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Biomedical subjects

Maja A Sommerfelt

Publications and source records attributed to Maja A Sommerfelt.

12 recordsLinked to original sources
PubMed2006

Long-term HIV-specific responses and delayed resumption of antiretroviral therapy after peptide immunization targeting dendritic cells.

Long-term HIV-specific immune responses and clinical outcomes were evaluated in HIV-infected patients previously immunized with p24-like peptides (Vacc-4x) targeting dendritic cells (DC). Vacc-4x-induced cellular immune responses were unchanged 1.5 years after completing immunization, and 62% were still off combined antiretroviral treatment (CART). The magnitude of early Vacc-4x responses determined whether the resumption of CART was clinically indicated 2 years after enrollment. These observations encourage further exploration of both Vacc-4x and other HIV peptide-based immunization regimens targeting DC.

AIDS Vaccines↗
PubMed2005

Multiple antigen concentrations in delayed-type hypersensitivity (DTH) and response diversity during and after immunization with a peptide-based HIV-1 immunotherapy candidate (Vacc-4x).

Delayed-type hypersensitivity (DTH) testing represents a simple in vivo method for monitoring cellular immune responses. In a phase II clinical trial on HIV-infected patients (n = 38) of the peptide-based HIV-1 immunotherapy candidate Vacc-4x, we monitored DTH responses to three antigen concentrations of Vacc-4x. We have shown that DTH can be used quantitatively to measure immune reactions to Vacc-4x and its individual peptide components. Our data stress the qualities and differences of induration and erythema, both in discriminating individual antigens and in monitoring immunizations over time. The data also indicate that DTH baseline-status might have important impact on immunization kinetics.

AIDS Vaccines↗
PubMed2005

Reduced viral burden amongst high responder patients following HIV-1 p24 peptide-based therapeutic immunization.

We have previously shown that HIV p24-like peptides (Vacc-4x) via activation of skin dendritic cells induced immune responses in 90% of HIV patients on highly active antiretroviral treatment (HAART). These patients (n=38) were here subjected to a final 14-week interruption of HAART. Patients with the highest delayed type hypersensitivity (DTH) responses to Vacc-4x-peptides before treatment interruption tended to achieve lower actual HIV RNA levels at the end of the study compared to Vacc-4x DTH low-responders (p=0.08) and significantly so in terms of viral loads relative to their individual pre-HAART HIV RNA set-points (p=0.04). CD4+ lymphocyte counts were maintained only among DTH high responders but decreased in the other patients during recurrent viremia (p</=0.02). No other pre-study differences in HIV history or p24-responses were found.

AIDS Vaccines↗
PubMed2005

Divergent in vitro and in vivo correlates of HIV-specific T-cell responses during onset of HIV viraemia.

BACKGROUND: Cellular immune responses to HIV-1 have been examined mainly in peripheral blood mononuclear cells (PBMC). During onset of HIV replication and antigenaemia after discontinuation of highly active antiretroviral therapy (HAART), PBMC may theoretically contain HIV-specific T cells that are qualitatively and quantitatively different from specific T cells dominating in the tissues. PBMC responses throughout HIV immunotherapy trials may therefore be skewed during recurrent viraemia. OBJECTIVE: To compare cellular HIV-specific in vitro responses in PBMC during onset of HIV viraemia with corresponding in vivo responses, represented by classical delayed-type hypersensitivity tests (DTH). METHODS: HIV patients (n = 38), pre-immunized with four HIV-1 p24-like consensus peptides (Vacc-4x) during HAART, were subjected to a 14-week treatment interruption with recurrent HIV viraemia. Proliferative T-cell responses to Vacc-4x p24 peptides, HIV p24 protein, and cytomegalovirus (CMV) proteins were measured in PBMC. Corresponding Vacc-4x peptide DTH were expressed as skin infiltrate areas after 48 h. RESULTS: After 14 weeks without HAART, HIV-1 RNA increased to 72,500 copies/ml (median). The Vacc-4x p24 peptide- and HIV-1 p24 protein-induced T-cell proliferation concurrently decreased by 81 and 93% in PBMC during viraemia (medians, P < or = 0.03), whereas proliferative responses to CMV antigens were stable. In contrast, the Vacc-4x DTH areas, rather tended to increase by 36% (P = 0.08) and contained infiltrates dominated by proliferating T cells and macrophages. CONCLUSIONS: Divergent in vitro and in vivo HIV-specific cellular immune responses were found during recurrent HIV viraemia. The clinical relevance of both surrogate markers for HIV-related immune responses should be compared in future studies.

