Antiviral gene expression in psoriasis.

BACKGROUND: Psoriasis patients have relatively infrequent cutaneous viral infections compared to atopic dermatitis patients. Increased expression of four antiviral proteins (MX1, BST2, ISG15 and OAS2) has been reported in psoriatic skin and genetic studies of psoriasis have identified susceptibility genes in antiviral pathways. OBJECTIVE: To determine if psoriasis is associated with pervasive expression of antiviral genes in skin and blood. METHODS: We performed RNA sequencing on skin samples of 18 subjects with chronic plaque psoriasis and 16 healthy controls. We examined the expression of a predefined set of 42 antiviral genes, each of which has been shown in previous studies to inhibit viral replication. In parallel, we examined antiviral gene expression in atopic dermatitis, non-lesional psoriatic skin and psoriatic blood. We performed HIV-1 infectivity assays in CD4+ peripheral blood T cells from psoriatic and healthy individuals. RESULTS: We observed significant overexpression of 16 antiviral genes in lesional psoriatic skin, with a greater than two-fold increase in ISG15, RSAD2, IRF7, MX2 and TRIM22 (P < 1E-07). None of these genes was overexpressed in atopic dermatitis skin (P < 0.0001) or non-lesional psoriatic skin. In contrast to the skin compartment, no differences in antiviral gene expression were detected in the peripheral blood of psoriasis cases compared to healthy controls. CD4+ T cells from both psoriatic and healthy patients supported HIV-1 infection at a similar rate. CONCLUSION: Our findings highlight psoriasis as an inflammatory disease with cutaneous but not systemic immune activation against viral pathogens.

HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy.

Therapeutic intervention with highly active antiretroviral therapy (HAART) can lead to suppression of HIV-1 plasma viremia to undetectable levels for 3 or more years. However, adherence to complex drug regimens can prove problematic, and subjects may temporarily discontinue HAART for variable periods. We studied 6 HIV-1-infected individuals who stopped therapy. Off HAART, levels of viremia were suppressed to fewer than 500 copies/mL in 2 subjects for more than 12 and more than 24 months, respectively, and in 1 subject for 4 months on 1 occasion. Three subjects failed to contain plasma viremia. Broad and strong HIV-1-specific immune responses were detected in subjects with prolonged suppression of viral replication. This longitudinal study suggests that containment of HIV-1 replication to low or undetectable levels after discontinuation of HAART is associated with strong virus-specific immune responses. Boosting of HIV-1-specific immune responses should be considered as an adjunctive treatment strategy for HIV-1-infected individuals on HAART.

Molecular tracking of an Human Immunodeficiency Virus nef specific cytotoxic T-cell clone shows persistence of clone-specific T-cell receptor DNA but not mRNA following early combination antiretroviral therapy.

The mechanisms that lead to maintenance of an active effector cytotoxic T-cell (CTL) response in Human Immunodeficiency Virus type-1 (HIV-1) infection are not well understood. We have investigated the role of antigen in maintenance of an HIV-1 specific CTL response by studying a patient (313-7) whose antigenic stimulus was reduced using antiretroviral drug therapy started within 90 days of HIV-1 infection. This patient made a primary monospecific CTL response to an HLA-C*0802 restricted epitope in nef (KAAVDLSHFL) prior to treatment. Within 7 days of starting treatment the nef specific CTL precursor frequency (CTLp) had decreased from 60/10(6) to 4/10(6) peripheral blood mononuclear cells (PBMC), coincident with a decline in viremia from 18 470 to 615 copies/ml. Both plasma viremia and nef specific CTLp remained at low levels for 180 days. The nef-specific CTL clone T-cell receptor (TCR) mRNA transcripts also decreased after treatment, but clone specific TCR DNA persisted. It appears that removal of antigen alters the state of HIV specific CTL from an activated effector population (detected in the CTLp assay and by measurement of clone specific RNA) to a non-activated quiescent population (detected by measurement of clone-specific DNA). This latter population may represent persisting HIV specific memory CTL.

Evaluation of Tomudex in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group study.

A phase II trial of Tomudex (raltitrexed, ZD 1694), a new thymidylate synthase inhibitor, was performed in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. This trial demonstrated that Tomudex was well tolerated in this patient population. Nausea and vomiting were minimal, and hematologic toxicities were relatively infrequent. Only one patient was withdrawn from the study due to toxicity (grade 4 diarrhea). One patient exsanguinated from a rent in the carotid artery in an area of tumor involvement, and was categorized as a grade 5 toxicity. Thus 25/27 patients were able to complete at least 2 cycles of treatment. Tomudex demonstrated a 3.7% response rate (95% CI 0.1-19%), with a median survival of 6 months in this highly resistant disease population. Tomudex is not considered active enough as monotherapy for further evaluation in this disease population.

Cytotoxic T cell induction with ratchet peptide libraries.

Immunization with synthetic peptides are used to induce cytotoxic T cell (CTL) responses in vivo. However, CTL peptide vaccines require the use of multiple peptides to overcome genetic diversity associated with MHC restriction, and prior epitope identification from the chosen protein template. We describe here a method whereby all nonamer sequences from a longer template can be synthesized simultaneously in a ratchet peptide library (RPL) covering all potential epitopes within a protein. We synthesized an RPL based on a template sequence from the Plasmodium berghei circumsporozoite (CS) protein (CSRPL). Using a lipopeptide formulation we immunized mice i.p. with the CSRPL and elicited CS specific CTL, which recognized the CS252-260 H-2Kd restricted CTL epitope.