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Biomedical subjects

F Gotch

Publications and source records attributed to F Gotch.

At least 19 recordsLinked to original sources
PubMed2004

Treatment of primary HIV-1 infection with nonnucleoside reverse transcriptase inhibitor-based therapy is effective and well tolerated.

OBJECTIVES: Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection. We investigated the use of a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen in this setting. METHODS: Twenty-one antiretroviral-naïve individuals with early HIV-1 disease were treated with a combination of efavirenz and Combivir (GlaxoSmithKline, Uxbridge, Middlesex, UK). They were evaluated for immune and lymphocyte function by standard immunological assays. RESULTS: The median time to an undetectable HIV-1 viral load was 12 weeks (range 4-36 weeks). CD4 and CD16/56 counts increased during treatment and CD8 counts decreased minimally. The main side-effects observed were transient sleep disturbances (five patients). In addition, we observed a decrease in lymphocyte activation as assessed by CD38 surface expression. CONCLUSIONS: This study demonstrates that primary HIV-1 infection can be treated with NNRTI-based HAART.

Adult↗
PubMed2003

Paclitaxel for anthracycline-resistant AIDS-related Kaposi's sarcoma: clinical and angiogenic correlations.

BACKGROUND: Murine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi's sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12. PATIENTS AND METHODS: Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m(2) every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel. RESULTS: The objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-alpha levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-alpha, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy. CONCLUSIONS: Angiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Loss of the CD56hiCD16- NK cell subset and NK cell interferon-gamma production during antiretroviral therapy for HIV-1: partial recovery by human growth hormone.

Previous studies have shown that human natural killer (NK) cells are lost from the periphery and are functionally suppressed during HIV-1 infection, and that the administration of highly active antiretroviral therapy (HAART) results in a recovery of NK cell numbers in HIV-1-infected individuals. However, despite this recovery, interleukin (IL)-2 + IL-12-driven interferon (IFN)-gamma production by NK cells has been shown to remain suppressed after HAART. Here we show that the innate immune factor IL-15 in combination with IL-12 is also unable to recover NK cell IFN-gamma production in HAART-treated individuals. Furthermore, we also demonstrate an imbalance in the distribution of CD56loCD16hi and CD56hiCD16- NK subsets after successful HAART, CD56hiCD16- cells being reduced substantially in HIV-1 patients on HAART. Treatment of patients with combined human growth hormone and antiretroviral therapy resulted in further enhancement in the absolute numbers and the proportion of NK cells in some individuals in the absence of parallel effects on CD4+ T cells. Furthermore, in these individuals HAART with growth hormone resulted in an enhancement of cytokine-driven NK cell activation and IFN-gamma production compared to the HAART-only baseline.

Anti-HIV Agents↗
PubMed2003

A pilot study of the safety and efficacy of thymosin alpha 1 in augmenting immune reconstitution in HIV-infected patients with low CD4 counts taking highly active antiretroviral therapy.

To study the safety and efficacy of thymosin alpha1 in stimulating immune reconstitution in combination with highly active antiretroviral therapy (HAART), a phase II randomized, controlled open-label trial of subcutaneous thymosin alpha1 was undertaken for 12 weeks. Twenty clinically stable patients with viral loads <400 copies/ml and CD4 counts less than 200 cells/microl were randomized to receive 3.2 mg thymosin alpha 1 subcutaneous injections twice weekly or no injections for 12 weeks. CD4 and CD8 counts, CD45 RO+ and RA+ subsets and signal joint T cell receptor excision circles (sjTREC) in peripheral blood mononuclear cells (PBMCs) were measured every 2 weeks. Thirteen patients received thymosin alpha 1 and seven were controls. Thymosin alpha 1 was well tolerated and there were no serious adverse events. There was no significant difference between the thymosin alpha1 and control groups in CD4, CD8 and CD45 lymphocyte subset changes at week 12; however, PBMC sjTREC levels increased significantly in the thymosin alpha 1-treated patients compared to controls at week 12. In conclusion, the increase in PBMC sjTREC levels in patients taking thymosin alpha1 may represent enhanced immune reconstitution; however, the clinical benefits and long-term consequences remain to be determined.