AIDS Vaccines↗
PubMed2004

HLA- and dose-dependent immunogenicity of a peptide-based HIV-1 immunotherapy candidate (Vacc-4x).

OBJECTIVE: The Vacc-4x immunotherapy candidate is composed of four modified peptides corresponding to conserved domains of the HIV-1 protein p24 that preferentially include HLA-A2 restricted elements. Dose-dependent safety and immunogenicity of Vacc-4x and the significance of a HLA-A2 haplotype were examined. DESIGN: Non-AIDS, HIV-1 infected healthy patients (n = 40) stable on HAART with CD4 counts > 300 x 10 cells/l were randomized to receive either low-dose or high-dose Vacc-4x over 26 weeks in an open, prospective phase II clinical trial. METHODS: Patients received a total of 10 intradermal injections, using recombinant granulocyte-macrophage colony stimulating factor as a local adjuvant. Vacc-4x-specific cellular responses were monitored in vivo by delayed-type hypersensitivity (DTH) skin test infiltrates and in vitro by both T-cell proliferation, and induction /secretion of cytokines. RESULTS: Most patients developed Vacc-4x-specific DTHs (90%) and proliferative T-cell responses (80%) that were inter-related in magnitude. High-dose Vacc-4x generally induced stronger specific immune responses than low dose in terms of DTH areas and CD4 and CD8 T-cell proliferation. Only HLA-A2 negative patients had a definite dose advantage, and this subgroup had in fact the best overall DTH and proliferative responses. In contrast, no significant dose difference was observed for HLA-A2 positive patients. No serious adverse events were reported. CONCLUSIONS: HIV-associated specific responses were safely induced in most patients by Vacc-4x in a dose-dependent manner and were also influenced by the HLA haplotype.

AIDS Vaccines↗
PubMed2004

A simple semi-rapid HIV-1&2 confirmatory immunoassay using magnetic particles.

The Bionor HIV-1&2 Confirmatory Test is a semi-rapid simple immunoassay based on magnetic particles for the confirmation of serological status to human immunodeficiency virus (HIV). The specificity and sensitivity of this assay was evaluated by comparison with the Diagnostic Biotechnology HIV-1 Western blot (WB) 2.2 and the HIV-2/SBL-6669 WB. Bionor's confirmatory test demonstrated 98% specificity when testing sero-negative blood donors and false positive sera in screening tests compared to 81.5 and 71.6%, respectively, using the HIV-1 WB. The sensitivity of this assay for HIV-1 antibody positive sera was 97.9% compared to the WB which was 99.5%. When testing confirmed HIV-2 antibody positive samples, 2/100 scored negative using this confirmatory test similar to other HIV-2 peptide-based line immunoassays available commercially, whilst 8/100 were indeterminate reacting to HIV-2 membrane antigens only. Bionor's confirmatory test detected HIV-1 seropositivity earlier than the WB in longitudinal seroconversion panels and could discriminate between HIV-1 and -2 infection. The number of indeterminate responses was generally reduced significantly using Bionor's confirmatory test compared to the HIV-1 WB. The greater specificity, speed and ease of interpretation of Bionor's confirmatory test renders it an attractive and cost effective alternative to the WB for confirming HIV serological status worldwide.

AIDS Serodiagnosis↗
PubMed2004

Novel peptide-based HIV-1 immunotherapy.

Therapeutic immunisation of human immunodeficiency virus type 1-infected individuals should be actively pursued in the first instance to augment highly active antiretroviral therapy regimens. Peptide-based immunotherapeutic strategies offer considerable advantages over conventional approaches, particularly regarding safety. Peptide design itself is becoming increasingly sophisticated, with the rapid evolution of bioinformatics tools that can analyse not only T cell epitopes, but also their potential for successful presentation on diverse human leukocyte antigen (HLA) class I or II following intracellular processing by antigen-presenting cells (APCs). By targeting conserved viral domains, peptides acquire improved reactivity to diverse viral strains. Dendritic cells represent a powerful route of administration, as they are the most potent APCs and can present exogenous peptides on both HLA class I and II through the process of cross-presentation. In this way, soluble peptides can thereby stimulate both CD4+ and CD8+ T cells.

