ABSTRACT
Long-acting injectable antiretroviral treatment (LAI ART), such as a bimonthly injection of cabotegravir/rilpivirine, is a promising HIV treatment option. LAI ART may particularly benefit people who are reluctant to initiate or are poorly adherent to daily oral pills and not virally suppressed. However, the acceptability and feasibility of LAI ART among individuals with viremia in Africa has not been well studied. We conducted qualitative in-depth interviews with 38 people living with HIV with viral load ≥1000 copies/mL and 15 medical and nursing staff, and 6 focus group discussions with peer health workers, to examine acceptability and feasibility of LAI ART in south-central Uganda. Transcripts were thematically analyzed through a team-based framework approach. Most people living with HIV reacted positively toward LAI ART and endorsed interest in taking it themselves. Most felt LAI ART would make adherence easier by reducing the challenge with remembering daily pills, particularly in the context of busy schedules, travel, alcohol use, and dietary requirements. Participants also appreciated the privacy of injections, reducing the likelihood of stigma or inadvertent HIV serostatus disclosure with pill possession. Concerns about LAI ART included side effects, perceived medication effectiveness, fear of injection, and medical mistrust and conspiracy beliefs. Health workers and participants with viremia also noted health system challenges, such as stockouts and monitoring treatment failure. However, they felt the health system could overcome these challenges. Implementation complexities must be addressed as LAI ART is introduced and expanded in Africa to best support viral suppression and address HIV care continuum gaps.
Subject(s)
Anti-HIV Agents , HIV Infections , Humans , HIV Infections/drug therapy , Uganda , Feasibility Studies , Trust , Viremia/drug therapy , Anti-Retroviral Agents/therapeutic use , Anti-HIV Agents/therapeutic useABSTRACT
DNAM-1 is an activating immunoreceptor on T cells and natural killer (NK) cells. Expression levels of its ligands, CD155 and CD112, are up-regulated on tumor cells. The interaction of DNAM-1 on CD8+ T cells and NK cells with the ligands on tumor cells plays an important role in tumor immunity. We previously reported that mice deficient in DNAM-1 showed accelerated growth of tumors induced by the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Contrary to those results, we show here that tumor development induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) together with DMBA was suppressed in DNAM-1-deficient mice. In this model, DNAM-1 enhanced IFN-γ secretion from conventional CD4+ T cells to promote inflammation-related tumor development. These findings suggest that, under inflammatory conditions, DNAM-1 contributes to tumor development via conventional CD4+ T cells.
Subject(s)
Antigens, Differentiation, T-Lymphocyte , Neoplasms , Animals , Antigens, Differentiation, T-Lymphocyte/metabolism , Inflammation/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural , Ligands , MiceABSTRACT
Lung cancer accounts for the highest death rate among cancers worldwide, with most patients being diagnosed with non-small cell lung cancer (NSCLC), urging more effective therapies. We report that JK273, a pyrrolo[2,3-d]pyrimidine analog, which inhibits α4 integrin signaling, showed a selective cytotoxic effect against HCI-H460 NSCLC cells, with an IC50 of 0.98 ± 0.15 µM, but showed less sensitivity to fibroblasts with a selectivity index (SI) greater than 30. This effect was attributed to cell cycle arrest at S phase by JK273 treatment, resulting in the apoptosis of NCI-H460 cells, further confirmed by exposing phosphatidylserine and morphological changes. Taken together with the previous study of JK273 inhibiting cell migration, we propose that JK273 could serve as an antitumor compound to specifically target cancer cells but not non-cancerous cells by triggering programmed cell death, in addition to anti-metastatic effects in cancer therapy.
Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Integrin alpha4/genetics , S Phase/drug effects , Signal Transduction/drug effects , Tubercidin/analogs & derivatives , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression , HeLa Cells , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Integrin alpha4/metabolism , Jurkat Cells , MCF-7 Cells , Organ Specificity , Phosphatidylserines , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Signal Transduction/genetics , Tubercidin/pharmacologyABSTRACT
DNAM-1 is an activating receptor expressed on NK cells and T cells and plays an important role in cytotoxicity of these cells against target cells. Although the role of DNAM-1 in the function of T cells and NK cells has been well studied, the expression and function of DNAM-1 on myeloid cells have been incompletely understood. In this study, we investigated expression of DNAM-1 on monocyte subsets in mouse peripheral blood and found that only inflammatory monocytes (iMos), but not patrolling monocytes (pMos), expressed high levels of DNAM-1. In addition, we found that DNAM-1 was highly expressed on iMos, rather than pMos, also in human. Furthermore, we found that DNAM-1 on inflammatory monocytes was involved in cell adhesion to CD155-expressing cells. Therefore, we propose that expression of DNAM-1 on inflammatory monocytes are evolutionally conserved and act as an adhesion molecule on blood inflammatory monocytes.