Adult↗
PubMed2002

Thymic activity in late-stage HIV-1 infected individuals receiving highly active antiretroviral therapy: potential effect of steroid therapy.

OBJECTIVE: Our objective was to monitor the effect of steroid therapy on the thymic output and function of late-stage HIV-1-infected patients undergoing highly active antiretroviral therapy (HAART). DESIGN: The indirect measurement of T cells that have recently emigrated from the thymus as a means of quantifying thymic output, and therefore thymic function, was achieved through use of the polymerase chain reaction-based signal joint T cell receptor rearrangement excision circles (sjTREC) assay. Proliferative capacity and interleukin (IL)-2 and IL-4 production by T cells after antigenic, mitogenic and IL-2 stimulation were also analysed. METHOD: Measurements were made of sjTREC levels in peripheral blood mononuclear cell DNA samples from five HIV-1 infected patients (one on steroid therapy prior to and at the time of sample extraction) receiving HAART. IL-2 and IL-4 production and proliferative capacity were also measured in three patients, including the patient receiving steroids. RESULT: The sjTREC assay gave an extremely weak result for the patient on steroids but, under the same assay conditions, provided clear, positive readings for the four patients not on steroids. Comparison of the patients' cytokine profiles revealed that IL-2 production was generally low or absent in all three patients tested but that IL-4 production was significantly higher in the patient given steroids. Functional potential as revealed by proliferation assays showed very low or absent cellular proliferation. CONCLUSION: The thymic contribution to the restoration of T lymphocyte numbers, particularly during the treatment of HIV-1 infection, may become compromised if thymic inhibitory factors such as steroids are used. Furthermore, the use of steroids may also favour the development of a T helper 2 response, which could prove particularly undesirable during HIV-1 infection.

Adult↗
PubMed2001

Immune responses and reconstitution in HIV-1 infected individuals: impact of anti-retroviral therapy, cytokines and therapeutic vaccination.

Most patients with chronic HIV-1 infection lack functional CD4(+) and CD8(+) HIV-1-specific T cells with proliferative and cytolytic capacity, respectively. This is despite being able to produce intracellular cytokines in response to viral antigens. Protease inhibitor (PI)-based highly active anti-retroviral therapy (HAART) is unable to completely eradicate virus and fails to enable total restoration of immunity including induction of anti-HIV-1 responses. We have taken novel approaches towards the treatment of chronic HIV-1 disease with the aim of instigating long-term non-progressor status and depletion of virus reservoirs. HIV-1-specific CD4(+) and CD8(+) T cell responses were measured following the administration of cytokines, during therapeutic vaccination, and following treatment interruption (TI) or drug therapy change. Administration of cytokines, with or without therapeutic vaccination, in HAART treated patients, improved both CD4(+) and CD8(+) HIV-1-specific T cell responses even in late-stage disease. Virus-specific T cell responses were also seen during TI or when transient viraemia was apparent, and following therapy change from a PI- to a non-nucleoside-based HAART regimen. Reconstitution of HIV-1-specific immune responses was found to be transient and reversal to the previous anergic state was rapid. Viral reservoirs in the latently infected resting CD4(+) T cells, on follicular dendritic cells of germinal centers or even in infected thymic epithelium may be involved in clonal suppression and anergy. These may present major obstacles to the maintenance of HIV-1-specific responses and the eventual eradication of HIV-1.

AIDS Vaccines↗
PubMed2001

Loss of blood CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load.