Animals↗
PubMed2003

The endogenous langur type D retrovirus PO-1-Lu and its exogenous counterparts in macaque and langur monkeys.

PO-1-Lu, the endogenous type D retrovirus of langurs (Trachypithecus obscurus) has previously been considered a progenitor to the prototype type D retrovirus, Mason Pfizer monkey virus (M-PMV/SRV-3), that became established in macaque monkeys (Macaca spp.) following a zoonosis. This study reevaluates this hypothesis to include other exogenous SRVs. New sequence information from the gp70(SU)-encoding region of PO-1-Lu shows striking similarity to the newly identified exogenous langur retrovirus, SRV-6, recently isolated from the Hanuman Langur (Semnopithecus entellus). An unrooted, bootstrapped neighbor-joining tree derived from env gene nucleotide sequences shows PO-1-Lu and SRV-6 appear more closely related genetically to SRV-2 than SRV-1 or SRV-3 (M-PMV). This is also reflected in our observations that the M-PMV envelope glycoprotein precursor gPr86(Env) and gp70(SU) were antigenically distinct from PO-1-Lu, although the gp22(TM) glycoproteins were antigenically cross-reactive. The potential that SRV-6 represents an exogenous form of PO-1-Lu that has arisen following a recent zoonosis is discussed.

Amino Acid Sequence↗
PubMed2003

Membrane transplantation to correct integral membrane protein defects.

In this report we show that the tendency of certain viruses to carry host membrane proteins in their envelopes can be harnessed for transplantation of small patches of plasma membrane, including fully functional, polytopic ion channel proteins and their regulatory binding partners. As a stringent model we tested the topologically complex epithelial ion channel CFTR. Initially an attenuated vaccinia virus was found capable of transferring CFTR in a properly folded, functional and regulatable form to CFTR negative cells. Next we generated viruslike particles (VLPs) composed of retroviral structural proteins that assemble and bud at the host cell plasma membrane. These particles were also shown to mediate functional ion channel transfer. By testing the capacity of complex membrane proteins to incorporate into viral envelopes these experiments provide new insight into the permissiveness of viral envelopment, including the ability of incorporated proteins to retain function and repair defects at the cell surface, and serve as a platform for studies of ion channel and membrane protein biochemistry.

Animals↗
PubMed2002

The influence of CD4 and CXCR4 on maedi-visna virus-induced syncytium formation.

CD4 is the principal binding site for human and simian immunodeficiency virus (HIV/SIV) receptor interactions and the a chemokine receptor CXCR4 has been implicated as a primordial lentivirus receptor. This study sought to determine the relevance of CD4 and CXCR4 in virus-receptor interactions for the prototype lentivirus, maedi-visna virus (MVV) of sheep. Neither CD4 nor alpha/beta chemokine receptors represent principal receptors for MVV since human osteosarcoma cells devoid of these molecules were susceptible to productive infection. Interestingly, the presence of either CD4 and/or CXCR4 on indicator cells dramatically enhanced MVV-induced cell fusion (syncytium formation) for three independent virus strains. Syncytium formation results from virus-receptor interactions and can be inhibited by receptor ligands. However, neither SDF-la that binds CXCR4 nor recombinant gp120 (rgp120) that binds CD4 could specifically inhibit the observed enhancement of MVV-induced cell fusion under conditions that significantly reduced HIV-1-induced cell fusion. Our observations suggest that CD4 and CXCR4 may represent optional auxiliary components of an MVV receptor (or receptor complex) that facilitate MVV-mediated membrane fusion events, a feature important for virus entry. This potential accessory role for CXCR4 in MW receptor interactions may reflect the distant relationship between the ovine (MVV) and the human/feline lentiviruses (HIV/FIV).

Amino Acid Sequence↗