Peter Gulick

Neutropenia during HIV Infection: Adverse Consequences and Remedies

Neutropenia frequently occurs in patients with Human immunodeficiency virus (HIV) infection. Causes for neutropenia during HIV infection are multifactoral, including the viral toxicity to hematopoietic tissue, the use of myelotoxic agents for treatment, complication with secondary infections and malignancies, as well as the patients association with confounding factors which impair myelopoiesis. An increased prevalence and severity of neutropenia is commonly seen in advanced stages of HIV disease. Decline of neutrophil phagocytic defense in combination with the failure of adaptive immunity renders the host highly susceptible to developing fatal secondary infections. Neutropenia and myelosuppression also restrict the use of many antimicrobial agents for treatment of infections caused by HIV and opportunistic pathogens. In recent years, HIV infection has increasingly become a chronic disease because of progress in antiretroviral therapy (ART). Prevention and treatment of severe neutropenia becomes critical for improving the survival of HIV-infected patients.

Analysis of heterogeneity in daunorubicin uptake by human leukemia cells using laser flow cytometry

SummaryHeterogeneity in daunorubicin uptake by leukemic blast cells obtained from the bone marrow of 16 patients with acute leukemia (10 acute nonlymphocytic leukemia and 6 acute lymphocytic leukemia) was determined by laser flow cytometry following drug treatment in vitro for 1 hr. Fluorescence profiles of cellular anthracycline levels in the various samples indicated a marked heterogeneity in daunorubicin uptake and the range of detectable drug fluorescent cells was 34% – 99%. A retrospective analysis of disease outcome in these patients who were treated with a daunorubicin or doxorubicin containing induction regimen indicated the following: (a) 8 of 11 patients who entered complete remission had > 80% of leukemic blast cells accumulating detectable amounts of daunorubicin; and (b) 3 of 4 patients who did not respond to chemotherapy had < 40% of the leukemic blast cells accumulating detectable amounts of daunorubicin. These results suggest that laser flow cytometry may be useful in determining qualitative and quantitative differences in daunorubicin levels in heterogeneous tumor cell populations.

Δ9-tetrahydrocannabinol Suppresses Secretion of Ifnα by Plasmacytoid Dendritic Cells From Healthy and Hiv-infected Individuals

Abstract: Plasmacytoid dendritic cells (pDCs) play a crucial role in host antiviral immune response through secretion of type I interferon. Interferon alpha (IFN&agr;), a type I IFN, is critical for mounting the initial response to viral pathogens. A consequence of Human Immunodeficiency Virus-1 (HIV) infection is a decrease in both pDC number and function, but prolonged pDC activity has been linked with progression from HIV infection to the development of AIDS. Patients with HIV in the United States routinely use cannabinoid-based therapies to combat the side effects of HIV infection and antiretroviral therapy. However, cannabinoids, including &Dgr;9-tetrahydrocannabinol (THC), are well-characterized immunosuppressants. Here, we report that THC suppressed secretion of IFN&agr; by pDC from both healthy and HIV+ donors through a mechanism involving impaired phosphorylation of interferon regulatory factor 7. These results suggest that THC can suppress pDC function during the early host antiviral response by dampening pDC activation.

Dermatomyositis Associated With Fallopian Tube Carcinoma

Dermatomyositis (DM) is an idiopathic inflammatory myopathy associated with characteristic cutaneous and extracutaneous manifestations, including malignancy. Primary fallopian tube carcinoma (FTC) is the least common site of origin for a malignant neoplasm of the female genital tract. This report describes the first documented case of DM and concurrent FTC in the United States. A 62-year-old woman presented with DM and was subsequently found to have FTC. During her clinical course, she had improvement in strength and function with treatment of the underlying FTC, which also correlated with lower creatinine phosphokinase levels. An association between DM and FTC may exist because of significant functional strength improvements after tumor removal and chemotherapy.

HIV-infected cannabis users have lower circulating CD16+ monocytes and IP-10 levels compared to non-using HIV patients.

Objective: Chronic immune activation and elevated numbers of circulating activated monocytes (CD16+) are implicated in HIV-associated neuroinflammation. The objective was to compare the level of circulating CD16+ monocytes and IFN-&ggr;-inducible protein 10 (IP-10) between HIV-infected cannabis users (HIV+MJ+) and noncannabis users (HIV+MJ−) and determine whether in-vitro &Dgr;9-Tetrahydrocannabinol (THC), a constituent of cannabis, affected CD16 expression as well as IP-10 production by monocytes. Design: The levels of circulating CD16+ monocytes and IP-10 from HIV+MJ− and HIV+MJ+ donors were examined. In-vitro experimentation using THC was performed on primary leukocytes isolated from HIV−MJ−, HIV+MJ− and HIV+MJ+ donors to determine if THC has an impact on CD16+ monocyte and IP-10 levels. Methods: Flow cytometry was used to measure the number of blood CD16+ monocytes and plasma IP-10 from HIV+MJ− and HIV+MJ+ donors. Peripheral blood mononuclear cells were isolated from HIV−MJ− and HIV+ (MJ− and MJ+) donors for in-vitro THC and IFN&agr; treatment, and CD16+ monocytes and supernatant IP-10 were quantified. Results: HIV+MJ+ donors possessed a lower level of circulating CD16+ monocytes and plasma IP-10, compared with HIV+MJ− donors. Further, monocytes from HIV+MJ+ donors were unable to induce CD16 expression when treated with in-vitro IFN&agr;, whereas HIV−MJ− and HIV+MJ− donors displayed pronounced CD16 induction, suggesting anti-inflammatory effects by cannabis. Lastly, in-vitro THC treatment impaired CD16− monocyte transition to CD16+ and monocyte-derived IP-10. Conclusion: Components of cannabis, including THC, may decelerate peripheral monocyte processes that are implicated in HIV-associated neuroinflammation.

Interferon-α–Mediated Activation of T Cells from Healthy and HIV-Infected Individuals Is Suppressed by Δ9-Tetrahydrocannabinol

Patients with HIV routinely use medicinal cannabinoids to treat neuropathic pain, anxiety, and human immunodeficiency virus (HIV)–associated wasting. However, Δ9-tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in cannabis, suppresses T-cell function and secretion of interferons, both critically important in the antiviral immune response. Interferon-α (IFNα), a key cytokine in T-cell activation and peripheral control of HIV infection, can potentiate responsiveness to interleukin-7 (IL-7), a crucial homeostatic cytokine for peripheral T-cell maintenance. The objective of this investigation was to compare the response of T cells to stimulation by IFNα and IL-7 in T cells from healthy and HIV+ donors in the absence and presence of THC. To compare T-cell responses between healthy and HIV+ donors signaling through IFNα receptor, IFNα-induced expression of IL-7α receptor (IL-7Rα), cognate signaling through IL-7R, and on IL-7–mediated T-cell proliferation were measured by flow cytometry and real-time quantitative polymerase chain reaction. CD8+ T cells from HIV+ donors showed a diminished response to IFNα-induced phosphorylated signal transducer and activator of transcription-1 activation compared with CD8+ T cells from healthy donors, whereas CD4+ T cells from HIV+ donors and healthy donors were comparable. Treatment with IFNα promoted IL-7R expression and potentiated IL-7–induced STAT5 phosphorylation to augment IL-7–mediated proliferation by T cells from healthy and HIV+ donors. Finally, HIV+ donors exhibited reduced sensitivity to THC-mediated suppression by IFNα- and IL-7–mediated stimulation compared with healthy donors. These results further support THC as being immune suppressive while identifying putatively beneficial aspects of cannabinoid-based therapies in HIV+ patients.