Age effects on telomere length and telomerase expression in peripheral blood lymphocytes were analyzed from 121 normal individuals age newborn to 94 years and revealed several new findings. 1) Telomere shortening was observed in CD4+ and CD8+ T and B cells with age. However, the rate of telomere loss was significantly different in these populations, 35 ± 8, 26 ± 7, and 19 ± 7 bp/year for CD4+ and CD8+ T and B cells, respectively. In addition, CD4+ T cells had the longest average telomeres at all ages, followed by B cells, with CD8+ T cell telomeres the shortest, suggesting that these lymphocyte populations may have different replicative histories in vivo. 2) Telomerase activity in freshly isolated T and B cells was indistinguishably low to undetectable at all ages but was markedly increased after Ag and costimulatory receptors mediated stimulation in vitro. Furthermore, age did not alter the magnitude of telomerase activity induced after stimulation of T or B lymphocytes through Ag and costimulatory receptors or in response to PMA plus ionomycin treatment. 3) The levels of telomerase activity induced by in vitro stimulation varied among individual donors but were highly correlated with the outcome of telomere length change in CD4+ T cells after Ag receptor-mediated activation. Together, these results indicate that rates of age-associated loss of telomere length in vivo in peripheral blood lymphocytes is specific to T and B cell subsets and that age does not significantly alter the capacity for telomerase induction in lymphocytes.

Key Points Cytokine-activated NK cells display distinct gene expression programs in response to cytokine withdrawal. IL-15 sustains antitumor functions of NK cells through mTOR-governed metabolic processes.

We sought to investigate how peripheral blood and tumorinfiltrating NK cells differ in patients with breast cancer and sarcoma, and if tumor-infiltrating NK cells develop immunoregulatory functions. Compared with peripheral blood NK cells, tumorinfiltrating NK cells undergo phenotypic changes and acquire the expression of several immune checkpoint receptors. The expression of these immune checkpoint molecules was significantly higher on NK cells expressing CD73. Mechanistically, NK cells and IL-10 (21, 22). More recently in the context of cancer, CD56 + CD3cells in patients with ovarian cancer suppressed the growth of T cells, as observed within an ex vivo expansion of tumor-infiltrating lymphocytes (TILs). Even though it was demonstrated that the suppression was mediated by NKp46 engagement, the underlying mechanisms of how NK cells suppress are still unclear (23). It is also still unclear how conventional NK cells can undergo a phenotypic switch to suppress other TIL populations and contribute to tumor immune escape.

Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38+ HLA-DR+ CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals.

Foamy viruses (FV) are the oldest known genus of retroviruses and have persisted in nonhuman primates for over 60 million years. FV are efficiently transmitted, leading to a lifelong nonpathogenic infection. Transmission is thought to occur through saliva, but the detailed mechanism is unknown. Interestingly, this persistent infection contrasts with the rapid cytopathicity caused by FV in vitro, suggesting a host defense against FV. To better understand the tissue specificity of FV replication and host immunologic defense against FV cytopathicity, we quantified FV in tissues of healthy rhesus macaques (RM) and those severely immunosuppressed by simian immunodeficiency virus (SIV). Contrary to earlier findings, we find that all immunocompetent animals consistently have high levels of viral RNA in oral tissues but not in other tissues examined, including the small intestine. Strikingly, abundant viral transcripts were detected in the small intestine of all of the SIV-infected RM, which has been shown to be a major site of SIV (and human immunodeficiency virus)-induced CD4 ؉ T-cell depletion. In contrast, there was a trend to lower viral RNA levels in oropharyngeal tissues of SIV-infected animals. The expansion of FV replication to the small intestine but not to other CD4 ؉ T-cell-depleted tissues suggests that factors other than T-cell depletion, such as dysregulation of the jejunal microenvironment after SIV infection, likely account for the expanded tissue tropism of FV replication.

