Showing papers by "Phillip D. Markham published in 1997"

Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization

Abstract: A combination AIDS vaccine approach consisting of priming with adenovirus-HIV-1MN gp160 recombinants followed by boosting with HIV-1SF2 gp120 was evaluated in chimpanzees. Long-lasting protection, requiring only three immunizations, was achieved against a low-dose challenge with the SF2 strain of HIV-1 and a subsequent high-dose SF2 challenge administered 1 year later without an intervening boost. Notably, neutralizing antibody responses against both clinical and laboratory isolates developed in three chimpanzees and persisted until the time of high-dose challenge. The possibility that cytotoxic T-lymphocytes contribute to low-dose protection of a chimpanzee lacking neutralizing antibodies is suggested. Our results validate the live vector priming/subunit booster approach and should stimulate interest in assessing this combination vaccine approach in humans.

Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice.

Abstract: Inflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma are increased in sera and lesions of Kaposi's sarcoma (KS) patients. Previous data have indicated that the combination of these cytokines as found in conditioned media from activated T cells induces normal endothelial cells to acquire the features of KS spindle cells (KS cells) including spindle morphology, marker expression, and the responsiveness to the effects of HIV-1 Tat protein. Conditioned media from activated T cells or the single cytokines also induce AIDS-KS cells to produce and release basic fibroblast growth factor (bFGF). bFGF is highly expressed also by in situ KS cells and mediates KS-like lesion formation after inoculation of the cells in nude mice. Here we show that both large and small vessel endothelial cells chronically exposed to inflammatory cytokines produce and release bioactive bFGF in the absence of cell death. In addition, after this treatment, endothelial cells acquire angiogenic capability and induce KS-like lesions after inoculation in nude mice. Production and release of bFGF is induced in a synergistic fashion by TNF-alpha, IL-1beta, and IFN-gamma, and its release is further promoted by low cell density and by the serine proteases plasmin and thrombin. These results indicate that inflammatory cytokines induce endothelial cells to export bFGF and to acquire angiogenic properties, a key feature of the KS cell phenotype, and suggest a mechanism by which these cytokines can cooperate in the induction of KS.

Didanosine but Not High Doses of Hydroxyurea Rescue Pigtail Macaque from a Lethal Dose of SIVsmmpbj14

Abstract: It has been previously reported that hydroxyurea (HU) displays anti-HIV-1 activity and potentiates the antiviral effects of didanosine (ddI) in vitro. To assess the antiviral efficacy of HU in an animal model, the effects of HU and ddI, either individually or as combination therapy, were tested in a model using infection of pigtail macaque with the acutely fatal variant SIV(smpbj14). At the high dosage used (100 mg/kg/day), HU monotherapy failed to protect the exposed animals from viral infection and death, which occurred within 10 days postinoculation. However, both of the ddI-treated animals (5 mg/kg/day) survived the SIV(smmpbj14) lethal dose and displayed a reduction in viral load (undetectable SIV RNA or p27gag) in the primary phase of infection. Of the animals treated with the combination of drugs, one died at day 18 after infection and failed to seroconvert to viral antigens. These data suggest that a high dose of HU monotherapy does not protect against death induced by SIV(mmpbj14). However, lower doses of HU as monotherapy or combination therapy deserve further evaluation for their therapeutic effects.