The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. 1986.
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Amino Acid Sequence↗
Biomedical subjects
F M Gotch
Publications and source records attributed to F M Gotch.
Immune modulation and reconstitution of HIV-1-specific responses: novel approaches and strategies.
Efficacious protection for future generations from HIV-1 infection through the development of prophylactic vaccines is the best hope for the millions of individuals living with the threat of HIV-1 infection. Advances in the development of non-curative chemotherapy for those already infected have changed the course of the epidemic for those with access to the drugs. However in the ten years since the advent of highly active anti-retroviral therapy, the expectancy of curative chemotherapy has been quashed, and the constant need for a next generation of drugs is evident. As our understanding of HIV-1 pathogenesis increases, it is becoming apparent that novel approaches and strategies will be required to halt the global progression of HIV-1. Immune-based therapies are being considered in the context of effective antiretroviral therapy. Such immune-based therapy must allow the induction or regeneration of HIV-1-specific T-cell responses with the potential to control viremia and purge viral reservoirs. Studies of therapy substitution, treatment interruption, therapeutic vaccines and/or cytokines and/or hormones have been carried out and are briefly summarised in this review.
AIDS Vaccines↗
Regulation of dendritic cell interleukin-12 secretion by tumour cell necrosis.
Dendritic cells (DCs) play a key role in the induction and regulation of antigen-specific immunity. Studies have shown that, similar to infection, cellular necrosis can stimulate DC maturation. However, the ability of necrotic cell death to modulate DC cytokine secretion has yet to be explored. We investigated the regulation of interleukin (IL)-12 secretion by human DCs in response to tumour cell necrosis in an in vitro culture model. Two human tumour cell lines (K562 and JAr) were induced to undergo necrosis using heat injury and repeated cycles of freezing and thawing. Both types of tumour cells tested in this study, when injured, induced secretion of monomeric IL-12p40 by monocyte-derived DCs. Furthermore, priming DCs with necrotic cells augmented IL-12p70 secretion significantly in conjunction with CD40 cross-linking. This was physiologically relevant because cell death-pulsed DCs were more potent than non-pulsed DCs at stimulating T cells to proliferate and secrete interferon (IFN)-gamma. The Toll-like receptor 4 (TLR4) played a role in mediating the DC response to heat-killed, but not freeze/thaw-killed necrotic cells. For both methods of injury, proteins contributed to the effect of necrosis on dendritic cells, whereas DNA was involved in the effect of freeze/thawed cells only. These findings indicate that necrotic tumour cell death is not sufficient to induce bioactive IL-12p70, the Th1 promoting cytokine, but acts to augment its secretion via the CD40/CD40L pathway. The results also highlight that the mode of cell death may determine the mechanism of dendritic cell stimulation.
Animals↗
Immunological and virological consequences of patient-directed antiretroviral therapy interruption during chronic HIV-1 infection.
Increasing numbers of patients are choosing to interrupt highly active antiretroviral therapy (HAART). We describe the effect of patient-directed treatment interruption (PDTI) on plasma viral loads (pVL), proviral DNA (pDNA), lymphocyte subsets and immune responses in 24 chronically HIV-1 infected individuals. Patients were divided into group A with pVL > 50 copies/ml and group B with pVL < 50 copies/ml, prior to the PDTI. pVL rose significantly in group B during the first month off HAART and was associated with a significant decrease in CD4 T-cell count. At baseline there was a significant difference in HIV-1 pDNA levels between groups A and B, however, levels significantly increased in group B, but not in group A during PDTI becoming equivalent after 1 month PDTI. We have previously shown no increase in pDNA over the time of substitution in patients switching HAART regimens despite a small rebound in pVL. These observations indicate that to protect low pDNA levels PDTI should be discouraged and that changing regimen at the first sign of failure should be advised where possible. Only transient, no longer than 4 week, HIV-1-specific responses were observed during PDTI in 5/24 patients, 2 from group A and 3 from group B. The low numbers of responders and the transient nature of the anti-HIV-1 immune responses do not favour the auto-vaccination hypothesis.
Adult↗
Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infection.
