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


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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    • "Recently, repeated challenge models with SIV-infected splenocytes or peripheral blood cells applied to the vaginal tract of macaques have been developed . Genital ulcers (Kaizu et al., 2006; Weiler et al., 2008) or progesterone treatment to thin the epithelium (Salle et al., 2010) can facilitate infection; however, a standardized repeated low-dose challenge model that does not require artificial epithelial disruption or thinning would better recapitulate HIV infection and may be important to the vaccine field. Vaccineinduced protection from cell-associated virus may differ from what is needed to protect from cell-free virus, reinforcing the need for relevant models of cell-associated HIV transmission. "
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    ABSTRACT: The development of HIV vaccines has been hampered by the lack of an animal model that can accurately predict vaccine efficacy. Chimpanzees can be infected with HIV-1 but are not practical for research. However, several species of macaques are susceptible to the simian immunodeficiency viruses (SIVs) that cause disease in macaques, which also closely mimic HIV in humans. Thus, macaque-SIV models of HIV infection have become a critical foundation for AIDS vaccine development. Here we examine the multiple variables and considerations that must be taken into account in order to use this nonhuman primate (NHP) model effectively. These include the species and subspecies of macaques, virus strain, dose and route of administration, and macaque genetics, including the major histocompatibility complex molecules that affect immune responses, and other virus restriction factors. We illustrate how these NHP models can be used to carry out studies of immune responses in mucosal and other tissues that could not easily be performed on human volunteers. Furthermore, macaques are an ideal model system to optimize adjuvants, test vaccine platforms, and identify correlates of protection that can advance the HIV vaccine field. We also illustrate techniques used to identify different macaque lymphocyte populations and review some poxvirus vaccine candidates that are in various stages of clinical trials. Understanding how to effectively use this valuable model will greatly increase the likelihood of finding a successful vaccine for HIV. Curr. Protoc. Immunol. 102:12.14.1-12.14.30. © 2013 by John Wiley & Sons, Inc.
    Current protocols in immunology / edited by John E. Coligan ... [et al.] 10/2013; 102:12.14.1-12.14.30. DOI:10.1002/0471142735.im1214s102
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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(1):49. DOI:10.1186/1742-4690-7-49 · 4.19 Impact Factor
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