment recommendations. Observational data show high rates of toxicity and treatment failure with pentavalent antimonials, and their use is no longer recommended. Liposomal amphotericin B (L-AmB) is better tolerated, but outcomes are suboptimal, with mortality rates of 7-12%, and parasitological failure rates of up to 32%. Initial reports suggest that L-AmB and miltefosine in combination may be effective in HIV-associated visceral leishmaniasis; however, clinical trial data are lacking. Secondary prophylaxis reduces the rate of relapse, but optimal regimens have not been defined, and optimal timing of antiretroviral therapy initiation in patients with visceral leishmaniasis is unknown. Summary: Recent studies have demonstrated the inadequacy of current treatments for HIV-associated visceral leishmaniasis. Clinical trials are needed to improve early diagnosis, develop combination therapies and define effective secondary prophylaxis regimens.
    Current Opinion in Infectious Diseases 12/2012; 26(1). DOI:10.1097/QCO.0b013e32835c2198 · 5.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: SAMHD1 (sterile alpha motif and histidine/aspartic acid (HD) domain-containing protein 1) has been identified as a novel HIV-1 restriction factor in myeloid cells and resting CD4+ T lymphocytes. SAMHD1 restriction is antagonized by the lentiviral protein Vpx. Here, we comment on the latest knowledge of SAMHD1 biology, focusing on how it regulates the pool of intracellular nucleotides to control HIV replication. We discuss how HIV restriction by SAMHD1 and viral counter-restriction mechanisms may suggest new strategies for therapeutic intervention.
    Antiviral research 12/2012; 97(2). DOI:10.1016/j.antiviral.2012.12.009 · 3.94 Impact Factor
Show more