OBJECTIVES: We aimed to provide evidence of thymic reconstitution after highly active antiretroviral therapy (HAART) in HIV-1 infected patients and to correlate this with the restoration of peripheral naïve T cells. METHODS: Positron emission tomography (PET) enables definitive evidence of thymic activity, indicating functional potential. In this case study, a single patient who initiated HAART demonstrated reconstitution of the naïve T-cell pool and underwent thymic PET scans at baseline and 2 and 6 months following initiation of therapy. Two patients who failed to demonstrate such reconstitution acted as controls. These patients (mean age 27 years) had chronic HIV infection with low CD4 T-cell counts (mean 82, range 9-160 cells/microL blood). Increased function of the thymus visualized by PET was correlated with phenotypic changes in CD4 and CD8 T cells in the periphery measured by flow cytometry, and with numbers of recent thymic emigrants measured by quantification of the numbers of T-cell receptor excision circles (TRECs) in peripheral cells. RESULTS: In one patient, clear correlations could be drawn between visible activity within the thymus, as measured by increased [F18]fluorodeoxyglucose (FDG) uptake, and regeneration of naïve CD4 (CD45RA/CD62L) T cells, increased numbers of CD4 T cells, controlled viraemia and increased numbers of recent thymic emigrants. A second patient displayed no increase in peripheral CD4 count and no increase in thymic activity. The third patient elected to stop therapy following the 2-month time point. CONCLUSIONS: The use of PET suggests that thymic activity may increase after HAART, indicating that the thymus has the potential to be functional even in HIV-1 infected persons with low CD4 T-cell counts.
Adult↗
Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness.
Reconstitution of functional CD4(+) T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty-six antiretroviral naive patients received HAART over 16 weeks. Antigen-specific, mitogen and interleukin (IL)-2 induced lymphocyte proliferative responses and specific IL-2 and IL-4 production were assessed at each time-point, together with quantification of HIV-1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV-1 or neo-antigens. Recall antigens, mitogens and IL-2-induced renewed responses were associated with in-vitro production of IL-2, but not IL-4. Differential responsiveness to low versus high concentration IL-2 stimulus increases in a stepwise manner, suggesting normalization of IL-2 receptor expression and improved functionality. These increases in in-vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long-term organisms. In this context non-responsiveness to HIV-1 antigens suggests ongoing HIV-1 specific clonal T cell anergy.
Anti-HIV Agents↗
Restoration of human immunodeficiency virus-1-specific responses in patients changing from protease to non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.
The effect of altering antiretroviral therapy (ART) on responses to viral, recall and human immunodeficiency virus (HIV)-1-specific recombinant antigens and interleukin-2 (IL-2) in HIV-1-infected patients was assessed. A longitudinal cohort study in eight HIV-1 infected individuals following a clinically indicated therapy change (seven for drug intolerance and one for virological failure) from protease inhibitor (PI) to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimens was performed. CD4 T-cell counts, viral loads, lymphoproliferative responses, cytokine production and latent proviral deoxyribonucleic acid (DNA) were measured at baseline and at weeks 12 and 24 after therapy substitution. Following therapy-switch there was a 33% proportional increase in mitogen response (95% confidence interval (CI), 3-33%) and a 31% increase (95% CI, 15-48%) in viral and recall-antigen responses. Six patients developed proliferative responses to low concentration IL-2 stimulation. All patients demonstrated an increase in median HIV-1-specific responses, as three had detectable virus at baseline (two being viral rebound); this may reflect an autovaccination effect. Proviral DNA changes largely reflected plasma HIV-1 ribonucleic acid (RNA). In conclusion, NNRTI substitution for a PI may favour immune reconstitution with an improvement in HIV-1-specific responses, which may reflect differential effects on antigen processing and presentation, an autovaccination effect or alternatively a potential suppressive effect of the PI.
Anti-HIV Agents↗
Impact of NNRTI compared to PI-based highly active antiretroviral therapy on CCR5 receptor expression, beta-chemokines and IL-16 secretion in HIV-1 infection.
Interleukin-16 (IL-16) and the beta-chemokines (RANTES, monocyte chemotactic protein-1 (MCP-1), macrophage inhibitory protein (MIP)-1alpha and (MIP)-1beta) are soluble in vitro suppressors of macrophage tropic HIV-1 strains. The reduction of HIV-1 RNA plasma levels in late-stage patients receiving protease inhibitors has been associated with increased concentrations of MIP-1alpha, MIP-1beta, RANTES and IL-16 and a decrease in levels of MCP-1. We determined plasma levels of MCP-1, MIP-1alpha, MIP-1beta, RANTES and IL-16 during the first 16 weeks of highly active antiretroviral therapy (HAART) in chronic HIV-1-infected patients. Patients were administered one of two therapeutic regimens based on either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). No differences were seen in the levels of RANTES and IL-16 over the first 16 weeks of HAART in either treatment group. MCP-1 decreased significantly in the PI-treated group over the first 16 weeks of HAART (P = 0.0003). A significant increase was observed in the levels of MIP-1alpha and MIP-1beta in the NNRTI cohort (P = 0.0010 and P = 0.0012, respectively). A significant decrease in levels of MIP-1alpha and MIP-1beta (P = 0.0015 and P = 0.0299, respectively) was observed over the 16 weeks in the PI cohort. A significant difference was seen when the levels of MIP-1alpha and MIP-1beta were compared between the NNRTI and the PI cohorts at week 16 (P = 0.04 and P = 0.05, respectively). Evaluation of CCR5 expression ex vivo revealed no difference between the two treatment groups. Patients were genotyped for CCR5 Delta32 and the incidence of heterozygosity was lower than in the HIV-1 seronegative controls (3% compared to 19%).
