CD8+ T-Lymphocyte Response to Major Immunodominant Epitopes after Vaginal Exposure to Simian Immunodeficiency Virus: Too Late and Too Little

Wisconsin Primate Research Center, University of Wisconsin, Madison 53715, USA.
Journal of Virology (Impact Factor: 4.65). 08/2005; 79(14):9228-35. DOI: 10.1128/JVI.79.14.9228-9235.2005
Source: PubMed

ABSTRACT In the acute stage of infection following sexual transmission of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), virus-specific CD8+ T-lymphocyte responses partially control but do not eradicate infection from the lymphatic tissues (LTs) or prevent the particularly massive depletion of CD4+ T lymphocytes in gut-associated lymphatic tissue (GALT). We explored hypothetical explanations for this failure to clear infection and prevent CD4+ T-lymphocyte loss in the SIV/rhesus macaque model of intravaginal transmission. We examined the relationship between the timing and magnitude of the CD8+ T-lymphocyte response to immunodominant SIV epitopes and viral replication, and we show first that the failure to contain infection is not because the female reproductive tract is a poor inductive site. We documented robust responses in cervicovaginal tissues and uterus, but only several days after the peak of virus production. Second, while we also documented a modest response in the draining genital and peripheral lymph nodes, the response at these sites also lagged behind peak virus production in these LT compartments. Third, we found that the response in GALT was surprisingly low or undetectable, possibly contributing to the severe and sustained depletion of CD4+ T lymphocytes in the GALT. Thus, the virus-specific CD8+ T-lymphocyte response is "too late and too little" to clear infection and prevent CD4+ T-lymphocyte loss. However, the robust response in female reproductive tissues may be an encouraging sign that vaccines that rapidly induce high-frequency CD8+ T-lymphocyte responses might be able to prevent acquisition of HIV-1 infection by the most common route of transmission.

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    • "Interestingly, few virus-specific CTLs were detected in the gut of vaginally inoculated animals using similar (tetramer) techniques (Reynolds et al. 2005), which could reflect differences in CTL development or homing depending on the route of transmission, but this remains to be fully explored. In addition to cell-mediated immune responses, infection with SIV or HIV also results in generation of diverse antibody responses, although some strains of SIV are quite poor at eliciting neutralizing antibodies. "
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    • "In ,2 wk, a very small founder population of productively infected cells at the portal of entry progresses to systemic infection with a burst of virus production and depletion of gut CD4 þ T cells. At this point, a robust virus-specific immune response can contain viral replication only to a certain degree (Reynolds et al. 2005). Thus, the first days of infection at the mucosa when replication is limited to small clusters of infected cells are the periods of maximum virus vulnerability and represent a window of opportunity for intervention. "
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