Human immunodeficiency virus (HIV) infects and depletes CD4 IMPORTANCE Our study compares the intracellular replicative capacities of several different HIV isolates among different T cell subsets, providing a link between the differentiation of T h 17 cells and HIV replication. T h 17 cells are of key importance in mucosal integrity and in the immune response to certain pathogens. Based on our findings and the work of others, we propose a model in which HIV replication is favored by the intracellular environment of two CD4؉ T cell subsets that share several requirements for their differentiation: T h 17 and T fh cells. Characterizing cells that support high levels of viral replication (rather than becoming latently infected or undergoing cell death) informs the search for new therapeutics aimed at manipulating intracellular signaling pathways and/or transcriptional factors that affect HIV replication.

Circulating plasmacytoid dendritic cells (pDC) decline during HIV-1 infection, but at the same time they express markedly higher levels of interferon alpha (IFNα), which is associated with HIV-1 disease progression. Here we show an accumulation of pDC in lymph nodes (LN) of treatment-naïve HIV-1 patients. This phenomenon was associated with elevated expression of the LN homing marker, CCR7, on pDC in peripheral blood of HIV-1 patients, which conferred increased migratory capacity in response to CCR7 ligands in ex vivo functional assays. LN-homed pDC of HIV-1 patients presented higher CD40 and lower BDCA2 levels, but unchanged CD83 and CD86 expression. In addition, these cells expressed markedly higher amounts of IFNα compared to uninfected individuals, and were undergoing faster rates of cell death. These results demonstrate for the first time that in asymptomatic, untreated HIV-1 patients circulating pDC up-regulate CCR7 expression, accumulate in lymph nodes, and express high amounts of IFNα before undergoing cell death. Since IFNα inhibits cell proliferation and modulates immune responses, chronically high levels of this cytokine in LN of HIV-1 patients may impair differentiation and immune function of bystander CD4+ T cells, thus playing into the mechanisms of AIDS immunopathogenesis.

IntroductionThe mucosal immune system is the initial physical and immunologic barrier that HIV encounters. During the acute phase of HIV infection, the gut-associated lymphoid tissue is a site of significant viral replication and rapid depletion of CD4 ϩ T cells. 1 Complete immune reconstitution does not occur in the gut even after initiation of highly active antiretroviral therapy. 2,3 The chemokine receptor CCR6 is of crucial importance in mucosal immunity whereby it mediates mucosal homeostatic and inflammatory conditions. 4 Lack of CCR6 in mice is associated with intestinal lymphoid structure defects, suggesting that it is required in the development of lymphoid tissues. 5,6 The cognate ligand for CCR6, macrophage inflammatory protein (MIP)-3␣ (CCL20), is chemotactic for immature dendritic cells (DCs), effector/memory T cells, and B cells. 4,7 In addition to MIP-3␣, human ␤-defensin 2 (hBD2) is chemotactic for memory T cells, immature DCs, and tumor necrosis factor-␣-treated neutrophils via CCR6. 8,9 CCR6 is expressed on cell populations implicated in HIV infection, including DCs and effector/memory CD8 ϩ and CD4 ϩ T cells. [10][11][12] CCR6 ϩ memory T cells are selectively depleted from peripheral blood during HIV disease progression of which the majority of CD4 ϩ T cells that express the HIV coreceptor CCR5 also express CCR6. 13 The differential depletion of specific subsets of T cells may contribute to disease progression. 1,2 CCR6 is also expressed on 2 populations of CD4 ϩ T cells in the gut, CD4 ϩ ␣4␤7 ϩ and T helper type 17 (TH 17 ) cells, that are highly relevant to HIV infection. CD4 ϩ memory T cells within the lamina propria of the gut coexpress CCR6 and the gut homing receptor ␣4␤7, 11 which has been implicated in the spread of HIV in the gut. 14 TH 17 cells are an important component of mucosal immune defenses against bacteria and fungi, and CCR6 is expressed on all interleukin-17 (IL-17)-producing TH 17 cells and is critical for TH 17 cell homing to Peyer patches. 15,16 TH 17 cells are depleted from the gut in persons infected with HIV and in pathogenic simian immunodeficiency virus rhesus macaque models of infection. 17 In HIV infection, the presence of mucosal TH 17 cells is negatively correlated with blood viremia and positively correlated with enhanced restoration of CD4 ϩ T cells in the gut. 18,19 However, in nonpathogenic simian immunodeficiency virus sooty mangabey models of infection, TH 17 cells within the gut are depleted during the acute phase of infection but are subsequently restored, suggesting this subset of cells may play a role in disease progression. 17 Interestingly, IL-17 is a potent inducer of both MIP-3␣ and hBD2 in epithelial cells. 20,21 The hBDs 1 to 3 are of particular interest in mucosal immunity because they are expressed by epithelial cells in mucosae, where they form an antimicrobial barrier and contribute, by their interaction with CCR6, to the homeostasis of lymphoid compartments. [22][23][24] Defensins exert their antimicrobial activity on a broad range of Gram-p...

T-cell-derived soluble factors that inhibit both X4 and R5 HIV are recognized as important in controlling HIV. Whereas three β chemokines, regulated-on-activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1α, and MIP-1β, account for the suppression of R5 HIV by blockade of HIV entry, the major components responsible for the inhibition of X4 HIV strains have not been identified previously. We identify these factors primarily as a mixture of three β chemokines [macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC), and I-309] and two RNases (angiogenin and RNase 4) of lesser potency and show that in a clade B population, some correlate with clinical status and are produced by both CD4 + and CD8 + T cells (chemokines, angiogenin) or only by CD8 + T cells (RNase 4). The antiviral mechanisms of these HIV X4-suppressive factors differ from those of the previously described HIV R5-suppressive β chemokines.