Chronic exposure to type-I IFN under lymphopenic conditions alters CD4 T cell homeostasis.

HIV infection and the associated chronic immune activation alter T cell homeostasis leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these outcomes are not totally defined and only partially explained by the direct cytopathic effect of the virus. In this manuscript, we addressed the impact of lymphopenia and chronic exposure to IFN-α on T cell homeostasis. In a lymphopenic murine model, this interaction led to decreased CD4 counts and CD8 T cell expansion in association with an increase in the Signal Transducer and Activator of Transcription 1 (STAT1) levels resulting in enhanced CD4 T cell responsiveness to IFN-α. Thus, in the setting of HIV infection, chronic stimulation of this pathway could be detrimental for CD4 T cell homeostasis.

CD4 and CD8 T cell immune activation during chronic HIV infection: roles of homeostasis, HIV, type I IFN, and IL-7.

Immune activation plays an important role in the pathogenesis of HIV disease. Although the causes are not fully understood, the forces that lead to immune dysfunction differ for CD4 and CD8 T cells. In this study, we report that the molecular pathways that drive immune activation during chronic HIV infection are influenced by differences in the homeostatic regulation of the CD4 and CD8 T cell pools. Proliferation of CD4 T cells is controlled more tightly by CD4 T cell numbers than is CD8 T cell proliferation. This difference reflects the importance of maintaining a polyclonal CD4 T cell pool in host surveillance. Both pools of T cells were found to be driven by viral load and its associated state of inflammation. In the setting of HIV-induced lymphopenia, naive CD4 T cells were recruited mainly into the proliferating pool in response to CD4 T cell depletion, whereas naive CD8 T cell proliferation was driven mainly by levels of HIV RNA. RNA analysis revealed increased expression of genes associated with type I IFN and common γ chain cytokine signaling in CD4 T cell subsets and only type I IFN-associated genes in CD8 T cell subsets. In vitro studies demonstrated enhanced STAT1 phosphorylation in response to IFN-α and increased expression of the IFNAR1 transcripts in naive and memory CD4 T cells compared with that observed in CD8 T cells. CD4 T cell subsets also showed enhanced STAT1 phosphorylation in response to exogenous IL-7.

Veterans Health Administration Primary Care Provider Adherence to Prescribing Guidelines for Systemic Hormone Therapy in Menopausal Women.

BACKGROUND: Systemic hormone therapy (HT) is effective for treating menopausal symptoms but also confers risks. Therefore, experts have developed clinical guidelines for its use. PURPOSE: We assessed primary care guideline adherence in prescribing systemic HT, and associations between adherence and provider characteristics, in four Veterans Health Administration (VA) facilities. METHODS: We abstracted medical records associated with new and renewal systemic HT prescriptions examining adherence to guidelines for documenting indications and contraindications; prescribing appropriate dosages; and prescribing progesterone. RESULTS: Average guideline adherence was 58%. Among new prescriptions, 74% documented a guideline-adherent indication and 28% documented absence of contraindications. Among renewals, 39% documented a guideline-adherent indication. In prescribing an appropriate dose, 45% of new prescriptions were guideline-adherent. Among renewal prescriptions with conjugated equine estrogen doses ≥0.625 mg or equivalent, 16% documented the dosing rationale. Among 116 prescriptions for systemic estrogen in women with a uterus, progesterone was not prescribed in 8. CONCLUSIONS: Guideline adherence in prescribing systemic HT was low among VA primary care providers. Failures to coprescribe progesterone put women at increased risk for endometrial cancer. IMPLICATIONS: Intervention development is urgently needed to improve guideline adherence among primary care prescribers of systemic HT for menopause. Similar assessments should be conducted in community settings.