Regulatory T (Treg) cells accumulate in the lymphoid tissues of human immunodeficiency virus (HIV)-infected individuals, contributing to the inability of the immune system to control virus replication. We investigate here Treg-cell numbers and functional markers (FOXP3, CTLA-4, IDO, and TGF-beta1) in lymphoid tissues from untreated infected hosts with progressive or nonprogressive disease (HIV-infected humans and simian immunodeficiency virus [SIV]-infected macaques). We found that increased numbers of FOXP3(+) T cells as well as increased expression of Treg-cell-associated functional markers were detected only during progressive disease. Such increases were not correlated with immune activation. Of importance, a high-perforin/FOXP3 ratio was associated with nonprogressive disease, suggesting that the immune control of virus replication represents a balance between cell-mediated immune responses and Treg-cell-mediated counter regulation of such responses. Furthermore, using an in vitro model of Treg-cell-HIV interactions, we showed that exposure of Treg cells to HIV selectively promoted their survival via a CD4-gp120-dependent pathway, thus providing an underlying mechanism for the accumulation of Treg cells in infected hosts with active viral replication. Considered together, our findings imply that therapeutic manipulation of Treg-cell number and/or function could improve immune control of HIV infection.

Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (T SCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a T SCM phenotype and stem cell-like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific T SCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of T SCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of T SCM cells.

A recombinant vaccine containing Aventis Pasteur’s canarypox vector (ALVAC)–HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC–simian immunodeficiency virus (SIV) and gp120 alum (ALVAC–SIV + gp120) equivalent vaccine, but not an ALVAC–SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

Loss of CD4 + T cells in the gut is necessary but not sufficient to cause AIDS in animal models, raising the possibility that a differential loss of CD4 + T-cell subtypes may be important. We found that CD4 + T cells that produce interleukin (IL)-17, a recently identified lineage of effector CD4 + T-helper cells, are infected by SIV mac251 in vitro and in vivo, and are found at lower frequency at mucosal and systemic sites within a few weeks from infection. In highly viremic animals, Th1 cells predominates over Th17 T cells and the frequency of Th17 cells at mucosal sites is negatively correlated with plasma virus level. Because Th17 cells play a central role in innate and adaptive immune response to extracellular bacteria, our finding may explain the chronic enteropathy in human immunodeficiency virus (HIV) infection. Thus, therapeutic approaches that reconstitute an adequate balance between Th1 and Th17 may be beneficial in the treatment of HIV infection.

Programmed death-1 (PD-1) is a critical mediator of virus-specific CD8 ؉ T-cell exhaustion. Here, we examined the expression of PD-1 on simian immunodeficiency virus (SIV)-specific CD8 ؉ T cells and its possible involvement in regulation of cytokine production, proliferation, and survival of these cells. The majority of SIV-specific CD8 ؉ T cells expressed a PD-1 high phenotype, independent of their differentiation status, in all tissues tested. PD-1 expression gradually declined on CD8 ؉ T cells specific for SIV-derived epitopes that had undergone mutational escape, indicating that antigen-specific TCR stimulation is the primary determinant of PD-1 expression. SIV-specific PD-1 high CD8 ؉ T cells produced IFN-␥, TNF-␣, and IL-2 under cognate peptide stimulation. While CD8 ؉ T cells that proliferated in response to antigen had a PD-1 high phenotype, it was determined that there was a reduced proliferative capacity of PD-1 high compared with PD-1 low SIVspecific CD8 ؉ T cells. PD-1 high SIV-specific CD8 ؉ T cells were highly susceptible to IntroductionVirus-specific CD8 ϩ T cells are the predominant effectors through which the immune system controls viral infections. 1,2 While several lines of evidence indicate that human immunodeficiency virus (HIV)-specific CD8 ϩ T cells are involved in the control of HIV replication, 3-10 several reports have focused on intrinsic defects in these cells to explain their failure to clear the virus, thereby leading to progression to acquired immunodeficiency syndrome (AIDS) in all infected individuals. [11][12][13][14] Similarly, simian immunodeficiency virus (SIV)-specific CD8 ϩ T cells contribute substantially to the partial control of viremia in rhesus macaques; depletion of CD8 ϩ T cells results in increased viremia in SIV-infected animals, 15,16 while viral escape at targeted epitopes accelerates disease progression and death in vaccinated animals. 4 Furthermore, in acute SIV infection, cytotoxic SIV-specific CD8 ϩ T cells appear concurrently with the waning of early viremia. 17 As in human infection with HIV, functional defects in SIV-specific CD8 ϩ T cells have been reported, potentially explaining why virtually all SIV-infected rhesus macaques progress to simian AIDS and death despite a readily measurable CD8 ϩ T-cell response. [17][18][19][20] Therefore, understanding factors that regulate the function(s) of SIV-and HIV-specific CD8 ϩ T cells is critical in the fight against AIDS.Chronic viral infection with ongoing antigenic stimulation often results in exhaustion of virus-specific CD8 ϩ T cells. 21,22 Chronically stimulated virus-specific CD8 ϩ T cells express only low levels of receptors for IL-7 and IL-15 23 and lose the ability to maintain homeostatic proliferation. In addition, they lose the ability to produce key cytokines that are critical for the maintenance of CD8 ϩ T-cell memory. 24 In humans, the function and phenotype of chronically stimulated CD8 ϩ T cells differ among viral infections. HIV-specific CD8 ϩ T cells are less polyfunctional and more sensitive ...

SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Among those persons with serious COVID-19 disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. Animal models of SARS-CoV-2 infection that manifest severe disease are needed to investigate the pathogenesis of COVID-19 induced ARDS and evaluate therapeutic strategies. Here we report ARDS in two aged African green monkeys (AGMs) infected with SARS-CoV-2 that demonstrated pathological lesions and disease similar to severe COVID-19 in humans. We also report a comparatively mild COVID-19 phenotype characterized by minor clinical, radiographic and histopathologic changes in the two surviving, aged AGMs and four rhesus macaques (RMs) infected with SARS-CoV-2. We found dramatic increases in circulating cytokines in three of four infected, aged AGMs but not in infected RMs. All of the AGMs showed increased levels of plasma IL-6 compared to baseline, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2 infection. Together, our results show that both RM and AGM are capable of modeling SARS-CoV-2 infection and suggest that aged AGMs may be useful for modeling severe disease manifestations including ARDS.

SummaryLow-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.

IntroductionThe induction and maintenance of immune responses to antigens is tightly regulated. Activation of T cells requires the interaction between the T-cell receptor and the antigen presented on the surface of an antigen-presenting cell (APC; first signal) and engagement of CD28 (second signal) by the costimulatory molecules B7-1 (CD80) and B7-2 (CD86). 1,2 Costimulation is particularly important for the initial T-cell response, promoting proliferation and survival. Following antigen stimulation, both CD28 and its negative regulatory, cytotoxic T lymphocyte antigen-4 (CTLA-4), are up-regulated on the cell surface and compete for their ligands, B7-1 and B7-2. CTLA-4 binds to both B7-1 and B7-2 with higher (10-to 20-fold) affinity than CD28, 3,4 and, in contrast to CD28, CTLA-4 suppresses T-cell activation. However, competition with CD28 for the costimulatory molecules is not likely to be the main mechanism responsible for CTLA-4 immunoregulatory activity. [5][6][7] Several lines of evidence suggest that expression of CTLA-4 by CD25 ϩ CD4 ϩ regulatory T (T reg ) cells plays a role in controlling peripheral T-cell tolerance and differentiation. 8,9 T reg cells are CD4 ϩ T lymphocytes that express high levels of the interleukin-2 (IL-2) receptor ␣-chain (CD25), and constitutively express CTLA-4. T reg cells inhibit the proliferation of T cells through contactdependent or cytokine-mediated (IL-10, transforming growth factor-␤ [TGF-␤]) inhibition of T-cell responses. 10 T reg cells can induce activation of the enzyme IDO in APCs via CTLA-4-mediated ligation of CD80/CD86. 11,12 IDO confers immunosuppressive activity to APCs. 11,12 Two mechanisms have been suggested as mediators of the T-cellsuppressive action of IDO 13 : degradation and consequent reduction of tryptophan, an essential amino acid required for T-cell proliferation; and generation of inhibitory tryptophan metabolites. Blocking CTLA-4 signals with monoclonal antibodies may provide an important tool to influence the host immune response in clinical settings. For example, synergy between anti-CD25 and anti-CTLA-4 monoclonal antibodies has been shown to be effective in antitumor therapy. 14,15 T reg cells may suppress a potentially successful adaptive host immune response to a pathogen. [16][17][18][19][20][21] In the case of HIV infection, CTLA-4 expression is higher in patients with advanced clinical symptoms compared with asymptomatic individuals, 22,23 and the frequency of CTLA-4-expressing CD25 ϩ CD4 ϩ T reg cells is increased in lymphoid tissues in untreated individuals infected with HIV-1. 24 Primary infection of macaques with simian immunodeficiency virus (SIV) is associated with an increase in T reg cells, IDO, TGF-␤, and IL-10. 25 Similarly, chronic SIV infection is associated with an accumulation of T reg cells in lymphoid tissues, including the gut, and an increased level of immunosuppressive cytokines (A. B., M. V., A. H., D. F., J. N., Valentina Cecchinato, G. F., G. M. S., and C. C., our unpublished results, October 2006).Here, we examined...