Foamy viruses (FV), the oldest known genus of Retroviridae, are unique among the retroviruses in having no disease association. It is not known why FV are non-pathogenic while infection by their closest relatives can be deadly. This may be related to the estimated 60 million years of coevolution of FV and their primate hosts. We review the current state of knowledge of FV infection, including information about the sites of viral replication and host immune responses, and discuss the role these may play in establishing persistent yet non-pathogenic infections. Whether FV has pathologic consequences in immunosuppressed hosts has not been thoroughly investigated. As most primates in HIV/SIV research are coinfected with FV, investigation into possible interactions between these viruses is of interest. The use of FV as a vector for gene therapy is also discussed.

Foamy viruses (FVs) are ancient retroviruses that are ubiquitous in nonhuman primates (NHPs). While FVs share many features with pathogenic retroviruses, such as human immunodeficiency virus, FV infections of their primate hosts have no apparent pathological consequences. Paradoxically, FV infections of many cell types in vitro are rapidly cytopathic. Previous work has shown that low levels of proviral DNA are found in most tissues of naturally infected rhesus macaques, but these proviruses are primarily latent. In contrast, viral RNA, indicative of viral replication, is restricted to tissues of the oral mucosa, where it is abundant. Here, we perform in situ hybridization on tissues from rhesus macaques naturally infected with simian FV (SFV). We show that superficial differentiated epithelial cells of the oral mucosa, many of which appear to be shedding from the tissue, are the major cell type in which SFV replicates. Thus, the innocuous nature of SFV infection can be explained by replication that is limited to differentiated superficial cells that are short-lived and shed into saliva. This finding can also explain the highly efficient transmission of FVs among NHPs.

Foamy viruses (FV) are retroviruses that naturally infect many hosts, including most nonhuman primates (NHPs). Zoonotic infection by primate FV has been documented in people inAsia who reported contact with free-ranging macaques. FV transmission in Asia is a concern, given abundant human-NHP contact, particularly at monkey temples and in urban settings. We have developed three assays capable of detecting the presence of FV in Asian NHP species that are commensal with humans: enzyme-linked immunosorbent assay (ELISA), Western blot assays using recombinant viral Gag protein, and an indicator cell line that can detect macaque FV. The recombinant ELISA correlates very well with the presence of FV sequences detected by PCR. We have used these assays to demonstrate both that FV is highly prevalent among free-ranging NHPs and that seroconversion occurs at a young age in these animals. These assays should also prove useful for large-scale analysis of the prevalence of FV infections in human populations in Asia that are commensal with free-ranging NHPs.Foamy viruses (FV) comprise a subfamily of retroviruses (22). FV were first identified over 50 years ago (10) as contaminants in monkey tissue culture explants. They are highly cytopathic in tissue culture. Infection of a number of cell types, including fibroblasts and epithelial cells, leads to rapid syncytium formation, vacuolization, and cell death. Despite this, infection in animal hosts does not produce a recognized disease state. Rather, FV establish a persistent asymptomatic infection in both natural and zoonotic hosts (reviewed in reference 23). Although proviral DNA can be found in nearly every tissue, indicating infection, the virus only replicates to a detectable level in the oral mucosa. Replication at this site facilitates transfer to other hosts through saliva (26). Although it is not known how latency is maintained in vivo, an in vitro latency model has been described in which viral replication is controlled at the transcriptional level (24).FV are widespread and have been isolated from a variety of nonprimate species, including cows, cats, and horses (reviewed in reference 27). All nonhuman primates (NHPs) examined to date, including gorillas, chimpanzees, orangutans, baboons, African green monkeys, and macaques (reviewed in reference 12) also harbor FV, called simian foamy viruses (SFV). Infection among captive populations of NHPs is high. Studies from captive and free-ranging populations show that up to 100% of adult NHPs are infected with SFV (2,7,8,16,17,19). Curiously, despite its widespread infection among NHPs, evidence suggests that there is no human-specific FV (reviewed in reference 23). A single report describing HFV (human foamy virus) in a tissue culture that was derived from a Kenyan man (1) is now believed to represent a zoonotic transmission of SFV from chimpanzees (32). There are several reports of zoonotic transmission of SFV from various taxa of NHPs. Many of the infected individuals, such as zoo keepers and animal care workers, had frequ...