Certain individuals are resistant to HIV-1 infection, despite repeated exposure to the virus. Although protection against HIV-1 infection in a small proportion of Caucasian individuals is associated with mutant alleles of the CCR5 HIV-1 coreceptor, the molecular mechanism underlying resistance in repeatedly HIV-1-exposed, uninfected individuals (EU) is unclear. In this study, we performed complementary transcriptome and proteome analyses on peripheral blood T cells, and plasma or serum from EU, their HIV-1-infected sexual partners, and healthy controls, all expressing wild-type CCR5. We report that activated T cells from EU overproduce several proteins involved in the innate immunity response, principally those including high levels of peroxiredoxin II, a NK-enhancing factor possessing strong anti-HIV activity, and IL-22, a cytokine involved in the production of acute-phase proteins such as the acute-phase serum amyloid A (A-SAA). Cell supernatants and serum levels of these proteins were up-regulated in EU. Moreover, a specific biomarker for EU detected in plasma was identified as an 8.6-kDa A-SAA cleavage product. Incubation of in vitro-generated myeloid immature dendritic cells with A-SAA resulted in CCR5 phosphorylation, down-regulation of CCR5 expression, and strongly decreased susceptibility of these cells to in vitro infection with a primary HIV-1 isolate. Taken together, these results suggest new correlates of EU protection and identify a cascade involving IL-22 and the acute phase protein pathway that is associated with innate host resistance to HIV infection. The course of HIV-1 infection is known to vary widely among individuals. In addition to long-term nonprogressors, who are asymptomatic and have normal CD4+ T cell counts despite a long history of untreated HIV-1 infection, certain individuals, defined as persistently exposed but uninfected (EU),4 are resistant to HIV infection despite repeated exposure via sexual or systemic routes (1, 2). Certain rare polymorphisms in the gene encoding CCR5, the principal coreceptor for primary strains or HIV-1, have been shown to confer a high degree of protection against HIV-1 infection to a very small proportion of the Caucasian population who are homozygous for these gene variants (3, 4, 5). However, this particular genetic variation cannot account for resistance to HIV-1 infection in all EU who carry the wild-type CCR5 gene, indicating that other mechanisms of protection against viral infection must exist. Additional resistance to HIV-1 infection is reportedly associated with the activity of HIV-1-specific helper and CTL (2, 6, 7) and with enhanced local mucosal IgA responses (8). Moreover, an association between resistance to HIV-1 infection and enhanced NK activity (9), as well as increased production of IFN-γ produced by CD4 T cells (10), CD8 antiviral factors (11), and defensins (12) has been described. More recently, the frequencies of CD4+ and CD8+ CD45RA−CCR7+ central memory cells, as well as terminally differentiated CD8+ CD45RA+CCR7− and CD27−CD28− T lymphocytes, were reported to be increased in EU, compared with HIV-1-infected patients (13), suggesting a role for the latter cells in preventing actual infection. However, the overall understanding of the molecular mechanisms underlying resistance to infection of EU with HIV-1 remains ill-defined. In the present study, we performed comparative transcriptome and proteome analyses on peripheral blood T cells and plasma or serum from EU, their HIV-1-infected sexual partners (HIV+), and healthy control subjects (HC) to investigate whether the differential expression of certain gene products by T cells from EU could be associated with long-lasting resistance to HIV-1 infection.