Mucosal Innate Immune Response Associated with a Timely Humoral Immune Response and Slower Disease Progression after Oral Transmission of Simian Immunodeficiency Virus to Rhesus Macaques

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Journal of Virology (Impact Factor: 4.44). 07/2007; 81(12):6175-86. DOI: 10.1128/JVI.00042-07
Source: PubMed


Mucosal transmission is the predominant mode of human immunodeficiency virus (HIV) infection worldwide, and the mucosal innate interferon response represents an important component of the earliest host response to the infection. Our goal here was to assess the changes in mRNA expression of innate mucosal genes after oral simian immunodeficiency virus (SIV) inoculation of rhesus macaques (Macaca mulatta) that were followed throughout their course of disease progression. The SIV plasma viral load was highest in the macaque that progressed rapidly to simian AIDS (99 days) and lowest in the macaque that progressed more slowly (>700 days). The mRNA levels of six innate/effector genes in the oral mucosa indicated that slower disease progression was associated with increased expression of these genes. This distinction was most evident when comparing the slowest-progressing macaque to the intermediate and rapid progressors. Expression levels of alpha and gamma interferons, the antiviral interferon-stimulated gene product 2'-5' oligoadenylate synthetase (OAS), and the chemokines CXCL9 and CXCL10 in the slow progressor were elevated at each of the three oral mucosal biopsy time points examined (day 2 to 4, 14 to 21, and day 70 postinfection). In contrast, the more rapidly progressing macaques demonstrated elevated levels of these cytokine/chemokine mRNA at lymph nodes, coincident with decreased levels at the mucosal sites, and a decreased ability to elicit an effective anti-SIV antibody response. These data provide evidence that a robust mucosal innate/effector immune response is beneficial following lentiviral exposure; however, it is likely that the anatomical location and timing of the response need to be coordinated to permit an effective immune response able to delay progression to simian AIDS.

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Available from: Kimberli A Schmidt
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    • "The increased expression of IFN-γ following SIV infection [47, 56, 57] is correlated with induction of CXCL9, CXCL10 and CXCL11, which are all CXCR3 ligands [52]. In a study of host responses to oral transmission of SIV, high CXCL9 and CXCL10 levels in lymph nodes after infection were associated with rapid progression of disease, whereas high levels of these chemokines in the oral mucosa were associated with slow progression of disease [58]. Induction of CCL19 could be associated with increased recruitment of mature DCs [54, 59, 60], in which CCL19 is highly expressed [61]. "
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    ABSTRACT: Chemokines are small chemoattractant cytokines involved in homeostatic and inflammatory immune cell migration. These small proteins have multiple functional properties that extend beyond their most recognized role in controlling cellular migration. The complex immunobiology of chemokines, coupled with the use of subsets of chemokine receptors as HIV-1 and SIV entry co-receptors, suggests that these immunomodulators could play important roles in the pathogenesis associated with infection by HIV-1 or SIV. This review provides an overview of the effects of pathogenic infection on chemokine expression in the SIV/macaque model system, and outlines potential mechanisms by which changes in these expression profiles could contribute to development of disease. Key challenges faced in studying chemokine function in vivo and new opportunities for further study and development of therapeutic interventions are discussed. Continued growth in our understanding of the effects of pathogenic SIV infection on chemokine expression and function and the continuing development of chemokine receptor targeted therapeutics will provide the tools and the systems necessary for future studies of the roles of chemokines in HIV-1 pathogenesis.
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    • "Although conventional wisdom suggests that primary human infection of permissive cells actually occurs in the gut [9,35], the oral mucosa in primate models becomes infected within a day of atraumatic oral mucosal exposure to SIV-1 [8,36]. Infection becomes marked in the GI tract four days after initial exposure, suggesting that virus disseminates from an oral focus. "
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    ABSTRACT: Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers. To determine the plausibility that oral keratinocytes are primary targets of HIV-1, we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner. To study the fate of HIV-1, immortalized oral keratinocytes (OKF6/TERT-2; TERT-2 cells) were characterized for the fate of HIV-specific RNA and DNA. At 6 h post inoculation with X4 or R5-tropic HIV-1, HIV-1gag RNA was detected maximally within TERT-2 cells. Reverse transcriptase activity in TERT-2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Deltaenv-EGFP. AZT inhibited EGFP expression in a dose-dependent manner, suggesting that viral replication can be supported if receptors are bypassed. Within 3 h post inoculation, integrated HIV-1 DNA was detected in TERT-2 cell nuclei and persisted after subculture. Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation, suggesting that HIV replication may abort and that infection is non-productive. Within 48 h post inoculation, however, virus harbored by CD4 negative TERT-2 cells trans infected co-cultured peripheral blood mononuclear cells (PBMCs) or MOLT4 cells (CD4+ CCR5+) by direct cell-to-cell transfer or by releasing low levels of infectious virions. Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner. Oral keratinocytes appear, therefore, to support stable non-replicative integration, while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h.
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    • "Yet, experimental evidence points to the plausibility that exposure of the oral mucosal epithelium to HIV-1 results in primary infection of the oral tissues followed by systemic dissemination. For example, when simian immunodeficiency virus (SIV) is non-traumatically swabbed on the gingival and buccal mucosa of primates, oral epithelial infection is evident within one day [3,4], while systemic infection occurs within a week [5]. Consistent with these observations, human oral epithelial cells of HIV-infected patients contain integrated HIV-1 DNA, which may result from either primary infection or systemic dissemination of the virus [6]. "
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