Adult↗
Comparative loss and maturation of peripheral blood dendritic cell subpopulations in African and non-African HIV-1-infected patients.
OBJECTIVES: To quantify the percentage of the two major subpopulations of blood dendritic cells (DC) in HIV-1-seropositive Ugandan individuals infected with non-clade B viruses and compare this with that seen in clade B HIV-1 infected non-African individuals. DC maturation/activation status was also investigated via the expression of CD86. METHODS: The percentage of blood DC was quantified by using flow cytometry. DC were identified as the lineage (CD3, CD14, CD16, CD19, CD20, CD56)-negative, HLA-DR-positive population and the two major subpopulations were differentiated by CD11c expression. RESULTS: The percentage of blood DC was reduced significantly in HIV-1-seropositive African individuals when compared with controls (0.21 and 0.39% respectively). A similar reduction was also seen in non-African patients residing in the UK (0.19% compared with 0.36% for controls). However, there was no selective loss in either CD11c-positive or CD11c-negative subpopulations. The percentage of blood DC expressing CD86 was significantly greater in HIV-1-seropositive individuals when compared with controls and the increased expression was largely confined to CD11c-negative DC. CONCLUSIONS: Africans infected with non-clade B HIV-1 showed similar reductions in the percentage of blood DC to non-Africans infected with clade B viruses. There was no selective loss of either DC subpopulation, suggesting that the ability of DC to acquire and present antigens or to produce interferon-alpha may both be impaired in HIV-1 infection.
Adult↗
Outcomes of a trial of HIV-1 immunogen in patients with HIV infection.
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AIDS Vaccines↗
T-cell re-population in HIV-infected children on highly active anti-retroviral therapy (HAART).
In this pilot study, we address the nature of the re-population of the T-cell compartment in HIV-1+ (Human Immunodeficiency Virus 1), vertically infected children placed on successful regimens of HAART (highly active anti-retroviral therapy) incorporating 2 NRTI and a protease inhibitor. The clonality of the T-cell compartment and the abundance of RTEs (Recent Thymic Emigrants) were determined 2 weeks before and 20 weeks after initiation of HAART in a subgroup of children taking part in the PENTA (Paediatric European Network for the Treatment of AIDS) 5 trial. Analysis of the clonality of the circulating T-cell compartment was assessed using CDR3 spectratyping and analysed using the Kolmogorov-Smirnov two sample test. This revealed that a high degree of T-cell clonal restriction still exists 5 months into therapy, despite the appearance of previously undetectable T-cell clones within the periphery. We detected no increase in RTE abundance in this 5 month period, as determined by PCR detection of TRECs (T-Cell Receptor Excision Circles). We conclude that the observed re-population of T cells within the periphery of treated children is heavily reliant upon the maintenance/expansion of pre-existing cells during the 5 month period immediately following the initiation of therapy.
Adolescent↗
Candidate vaccines for immunotherapy in HIV.
In this short article we review the immunopathology of HIV infection and delineate the kinds of immune responses seen in acute infection and in long-term nonprogression that are understood to be necessary if the host is to maintain long-term control of the virus. In this context we discuss the potential promise of therapeutic vaccination in HIV infection.
AIDS Vaccines↗
Immunomodulation in HIV-1 infection in the HAART era.
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Acquired Immunodeficiency Syndrome↗
Loss of CD4+ T cell proliferative ability but not loss of human immunodeficiency virus type 1 specificity equates with progression to disease.
In this study, we compared human immunodeficiency virus (HIV) type 1-specific proliferative responses with HIV-1-induced intracellular cytokine production in a cohort of clinically nonprogressing patients and individuals with progressive HIV-1 infection. We found strong HIV-1-specific proliferative responses in the clinical nonprogressor cohort that correlated with significant numbers of circulating HIV-1-specific CD4(+) T cells. In contrast, HIV-1-specific proliferative responses were absent in most individuals with progressive HIV-1 infection, even though interferon-gamma-producing HIV-1-specific CD4(+) T cells were detectable by flow cytometry. The implication of these data is that the important dysfunction seen in most HIV-positive patients from very early in disease may be an inability of HIV-1-specific CD4(+) memory T cells to proliferate in response to HIV antigens rather than an absolute loss of circulating virus-specific CD4(+) T cells.
Antigens, Viral↗
Making smarter immunotherapies.
