Genomics has the potential to benefit overall health by ensuring that citizens and patients receive timely and effective diagnosis, information, and treatment. Much progress has been made in genetic ...risk assessment for a wide variety of conditions, with implications for implementation of personalized medicine (PM). PM strategies include the use of decision-making processes based on biomarker-driven approaches that may have the desired discriminatory accuracy to distinguish between high-risk and low-risk subjects and may guide prevention strategies, prophylactic and therapeutic decisions. Many countries in Europe have nascent PM programmes, and human genomics is undergoing a step change from being a predominantly research-driven activity to one driven through healthcare. However, for any healthcare system, the integration of genomic data for PM requires extensive adjustments. These adjustments include, the development of technical infrastructure, competences and ethical legal social implications frameworks, for acquiring, storing, sharing, interpreting and delivering genomic information. This workshop will discuss how the access to genomic and linked phenotypic data at population-scale has tremendous potential to effectively advance PM in healthcare systems, but to fully realise this ambition, it is crucial that a genome and health data-sharing framework is developed and can effectively reach healthcare systems in European Member States and beyond.
Key messages
The adoption of genomics by European healthcare systems is crucial to fulfill the potential of Personalised Medicine for patients and citizens.
Effective data sharing agreements are needed, because without them the personalised healthcare approach will not work.
Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well known to modulate immune responses by preventing ...the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however remains controversial. Using the simian immunodeficiency virus/macaque model of HIV pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. Sixteen rhesus macaques were divided into two groups; four were administered saline and 12 others morphine routinely. Both groups of animals were then inoculated with SIVmacR71/17E and followed longitudinally for disease pathogenesis. The morphine group (M+V) exhibited a trend towards higher mortality rates and retardation in weight gain compared to the virus-alone group. Interestingly, a subset of M+V animals succumbed to disease within weeks post-infection. These rapid progressors also exhibited a higher incidence of other end-organ pathologies. Despite the higher numbers of circulating CD4+ and CD8+ T cells in the M+V group, CD4/CD8 ratios between the groups remained unchanged. Plasma and CSF viral load in the M+V group was at least a log higher than the control group. Similarly, there was a trend toward increased virus build-up in the brains of M+V animals compared with controls. A novel finding of this study was the increased influx of infected monocyte/macrophages in the brains of M+V animals.
In an in vitro coculture model of monocyte-derived, cultured human dendritic cells (DC) with autologous CD4(+) resting T cells, CCR5 (R5)-tropic strains of HIV-1, but not CXCR4 (X4)-tropic strains, ...were transmitted to resting CD4+ T cells, leading to prolific viral output, although DC were susceptible to infection with either strain. Macrophages, which were also infectable with either R5- or X4-tropic strains, did not transmit infection to CD4+ cells. Highly productive HIV infection in this model appeared to be a consequence of heterokaryotic syncytium formation between infected DC and T cells since syncytia formation developed only in R5-infected DC/CD4+ cocultures. These results suggested that the unique microenvironment derived from the fusion between the infected DC and CD4+ cell was highly permissive and selective for replication of R5-tropic viruses. The apparent selectivity for R5-tropic strains in such syncytia was attributable neither to differential DC-mediated activation nor to selective modulation of induction of alpha- or beta-chemokines in the infected DC. This model of HIV replication may provide useful insights into in vitro correlates of HIV pathogenicity.
The pattern of neurological disease caused by human immunodeficiency virus (HIV) infection of the central nervous system (CNS) was investigated using a macaque model of acquired immune defiency ...syndrome (AIDS). Seven of nine macaques inoculated with neurovirulent simian imunodeficiency virus (SIVmac ) developed AIDS within 3 months. Four of these had clinically obvious neurological disease and extensive conduction defects in the form of latency increases in evoked potential (EP) responses. Neuropathologically, all four animals had disseminated white matter disease in the form of multifocal, perivascular and nodular parenchymal mononuclear cell infiltrates, along with extensive involvement of the cortical grey matter, leptomeninges and intracranial portions of cranial nerves. A brisk multinucleated giant cell (MGC) response was a frequent accompaniment in the affected areas. Three of the animals in this group also showed spongiform vacuolation in the occipital grey matter, a lesion described only rarely in HIV encephalitis. In the remaining three animals, there was only minimal evidence of overt neurological impairment or conduction defects. These animals had only mild to moderate neuropathological changes and lesions were virtually confined to the white matter regions of the brain. MGC responses were rare or absent in the CNS of these animals. Neuropathological findings in this SIVmac model have therefore shown good correlation with the severity of clinical and neurophysiological changes, and are reminiscent of HIV‐1 encephalitis. More importantly, white matter involvement was a consistent finding in the affected macaques, regardless of the duration and severity of disease, or type of virus inoculated, suggesting an unusual susceptibility for lentiviral infection in these regions of the macaque CNS.
Comparative studies were performed to determine the neuropathogenesis of infection in macaques with simian human immunodeficiency virus (SHIV)89.6P and SHIVKU. Both viruses utilize the CD4 receptor
...and CXCR4 co‐receptor. However, in addition, SHIV89.6P uses the CCR5
co‐receptor. Both agents are dual tropic for CD4+ T cells and
blood‐derived macrophages of rhesus macaques. Following inoculation into
macaques, both caused rapid elimination of CD4+ T cells but
they varied greatly in mechanisms of neuropathogenesis. Two animals
infected with SHIV89.6P developed typical lentiviral encephalitis in
which multinucleated giant cell formation, nodular accumulations of
microglial cells, activated macrophages and astrocytes, and perivascular
accumulations of mononuclear cells were present in the brain. Many of the
macrophages in these lesions contained viral RNA. Three macaques infected
with SHIVKU and killed on days 6, 11 and 18, respectively, developed a slowly progressive infection in the CNS but macrophages were not productively infected and there were no pathological changes in the brain. Two other animals infected with this virus and killed several months later showed minimal infection in the brain even though one of the two developed encephalitis of unknown etiology. The basic difference in the mechanisms of neuropathogenesis by the two viruses may be related to co‐receptor usage. SHIV89.6P, in utilizing the CCR5 co‐receptor, caused neuropathogenic effects that are similar to other neurovirulent primate lentiviruses.
Lymphocyte-tropic (L-tropic) SIVmac predictably causes immunosuppression and AIDS in rhesus macaques. SIV encephalitis, on the other hand, is caused mainly by macrophage-tropic (M-tropic) SIVmac. We ...have previously described the derivation of M-tropic, neuroadapted SIVmac from molecularly cloned, L-tropic SIVmac239. In this report we show that inoculation of four macaques with neuroadapted virus resulted in L-tropic SIVmac-related diseases in all four but neurological disease in only two of the four animals. Because cocultivation of infected macrophages with CD4+ lymphocytes results in production of tumor necrosis factor alpha and interleukin-6, we asked whether infiltration of supernatant fluids containing these cytokines into the brains of macaques infected with neuroadapted virus would enhance the development of neurological disease. These procedures failed to promote productive virus replication in the brain. Thus, although different degrees of immunosuppression and AIDS could be induced predictably with L-tropic virus, induction of neurological disease was not predictable even when animals were inoculated with neuroadapted M-tropic virus and inflammatory cytokines were infiltrated into the brains of these animals.
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