In 2003, a zoonotic outbreak of human monkeypox occurred in North America. The outbreak was the first time that this virus caused human disease outside Africa. Subsequent investigation confirmed that the source of the outbreak was an imported consignment of African mammals from the West African nation of Ghana. Subsequently, the virus moved to captive native North American species, including Cynomys species (prairie dogs) (10,21,23). Human cases were infected through contact with infected animals, principally prairie dogs (19,23). Viral isolates associated with the outbreak were genetically characterized as West African variants of monkeypox distinct from Central African viruses (20). During the outbreak, and in a follow-up study, specimens from suspected cases and their contacts were submitted to the Centers for Disease Control and Prevention (CDC) for laboratory testing. Laboratory testing included virological testing (culture and PCR) of presumptive virus-containing specimens for case confirmation and analysis of immunological markers from blood or serum samples. Immunological analysis included serologic testing for orthopoxvirus (OPX)-specific antibodies (immunoglobulin G [IgG] and IgM) and virus-specific cellular (CD4, CD8, and B-cell) immunity evaluation in cases and contacts.In this study, we evaluated human monkeypox cases and household contacts of monkeypox-infected animals and report the characterization of the convalescent and long-term memory (1-year) immune response to monkeypox infection during this outbreak. Correlations between immunological markers, smallpox vaccination status, and infection outcomes are evaluated, as well as memory immune responses in previously vaccinated individuals within this cohort. MATERIALS AND METHODS Specimens.Response to the 2003 U.S. monkeypox outbreak involved the collection of information related to lab results, exposure characteristics, clinical features of illness, and other epidemiologic features. Teams of clinicians, epidemiologists, and microbiologists from the CDC and the six affected states collected information and samples from cases and contacts of cases. Patient specimens were sent to the CDC as a part of the outbreak investigation, and confirmation of suspect cases was based on identification of virus in tissuederived specimens (21). As an extension of the outbreak investigation, a followup, household-based, Institutional Review Board-approved, case control study was initiated to assess exposures, clinical markers of disease severity, and immune responses at 7 to 14 weeks (convalescent) and at 1 year postexposure. Specimens were collected at convalescent and 1-year time points, and clinical and epidemiologic information was collected with a standardized questionnaire. A total of 92 persons enrolled in the study. Eighteen of those enrolled were excluded from the analysis due to unknown vaccination status or unwillingness to provide biological samples. A total of 72 individuals were considered in these analyses. Enrolled individuals were categorized into ...

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The currently used smallpox vaccine is associated with a high incidence of adverse events, and there is a serious need for a safe and effective alternative vaccine. Here, we carried out a longitudinal evaluation of vaccinia virus-specific CD4 and CD8 T cells in smallpox-vaccinated individuals by using a highly sensitive intracellular cytokine staining assay. Our results demonstrate that, in addition to the CD8 response, the smallpox vaccinations raised a robust CD4 response with a Th1-dominant cytokine profile. These CD4 T cells were stable and exhibited only a twofold contraction between peak effector and memory phases compared with an approximate sevenfold contraction for CD8 cells. A significant proportion of vaccinated individuals lost detectable CD8 memory while maintaining CD4 memory. After a booster immunization, these individuals generated a robust CD8 response, which some of them rapidly lost. Thus, the current smallpox vaccine provides long-lasting CD4 help that may be critical for long-lived B-cell memory. We suggest that the provision of adequate CD4 help for CD8 and humoral effector functions will be critical to the success of the next generation of smallpox vaccines.

FOXP3+CD8+ T cells are present at low levels in humans; however, the function of these cells is not known. In this study, we demonstrate a rapid expansion of CD25+FOXP3+CD8+ regulatory T cells (Tregs) in the blood and multiple tissues following a pathogenic SIV infection in rhesus macaques. The expansion was pronounced in lymphoid and colorectal mucosal tissues, preferential sites of virus replication. These CD8 Tregs expressed molecules associated with immune suppressor function such as CTLA-4 and CD39 and suppressed proliferation of SIV-specific T cells in vitro. They also expressed low levels of granzyme B and perforin, suggesting that these cells do not possess killing potential. Expansion of CD8 Tregs correlated directly with acute phase viremia and inversely with the magnitude of antiviral T cell response. Expansion was also observed in HIV-infected humans but not in SIV-infected sooty mangabeys with high viremia, suggesting a direct role for hyperimmune activation and an indirect role for viremia in the induction of these cells. These results suggest an important but previously unappreciated role for CD8 Tregs in suppressing antiviral immunity during immunodeficiency virus infections. These results also suggest that CD8 Tregs expand in pathogenic immunodeficiency virus infections in the nonnatural hosts and that therapeutic strategies that prevent expansion of these cells may enhance control of HIV infection.

Progressive disease caused by pathogenic SIV/HIV infections is marked by systemic hyperimmune activation, immune dysregulation, and profound depletion of CD4+ T cells in lymphoid and gastrointestinal mucosal tissues. IL-17 is important for protective immunity against extracellular bacterial infections at mucosa and for maintenance of mucosal barrier. Although IL-17–secreting CD4 (Th17) and CD8 (Tc17) T cells have been reported, very little is known about the latter subset for any infectious disease. In this study, we characterized the anatomical distribution, phenotype, and functional quality of Tc17 and Th17 cells in healthy (SIV−) and SIV+ rhesus macaques. In healthy macaques, Tc17 and Th17 cells were present in all lymphoid and gastrointestinal tissues studied with predominance in small intestine. About 50% of these cells coexpressed TNF-α and IL-2. Notably, ∼50% of Tc17 cells also expressed the co-inhibitory molecule CTLA-4, and only a minority (<20%) expressed granzyme B suggesting that these cells possess more of a regulatory than cytotoxic phenotype. After SIV infection, unlike Th17 cells, Tc17 cells were not depleted during the acute phase of infection. However, the frequency of Tc17 cells in SIV-infected macaques with AIDS was lower compared with that in healthy macaques demonstrating the loss of these cells during end-stage disease. Antiretroviral therapy partially restored the frequency of Tc17 and Th17 cells in the colorectal mucosa. Depletion of Tc17 cells was not observed in colorectal mucosa of chronically infected SIV+ sooty mangabeys. In conclusion, our results suggest a role for Tc17 cells in regulating disease progression during pathogenic SIV infection.