Human blood contains at least 2 subpopulations of antigen-presenting dendritic cells (DCs) that can be differentiated by their expression of CD11c. Myeloid DCs (myDCs), which are CD11c(+), trap invading pathogens in the tissues and then migrate to lymphoid tissues where they stimulate pathogen-specific T-cell responses. Plasmacytoid DCs (pcDCs), which are CD11c(-), secrete interferon-alpha in response to viral infections. This study reports that in HIV-1 infection there is a progressive depletion of both these DC populations and that this correlates with an increasing HIV-1 plasma virus load. The median numbers of myDCs and pcDCs were 6978/mL and 9299/mL, respectively, in healthy male controls and 2298/mL and 1640/mL, respectively, in patients with more than 10(5) HIV-1 RNA copies/mL. Both DC populations expressed CD4, CCR5, and CXCR4. The findings suggest that loss of DCs in HIV infection may contribute to disease progression.

CD4 Antigens↗
PubMed2001

A point mutation in CD45 may be associated with an increased risk of HIV-1 infection.

The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Here we show that abnormal CD45 splicing caused by a C77G transversion in exon A of the gene encoding CD45 (PTPRC) is associated with increased susceptibility to HIV-1 infection.

Alternative Splicing↗
PubMed2001

The exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans.

The leukocyte common (CD45) Ag is essential for normal T lymphocyte function and alternative splicing at the N terminus of the gene is associated with changes in T cell maturation and differentiation. Recently, a statistically significant association was reported in a large series of human thymus samples between phenotypically abnormal CD45 splicing and the presence of the CC chemokine receptor 5 deletion 32 (CCR5del32) allele, which confers resistance to HIV infection in homozygotes. We show here that abnormal splicing in these thymus samples is associated with the presence of the only established cause of CD45 abnormal splicing, a C77G transversion in exon A. In addition we have examined 227 DNA samples from peripheral blood of healthy donors and find no association between the exon A (C77G) and CCR5del32 mutations. Among 135 PBMC samples, tested by flow cytometric analysis, all those exhibiting abnormal splicing of CD45 also showed the exon A C77G transversion. We conclude that the exon A (C77G) mutation is a common cause of abnormal CD45 splicing and that further disease association studies of this mutation are warranted.

Alternative Splicing↗
PubMed2001

Molecular correlates in AIDS patients following antiretroviral therapy: diversified T-cell receptor repertoires and in vivo control of cytomegalovirus replication.

OBJECTIVES: To evaluate whether successful, long-term immune reconstitution in vivo can be achieved in end-stage AIDS patients following antiretroviral therapy (ART). METHODS: A 1-year prospective study of changes of CD4+ and CD8+ T-cell surface phenotypes, T-cell receptor (TCR) repertoires and capacity to control in vivo replication of cytomegalovirus (CMV) was performed in five treatment-naive end-stage AIDS patients (median CD4+ T-cell counts of 19 cells/microL) following therapy. Proportions of CD45RA+, CD45RO+ and CD28+ cells within the CD4+ and CD8+ subsets, were determined by flow cytometry. Changes in TCR Vbeta repertoires within the CD4+ and CD8+ T-cell compartments were evaluated using CDR3 spectratyping. CMV replication was determined by a sensitive polymerase chain reaction (PCR) assay using whole blood. RESULTS: Following ART, proportionate increases in 'naive' (CD45RA+) and 'memory' (CD45RO+) T cells were observed within both CD4+ and CD8+ T-cell subsets, while increased numbers of CD28+ T cells were mainly observed within the CD4+ subset. Diversification of CD4+ and CD8+ TCR repertoires was established concomitantly with renewed in vivo control of CMV replication. CONCLUSIONS: An important degree of molecular and functional immune recovery is possible in end-stage AIDS patients introduced to therapy. Diversification of TCR repertoires and the in vivo restoration of immunocompetence to control opportunistic infections clearly show that an important degree of molecular immune reconstitution is established following the initiation of ART even in late-stage AIDS.

ATP-Binding Cassette Transporters↗
PubMed2001

Detection and quantification of HIV-1 specific CD4 helper and CD8 cytotoxic cells: their role in HIV-1-infected individuals and vaccine recipients.

