Suppression of natural killer (NK) cell activity of spleen cells by thymocytes

The in vitro influence of thymus cells on natural killer cell activity of spleen cells against prelabeled target cells (YAC-I and RL[male symbol]I) has been studied in syngeneic as well as in allogeneic murine models. In mixing experiments to demonstrate suppression, total thymocytes have been found to have no effect on NK activity of syngeneic or allogeneic spleen cells. Among several thymocyte fractions separated by velocity sedimentation, a relatively faster sedimenting fraction showed remarkable suppression of NK activity by spleen cells against two target cells. The suppressive effect of this particular fraction on NK activity was demonstrated to be proportional to the cell dose. The suppressive function was resistant to irradiation at 1000 or 2000 rad administered in vitro and was not restricted by the major histocompatibility complex. Moreover, the thymocyte fraction which induced suppression was not sensitive to NK-mediated cytolysis by syngeneic spleen cells. The suppression of NK cytolysis in vitro by certain subpopulations of thymocytes as observed in the present studies may be consistent with a role for the thymus in regulating NK activity in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24461/1/0000736.pd

Opioids exacerbate inflammation in people with well-controlled HIV

IntroductionPeople with HIV (PWH) are known to have underlying inflammation and immune activation despite virologic control. Substance use including opioid dependence is common in this population and is associated with increased morbidity and reduced lifespan. The primary objective of the present study termed opioid immunity study (OPIS), was to investigate the impact of chronic opioids in PWH.MethodsThe study recruited people with and without HIV who had opioid use disorder (OUD). Study participants (n=221) were categorized into four groups: HIV+OP+, n=34; HIV-OP+, n=66; HIV+OP-, n=55 and HIV-OP-, n=62 as controls. PWH were virally suppressed on ART and those with OUD were followed in a syringe exchange program with confirmation of OP use by urine drug screening. A composite cytokine score was developed for 20 plasma cytokines that are linked to inflammation. Cellular markers of immune activation (IA), exhaustion, and senescence were determined in CD4 and CD8 T cells. Regression models were constructed to examine the relationships of HIV status and opioid use, controlling for other confounding factors.ResultsHIV+OP+ participants exhibited highest inflammatory cytokines and cellular IA, followed by HIV-OP+ for inflammation and HIV+OP- for IA. Inflammation was found to be driven more by opioid use than HIV positivity while IA was driven more by HIV than opioid use. In people with OUD, expression of CD38 on CD28-CD57+ senescent-like T cells was elevated and correlated positively with inflammation.DiscussionGiven the association of inflammation with a multitude of adverse health outcomes, our findings merit further investigations to understand the mechanistic pathways involved

S-nitrosoglutathione modulates CXCR4 and ICOS expression

The expression of CXCR4, a membrane protein which is involved in the entry of HIV-1, is down-modulated from the cell surface by Phorbol 12-myristate 13-acetate (PMA) and the Ca+ ionophore, Ionomycin. Inducible co-stimulator (ICOS), which contributes to lymphocyte proliferation, is up-regulated by PMA/Ionomycin. We examined the influence of S-nitrosoglutathione (SNG), an inhibitor of Vacuolar H+-ATPase (V-ATPase), on the expression of CXCR4 and ICOS in PMA/Ionomycin-treated peripheral mononuclear cells (PBMC), and of CXCR4 alone in lymphoid cell lines. In this report, we show that SNG interferes with both effects of PMA/Ionomycin, namely CXCR4 down-regulation and ICOS up-regulation. These studies imply opposing roles of V-ATPase in the regulation of CXCR4 and ICOS. The influence of SNG in modulating the susceptibility of T cells to HIV-1 and on their immune responses needs further investigation

Determinants of HIV-specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIV-gag-specific responses with exogenous IL-15

Cellular immune responses play a central role in controlling HIV-1 infection. HIV-specific IFN-gamma production by CD8 T cells was evaluated in 17 HLA-A2+ HIV-infected pediatric patients (age range 1 month to 16 years) in an ELISPOT assay. Most patients (15/17) exhibited responses to HIV-gag, followed by responses to envelope gp120, gp41, and V3 loop. Only 7 patients responded to all four antigenic peptides. Treatment-related immune reconstitution of CD4 T cells was associated with increase in gag-specific responses, but these declined with prolonged viral suppression. Exogenous IL-15 resulted in augmentation of HIV-gag-specific response in 71% of patients, while IL-2 and IL-7 had variable effects, augmenting responses in 25% patients. Thus, HIV-specific CD8 T-cell responses are dependent on both CD4 T-cell help and antigenic stimulation. The cytokine IL-15 may be a useful modality as adjunctive therapy to augment HIV-specific memory CD8 T cells

The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals

Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy for suppression of HIV, but its effects on the immune system are relatively unknown. Recently, it has been reported that PIs inhibit lymphocyte apoptosis. In the present study we have investigated the effects of ex vivo addition of IDV on lymphocyte activation and apoptosis in cells from HIV-infected children (n = 18) and from healthy uninfected individuals (controls, n = 5) as well as in Jurkat and PM1 T-cell lines. Pretreatment of control peripheral blood mononuclear cell (PBMC) cultures with IDV resulted in a dose-dependent inhibition of lymphoproliferative responses to different activation stimuli. Additionally, this treatment led to cell-cycle arrest in G0/G1 phase in anti-CD3 monoclonal antibody–stimulated PBMC cultures in controls and in 15 of 18 HIV-infected children. Spontaneous- or activation-induced apoptosis of PBMCs from HIV-infected or uninfected individuals or of Fas-induced apoptosis in Jurkat and PM1 T cell lines were not inhibited by IDV. Moreover, IDV did not inhibit activation of caspases-1, -3, -4, -5, -9, and -8 in lysates of Jurkat T cells undergoing Fas-induced apoptosis. The findings indicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV

Discordant expression of perforin and granzyme A in total and HIV-specific CD8 T lymphocytes of HIV infected children and adolescents

Perforin and granzyme are cytotoxic effector molecules that are believed to play essential roles in cytotoxic T cell (CTL) activity. We tested the hypothesis that dysregulation of these effector molecules contributes to defects of CD8 antiviral immune responses in pediatric subjects in chronic stages of perinatal HIV infection. Studies of CD8 T cells were conducted in 33 treatment experienced HIV+ patients (median age, 10.6 years) and in 14 age-matched healthy controls. CD8 T cells specific for HIV Gag and Pol peptides were identified in HLA-A2+ patients by tetramer binding assays. HIV-specific and total CD8 T cells were examined for perforin, granzyme and expression of CD27, a marker that is lost in terminally differentiated cells. Three populations of CD8 T cells were identified: granzyme+ perforin+; granzyme+ perforin- and cells negative for both perforin and granzyme. In HIV infected patients, granzyme+ cells were increased in total CD8 T cells (39% versus 13% in controls) and were highest in HIV Gag-specific CD8 cells (42%). Perforin+ CD8 T cells were approximately fivefold fewer than granzyme+ CD8 T cells and were enriched in CD27 negative cells. Most HIV-specific CD8 cells were CD27+. Granzyme expression in CD8 T cells correlated negatively with CD4 percentage and positively with virus load. A disproportionate and generalized increase in CD27+, granzyme+, CD8 T cells is a hallmark of established pediatric HIV infection. These findings support the concept of skewed maturation, with failure of CD8 T cells to mature into perforin-enriched, CD27-negative, effector cells