Repeated Intravaginal Inoculation with Cell-Associated Simian Immunodeficiency Virus Results in Persistent Infection of Nonhuman Primates

Immunogenetics and Virology Unit, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53711, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 11/2006; 194(7):912-6. DOI: 10.1086/507308
Source: PubMed

ABSTRACT The goal of the present study was to develop a nonhuman primate model of intravaginal human immunodeficiency virus (HIV) transmission with cell-associated virus. Reproductively mature, cycling cynomolgus macaques with or without chemically induced, transient ulcers of the lower female reproductive tract repeatedly received challenge with a variable amount of in vitro simian immunodeficiency virus mac239-infected peripheral blood mononuclear cells. Persistent viremia was established with surprisingly few infectious lymphocytes containing physiologically relevant quantities of cell-associated virus. This model will be indispensable for the testing of vaccines and topical agents that are aimed toward the prevention of heterosexual transmission of HIV.

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Available from: Eva G Rakasz, Jun 10, 2014
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    • "HIV infection in vivo can be established by cell-free and cellassociated viruses. Infection by both cell-free and cell-associated virus has been observed in female macaques infected with simian immunodeficiency and chimeric viruses (SIV/SHIV) (Gupta et al., 2002; Kaizu et al., 2006; Khanna et al., 2002; Salle et al., 2010; Zhu et al., 1996), mice infected with HIV (Khanna et al., 2002), and indirectly in humans through genetic matching of HIV viruses sequenced from acutely infected women and from seminal cells and plasma from their infected partners (Zhu et al., 1996). Human cervical explant studies have also confirmed transmission of cell-free and cell-associated HIV (Gupta et al., 2002). "
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    ABSTRACT: A combination of prevention and treatment modalities will be needed to successfully control the global spread of HIV. Microbicides, drug products topically applied to mucosal surfaces to prevent HIV infection, are one of these biomedical interventions that hold great promise. In order to be efficacious, microbicides must overcome several challenges imposed by the mucosal microenvironment they intend to protect and the mischievous human immunodeficiency virus with its enormous capacity to adapt. Recent data, however, supports the establishment of the primo-infection by only a small number of founder viruses, which are highly vulnerable to microbicidal intervention at the initial stages of mucosal invasion. The biological foundation of these challenges and opportunities in microbicide development is explored in this review. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.
    Antiviral research 12/2010; 88 Suppl 1(supplement 1):S3-9. DOI:10.1016/j.antiviral.2010.09.011 · 3.94 Impact Factor
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    • "As an animal model, mucosal transmission of FIV has been developed extensively. FIV transmission mimics the diversity apparent in HIV-1 vaginal transmission and virus strains representing at least three subtypes of FIV can be transmitted across the vaginal, rectal, or oral mucosa by cell-associated as well as cell-free virus [34,78-83] similar to reported previously [84,85,72], mucosal exposure to cell-associated FIV resulted in greater virus burden than did exposure to cell-free FIV, particularly in the gut. This could be due to dose effect. "
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    ABSTRACT: Several lines of research suggest that exposure to cellular material can alter the susceptibility to infection by HIV-1. Because sexual contact often includes exposure to cellular material, we hypothesized that repeated mucosal exposure to heterologous cells would induce an immune response that would alter the susceptibility to mucosal infection. Using the feline immunodeficiency virus (FIV) model of HIV-1 mucosal transmission, the cervicovaginal mucosa was exposed once weekly for 12 weeks to 5,000 heterologous cells or media (control) and then cats were vaginally challenged with cell-associated or cell-free FIV. Exposure to heterologous cells decreased the percentage of lymphocytes in the mucosal and systemic lymph nodes (LN) expressing L-selectin as well as the percentage of CD4+ CD25+ T cells. These shifts were associated with enhanced ex-vivo proliferative responses to heterologous cells. Following mucosal challenge with cell-associated, but not cell-free, FIV, proviral burden was reduced by 64% in cats previously exposed to heterologous cells as compared to media exposed controls. The pathogenesis and/or the threshold for mucosal infection by infected cells (but not cell-free virus) can be modulated by mucosal exposure to uninfected heterologous cells.
    Retrovirology 05/2010; 7:49. DOI:10.1186/1742-4690-7-49 · 4.19 Impact Factor
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    • "Infected semen and cervico-vaginal secretions contain cell-free viruses and viruses associated with monocytes, macrophages and T lymphocytes (Coombs et al., 2003; D'Cruz & Uckun, 2006; Lederman et al., 2006), and both have been shown to be infectious (Coombs et al., 2003; Kaizu et al., 2006; Lederman et al., 2006). Modelling sexual transmission in cervical tissue explants and in animals has shown that HIV rapidly associates with dendritic cells/T-cell clusters, which are crucial in the spread of virus to the regional lymph nodes and subsequent systemic dissemination (Masurier et al., 1998; Shattock & Moore, 2003; Veazey & Lackner, 2003; Maher et al., 2005; Dhawan & Mayer, 2006; Lederman et al., 2006; Gupta & Klasse, 2006). "
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    ABSTRACT: Several classes of microbicides are being evaluated for the prevention of sexual HIV transmission. In vivo, the infectious dose and viral source involved in transmission remain uncertain and it is likely that women will use microbicides both before and after high-risk HIV exposure. Therefore, we evaluated HIV entry inhibitors (EIs) and reverse transcriptase inhibitors (RTIs) for their ability to block cell-free and cell-associated HIV-1 infection in co-cultures of monocyte-derived dendritic cells (MO-DC) and CD4+ T-cells using settings of pre- and post-exposure prophylaxis. In the pre-exposure assay, where compound was present before, during and 24 h after infection, all tested EIs (BMS806, TAK779 and T20) and RTIs (PMPA, TMC120 and UC781) blocked infection with 10(-4) multiplicity of infection (MOI) of cell-free virus at a dose between 100 and 10,000 nM, dependent on the compound used. At 10(-3) MOI, however, only T20 and the RTIs completely blocked infection. Furthermore, in experiments with cell-associated virus, EIs were ineffective, whereas RTIs actively blocked infection with similar potency as in the experiments with cell-free virus. In the post-exposure assay, where compound was added 2 h after infection and remained present for 24 h, EIs were inactive whereas RTIs blocked cell-free and cell-associated viral infections equally efficiently. Moreover, post-exposure prophylaxis initiated 24 h after infection with cell-free or cell-associated HIV-1 was still effective with 1,000 nM of TMC120. Both EIs and RTIs were non-cytotoxic at any tested concentration for MO-DC and CD4+ T-cells in co-culture. Our study shows that RTIs are potent inhibitors of cell-free and cell-associated virus used either in pre- or post-exposure settings. It highlights that parameters such as viral input, viral source, the time of compound addition and the target cells should be considered in microbicides evaluation.
    Antiviral chemistry & chemotherapy 02/2007; 18(3):141-51. DOI:10.1177/095632020701800304
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