We adoptively transferred donor-derived cytomegalovirus (CMV)-specific T-cell lines into 8 stem cell transplant recipients lacking CMV-specific T-cell proliferation. All patients, of whom one was infected by a CMV strain that was genotypically ganciclovir resistant, had received unsuccessful antiviral chemotherapy for more than 4 weeks. CMVspecific lines had been prepared by repetitive stimulation with CMV antigen, which increased the percentage of CMV-specific T cells and ablated alloreactivity completely even against patients mismatched for 1 to 3 HLA antigens. After transfer of 10 7 T cells/m 2 at a median of 120 days (range, 79-479 days) after transplantation, no side effects were noticed. Despite cessation of antiviral chemotherapy, the CMV load dropped significantly in all 7 evaluable patients, with a maximal reduction after a median of 20 days (range, 5-31 days). In 2 patients with high virus load, the antiviral effect was only transient. One of these patients received a second T-cell infusion, which cleared the virus completely. At a median of 11 days after transfer, CMV-specific T-cell proliferation was demonstrated in 6 patients, and an increase in CMV-specific CD4 ؉ T cells was demonstrated in 5 patients. In 6 patients, 1.12 to 41 CMV-specific CD8 ؉ T cells/L blood were detected at a median of 13 days after transfer, with an increase in all patients lacking CMV-specific CD8 ؉ T cells prior to transfer. Hence, anti-CMV cellular therapy was successful in 5 of 7 patients, whereas in 2 of 7 patients, who received an intensified immune suppression at the time of or after T-cell therapy, only transient reductions in virus load were obtained. (Blood. 2002;99: 3916-3922)
SUMMARY Dendritic cells (DCs) in mucosal surfaces are early targets for human immunodeficiency virus-1 (HIV-1). DCs mount rapid and robust immune responses upon pathogen encounter. However, immune response in the early events of HIV-1 transmission appears limited, suggesting that HIV-1 evade early immune control by DCs. We report that HIV-1 induces a rapid shutdown of autophagy and immunoamphisomes in DCs. HIV-1 envelope activated the mammalian target of rapamycin pathway in DCs, leading to autophagy exhaustion. HIV-1-induced inhibition of autophagy in DC increased cell-associated HIV-1 and transfer of HIV-1 infection to CD4+ T cells. HIV-1-mediated downregulation of autophagy in DCs impaired innate and adaptive immune responses. Immunoamphisomes in DCs engulf incoming pathogens and appear to amplify pathogen degradation as well as Toll-like receptor responses and antigen presentation. The findings that HIV-1 downregulates autophagy and impedes immune functions of DCs represent a pathogenesis mechanism that can be pharmacologically countered with therapeutic and prophylactic implications.
CD8 ؉ T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8 ؉ T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIVsuppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIVspecific CD8 ؉ T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8 ؉ T cells from infected donors. We report that attributes of CD8 ؉ T-cell effi- IntroductionCD8 ϩ T cells are essential for effective immunity against HIV-1, and the induction of such responses using vaccines has become a major objective in the strategy to halt the pandemic. 1 However, the recent outcome of the Merck STEP study, the most ambitious trial of an anti-HIV T cell-based vaccine conducted to date, has been a major disappointment. 2 Despite its immunogenicity, the vaccine failed both to prevent infection of vaccinated volunteers at high risk of acquiring HIV and to reduce viral load set points in infected vaccinees. This failure has roused the scientific community to step back and reconsider its basic knowledge of T cell-mediated efficacy. 3,4 Indeed, consensual opinion is that our general understanding of T-cell efficacy in HIV-1 infection is actually still limited, which represents a clear obstacle to the design of successful vaccines.Over recent years, qualitative attributes of CD8 ϩ T cells have increasingly become the focus of attempts to identify reliable correlates of immune protection against HIV. Among these, polyfunctionality 5 and HIV-suppressive activity 6 have been associated with spontaneous control of HIV infection and slower disease progression rates in infected patients. Of note, polyfunctionality is currently seen as the best correlate of T-cell efficacy measurable directly ex vivo. 7 Polyfunctional CD8 ϩ T cells are those that exhibit multiple effector functions (ie, degranulation and production of antiviral factors) simultaneously upon antigen encounter; this can be assessed after stimulation with cognate peptides by multiparametric flow cytometry (eg, mobilization of CD107 and intracellular production of interferon [IFN]-␥, tumor necrosis factor [TNF]-␣, interleukin-2 [IL-2], and macrophage-inflammatory protein [MIP]-1). 5 HIV-suppressive activity reflects the capacity of HIV-specific CD8 ϩ T cells to eliminate HIV-infected targets via classical class I major histocompatibility complex (MHC)-restricted cytotoxic lysis. 6,8 It can be assessed using primary CD4 ϩ T cells infected in vitro with HIV in the presence of...
DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide-exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus-T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.
DC-SIGN, a dendritic cell (DC)-specific lectin, mediates clustering of DCs with T lymphocytes, a crucial event in the initiation of immune responses. DC-SIGN also binds HIV envelope glycoproteins, allowing efficient virus capture by DCs. We show here that DC-SIGN surface levels are upregulated in HIV-1-infected DCs. This process is caused by the viral protein Nef, which acts by inhibiting DC-SIGN endocytosis. Upregulation of DC-SIGN at the cell surface dramatically increases clustering of DCs with T lymphocytes and HIV-1 transmission. These results provide new insights into how HIV-1 spreads from DCs to T lymphocytes and manipulates immune responses. They help explain how Nef may act as a virulence factor in vivo.
HIV-1 virions are efficiently captured by monocyte-derived immature dendritic cells (iDCs), as well as by cell lines expressing the lectin DC-SIGN. Viral infectivity can be retained for several days, and even enhanced, before transmission to CD4 ؉ lymphocytes. The role of DC-SIGN in viral retention and enhancement of infection is not fully understood and varies according to the cell line expressing the lectin. We studied here the mechanisms underlying this process. We focused our study on X4-tropic human immunodeficiency virus (HIV) strains, since they were widely believed not to replicate in iDCs. However, we first show that X4 HIV replicates covertly and slowly in iDCs. This is also the case in Raji-DC-SIGN cells, which are classically used to study HIV transmission. We used either single-cycle or replicative HIV and measured viral RT and replication to further demonstrate that transfer of incoming virions from iDCs or DC-SIGN ؉ cells occurs only on the short-term (i.e., a few hours after viral exposure). There is no long-term storage of original HIV particles in these cells. A few days after viral exposure, replicative viruses, and not single-cycle virions, are transmitted to CD4؉ cells. The cell-type-dependent activity of DC-SIGN reflects the ability of HIV to replicate covertly in some cells, and not in others.
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