There is a strong link between virus specific CD8 T-cell function and the efficiency of regulatory CD4 helper T cells. Controlling viraemia in HIV-1-infected individuals requires the maintenance of strong CD4 and CD8 T-cell responses. These responses should be elicited by prophylactic vaccination and by postexposure immunotherapy. This review will examine the methods that are available for the detection and quantification of HIV-1 specific CD4 and CD8 T-cell responses. We will also discuss the methods that should be used to identify these responses in HIV-1-infected individuals, seropositive recipients of immunotherapy and seronegative vaccinees. Finally, we will give examples of how responses observed in vitro relate to those known to occur in vivo.

AIDS Vaccines↗
PubMed2001

Immune interventions.

A better understanding of the immune response to HIV and the deleterious effect that HIV infection may have on the immune system in general, allows us to consider how best to restore protective immune responses to HIV and other opportunistic pathogens in the immunocompromised host. In this chapter, we summarise areas of current innovation and provide an update of the current state of knowledge concerning interventions which could result in the immunocompromised state being reversed. We describe the kinds of immune responses, which are thought to be useful in combating both the human immunodeficiency virus and other pathogenic organisms, and methods which are being considered to stimulate such responses. Lessons which may be learned from other disease states, which lead to immunodeficiency and methods for measuring successful outcome of treatment will be described.

AIDS Vaccines↗
PubMed2001

Plasmacytoid dendritic cells are highly susceptible to human immunodeficiency virus type 1 infection and release infectious virus.

Plasmacytoid dendritic cells (pcDC) and myeloid dendritic cells (myDC) are shown to express CD4 and low levels of CCR5 and CXCR4, but only myDC express DC SIGN, a C-type lectin that binds human immunodeficiency virus but does not mediate virus entry. Both DC types were more susceptible to infection with a macrophage than a lymphotropic strain of human immunodeficiency virus type 1, but pcDC were more readily infected than myDC.

CD4 Antigens↗
PubMed2001

The stability between two HIV-1 RNA measurements one year apart and the relationship with HIV subtype in rural Uganda.

We compared HIV-1 RNA levels using the nucleic acid sequenced based amplification (NASBA) test kit in 2 samples taken one year apart from participants infected with env subtype A or D in a population-based cohort in Uganda. Fifty participants were infected with subtype A and 70 with subtype D. HIV-1 RNA levels were significantly higher in subtype D unadjusted (P=0.001), and after adjusting for age, gender, and CD4 count (P<0.001). Eighty-six participants had HIV-1 RNA measurements in both years and 67 (78%) were within one log10 of their result a year before. There was no relationship between the difference in log viral load and proportion of CD4 change. Individuals infected with subtype D had a higher average increase in viral load and this was statistically significant if adjusted for baseline levels and CD4 count (P=0.015).

Adolescent↗
PubMed2001

Development of immunotherapeutic strategies for HIV-1.

In the majority of untreated patients, HIV-1 infection presents as a progressive disease of the immune system. Recent studies indicate that immune responses can be induced in HIV-1 infected individuals, leading to some immune control of virus replication. Such immune responses are also observed in small numbers of untreated HIV-1 infected long-term non-progressor (LTNP) patients, as well as in other viral infections (including those with human herpes viruses). Emerging novel technologies, animal studies and detailed immunological studies have proven invaluable in defining the immune responses that are associated with a favourable clinical outcome. Central effector and regulatory cells are HIV-1-specific CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes respectively. Fully functional antigen-presenting cells (APC) are also essential in all stages of HIV-1 infection and possibly some (but not all) antibody responses contribute to beneficial immunity. The availability of combination anti-retroviral drug therapy, which successfully controls viraemia, has enabled a beneficial outcome in many HIV-1 infected individuals. Since no chronically HIV-1 infected patient has been shown to eradicate virus, novel approaches utilising therapeutic immunisation and various cytokines to manipulate immune responses and to induce and steer immunity towards a desired phenotype are required. There is a clear rationale for immunotherapeutic intervention in chronic progressive HIV-1 infection, which forms the foundation for novel approaches aimed at inducing and maintaining immune control. Here we review the immunopathogenesis of HIV-1 infection and discuss the promises of therapeutic immunisation and immunotherapy in general and their potential in the treatment of chronic HIV-1 disease.

Animals↗