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Humans↗
Assessment of type 1 and type 2 cytokines in HIV type 1-infected individuals: impact of highly active antiretroviral therapy.
Although the effect of highly active antiretroviral therapy (HAART) on HIV-1 replication has been established, the mechanisms involved in restoration of immune responses and reconstitution remain unknown. This study provides evidence of changes in expression of type 1 and type 2 cytokine-specific mRNA occurring during HIV-1 infection, before and after initiation of HAART. Unstimulated PBMCs from nine HIV-1-infected individuals obtained at different time intervals before and after the initiation of HAART were assessed for specific IFN-gamma, IL-2, IL-4, and IL-10 mRNA expression, using RT-PCR. Correlation with CD4+ T cell counts and viral load was also carried out. Before initiation of HAART, in all patients, little expression of specific IFN-gamma and IL-2 (type 1 cytokine) mRNA was noted. In contrast, expression of specific IL-4 and/or IL-10 (type 2) mRNA was readily detectable in the majority of patients. After initiation of HAART there was a continuous increase in IFN-gamma and IL-2 mRNA expression, although the latter occurred in lower amounts. This paralleled a dramatic reduction in viral load and increase in CD4+ T cell counts. Type 2 cytokine-specific mRNA expression fell to undetectable levels and in some cases reappeared later in the course of HAART. Predominant expression of type 2 cytokine mRNA, before initiation of HAART, concurs with previous findings of a dominant antiproliferative, type 2 cytokine profile during HIV-1 infection. Reversion of the cytokine profile, after HAART, to a strong type 1 profile suggests that in addition to suppressing virus replication directly the immune system may be given a chance to recover.
Anti-HIV Agents↗
Evaluation of sperm washing as a potential method of reducing HIV transmission in HIV-discordant couples wishing to have children.
OBJECTIVE: A number of discordant couples, in whom the man is HIV positive and the woman is HIV negative, wish to have children. To conceive they must abandon protected sex, posing a risk of HIV transmission to the woman and so to the child. In such circumstances purification of spermatozoa ('sperm-washing') to inseminate the woman artificially has been proposed as a method of reducing the risk of transmission. Here we evaluate whether this does represent a true risk reduction. METHODS: Semen samples from HIV-positive patients were separated into spermatozoa, non-sperm cells (NSCs) and plasma fractions. The amount of viral RNA present in each fraction was measured and compared with the level in the peripheral blood. Each fraction was also assessed for the presence of proviral DNA. The ability of spermatozoa to be infected was assessed by evaluating for the presence of HIV receptors, i.e. CD4, CCR5 and CXCR4 on the surface of the sperm, by flow cytometry. RESULTS: A poor correlation was found between the levels of HIV in blood and semen. Within the semen the virus was restricted to the plasma and/or NSCs. All spermatozoa were negative for viral RNA or proviral DNA. Spermatozoa did not express significant levels of CD4, CCR5 or CXCR4, suggesting that they are unlikely to be major targets for HIV infection. CONCLUSIONS: These data suggest that spermatozoa are not major targets of HIV infection. Purifying spermatozoa reduced the level of HIV RNA and proviral DNA to below the detection limit of the assays irrespective of the amount of virus present in the unfractionated semen. On the basis of these data we would recommend 'sperm-washing' followed by insemination as a safer alternative to natural conception for HIV-discordant couples wishing to have children.
DNA, Viral↗
Alterations in blood leucocyte adhesion molecule profiles in HIV-1 infection.
CD4 and CD8 lymphocyte numbers in the gut lamina propria are grossly altered in HIV-1 infection, out of proportion to alterations in the circulation. Such alterations in lymphocyte counts in the tissues may be due to altered leucocyte migration from the blood. One factor affecting leucocyte migration is adhesion molecule expression. Levels of adhesion molecule expression on peripheral CD4 and CD8 lymphocytes, monocytes and neutrophils from HIV-1-infected (AIDS and non-AIDS) and low-risk control individuals were compared. CD11a, CD62L, CD44, CD49d and beta7 integrin expression were examined by FACS analysis of fresh whole blood. Significant alterations in adhesion molecule expression were detected in HIV infection. The most striking alterations were observed in the CD8 lymphocyte population. CD11a expression was increased and CD62L and CD44 decreased. The CD4 lymphocyte population followed a similar, though less striking, pattern of alteration in adhesion molecule expression. Neutrophils displayed significantly reduced expression of both CD11a and CD62L, but only after onset of AIDS. Monocytes from infected individuals without AIDS displayed a different pattern of altered adhesion molecule expression compared with individuals with AIDS. These findings suggest that in HIV infection, leucocyte functions, such as migration, which require adhesion molecules are abnormal.
Acquired Immunodeficiency Syndrome↗