The human T-cell leukemia virus type 1 (HTLV-1), identified as the first human oncogenic retrovirus 30 years ago, is not an ubiquitous virus. HTLV-1 is present throughout the world, with clusters of high endemicity located often nearby areas where the virus is nearly absent. The main HTLV-1 highly endemic regions are the Southwestern part of Japan, sub-Saharan Africa and South America, the Caribbean area and foci in Middle East and Australo-Melanesia. The origin of this puzzling geographical or rather ethnic repartition is probably linked to a founder effect in some groups with the persistence of a high viral transmission rate. Despite different socio-economic and cultural environments, the HTLV-1 prevalence increases gradually with age, especially among women in all highly endemic areas. The three modes of HTLV-1 transmission are mother to child, sexual transmission and transmission with contaminated blood products. Twenty years ago, de The and Bomford estimated the total number of HTLV-1 carriers to be 10-20 millions people. At that time, large regions had not been investigated, few population-based studies were available and the assays used for HTLV-1 serology were not enough specific. Despite the fact that there is still a lot of data lacking in large areas of the world and that most of the HTLV-1 studies concern only blood donors, pregnant women or different selected patients or high-risk groups, we shall try based on the most recent data, to revisit the world distribution and the estimates of the number of HTLV-1 infected persons. Our best estimates range from 5-10 millions HTLV-1 infected individuals. However, these results were based on approximately 1.5 billion of individuals originating from known endemic areas with reliable available epidemiological data. Correct estimates in other highly populated regions such as China, India, the Maghreb and East Africa is currently not possible, thus, the current number of HTLV-1 carriers is very probably much higher.

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Epidemiological Aspects and World Distribution of HTLV-1 Infection

Pesticides are widely used in agricultural and other settings, resulting in continuing human exposure. Epidemiologic studies indicate that, despite premarket animal testing, current exposures are associated with risks to human health. In this review, we describe the routes of pesticide exposures occurring today, and summarize and evaluate the epidemiologic studies of pesticide-related carcinogenicity and neurotoxicity in adults. Better understanding of the patterns of exposure, the underlying variability within the human population, and the links between the animal toxicology data and human health effects will improve the evaluation of the risks to human health posed by pesticides. Improving epidemiology studies and integrating this information with toxicology data will allow the human health risks of pesticide exposure to be more accurately judged by public health policy makers.

Health effects of chronic pesticide exposure: cancer and neurotoxicity.

Following infection of animals or humans, lentiviruses play a prolonged game of hide and seek with the host's immune system which results in a slowly developing multi-system disease. Emerging knowledge of the disease processes is of some relevance to acquired immune deficiency syndrome (AIDS), which is caused by a virus possessing many of the characteristics of a lentivirus.

Pathogenesis of lentivirus infections

Immunobiology of the mammary gland

We measured changes in basal release of nitric oxide and its effect on polymorphonuclear leukocyte (PMN) adherence to endothelial cells (ECs) in a feline model of myocardial ischemia (90 minutes) and reperfusion. Basal release of nitric oxide from the left anterior descending coronary artery (LAD) after myocardial ischemia/reperfusion and from the control left circumflex coronary artery (LCX) was assessed by NG-nitro L-arginine methyl ester (L-NAME)-induced vasocontraction. L-NAME induced a significant EC-dependent vasocontraction in control LCX rings (0.28 +/- 0.04 g), which was fully reversed by L-arginine but not D-arginine. L-NAME-induced vasocontraction of LAD rings was not significantly changed after 90 minutes of myocardial ischemia without reperfusion. However, 10 minutes of reperfusion reduced the L-NAME-induced vasocontraction to 0.13 +/- 0.04 g (p < 0.05), and this was restored by addition of 3 mM L-arginine but not D-arginine. Longer periods of reperfusion progressively decreased L-NAME-induced vasocontraction. After 270 minutes of reperfusion, L-NAME-induced vasocontraction was virtually abolished. Myocardial ischemia without reperfusion did not increase PMN adherence to ECs. However, PMN adherence to LAD ECs was significantly increased after 20 minutes of reperfusion (39 +/- 6 to 105 +/- 9 PMNs/mm2, p < 0.01), and incubation of LAD segments with L-arginine significantly attenuated this increase in PMN adherence. After 270 minutes of reperfusion, PMN adherence to LAD ECs was further increased to 224 +/- 10 PMNs/mm2 (p < 0.001). This increase in PMN adherence was almost completely blocked by MAb R15.7, a monoclonal antibody against CD18 of PMNs, and was significantly attenuated by MAb RR1/1, a monoclonal antibody against intercellular adhesion molecule-1 of ECs (p < 0.01). These results indicate that decreased basal release of endothelium-derived relaxing factor after myocardial ischemia/reperfusion precedes enhanced PMN adherence to the coronary endothelium, which may lead to PMN-induced myocardial injury.

Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to coronary endothelium.

Pathogenesis of Experimental Feline Leukemia Virus Infection

THYMIC atrophy and suppression of cell-mediated immunity (CMI) have been associated with feline leukaemia virus (FeLV) infection in cats1–5. Impairment of CMI by FeLV and other oncogenic retroviruses has been attributed to impaired lymphoid function caused by viral infection of lymphoid tissues5,6. This explanation for FeLV-related immunosuppression is plausible as lymphoid cells are the targets for oncogenesis3,7 and atrophy of the thymus occurs early in the course of FeLV infection1,3,4. However, FeLV-associated immunological impairment is not due simply to viral destruction of the thymus as surgical thymectomy of kittens does not result in demonstrable immunosuppression8. Moreover, several observations indicate that the depressed CMI response of preleukaemic FeLV-infected cats may be due to T-cell unresponsiveness rather than T-cell deficiency: the circulating T-cell population is not decreased during the preleukaemic stage of the FeLV infection2; lymphocytes from FeLV-infected cats are unresponsive to phytomitogen-induced lymphocyte blastogenesis (LBT)2; and inhibition of the LBT response of normal feline lymphocytes can be produced by serum from FeLV-infected cats9. We have found that the unresponsiveness of feline lymphocytes to concanavalin A(Con A) also can be induced with FeLV inactivated by ultraviolet light10. Similar depressed mitogenic responses have been reported for mouse lymphocytes incubated with disrupted murine leukaemia virus11. Here we report that the mediator of FeLV-associated lymphocyte unresponsiveness seems to be the 15,000 molecular weight virion protein (p15) of FeLV.

Abrogation of lymphocyte blastogenesis by a feline leukaemia virus protein.

Sixty-seven specific-pathogen-free cats of various ages (newborn, 2 wk, 1 mo, 2 mo, 4 mo, and 1 yr) were inoculated ip with either the Rickard (R) or the Kawakami-Theilen (KT) strain of feline leukemia virus (FeLV). Susceptibility to FeLV was judged by induction of a) FeLV group-specific antigens (gsa) in leukocytes, b) FeLV-related disease, c) antibody to feline oncornavirus-associated cell membrane antigen (FOCMA), and d) virus-neutralizing (VN) antibody. Susceptibility to FeLV-decreased with age. Persistent viremia and FeLV-related disease developed in 100% of cats inoculated as newborns, in 85% of cats inoculated at 2 weeks to 2 months of age, and in 15% of cats inoculated at 4 months or 1 year of age. Cats susceptible to FeLV leukemogenesis became persistently FeLV gsa-positive (viremic) at 4 weeks post inoculation and thereafter and produced little or no FOCMA or VN antibody. Cats that resisted leukemogenesis by FeLV all developed persistent FOCMA and VN titers and never became FeLV gsa-positive. The disease in inoculated cats was influenced by virus strain; FeLV-R induced predominantly thymic lymphosarcoma, whereas FeLV-KT caused fatal nonregenerative anemia without concurrent neoplasia.

Feline Leukemia Virus Infection: Age-Related Variation in Response of Cats to Experimental Infection

In most cats exposed to the contagious1 feline leukemia virus (FeLV), viral replication is contained in target haematopoietic tissues2 and elicits humoral immunity to FeLV and to the feline oncornavirus-associated cell membrane antigen (FOCMA)3–6. Recently, we and others have considered that these ostensibly self-limiting infections might be persistent nonproductive (latent) infections in certain haematopoietic cells. This hypothesis could account for the relapsing viraemias7, protracted incubation periods8, persistently high titres of antiviral and anti-FOCMA antibodies8, appearance of FeLV p27 antigen in serum of otherwise non-viraemic animals9 and occurrence of FeLV -negative but FOCMA-positive leukaemias in naturally infected pet cats10,11. Here we describe the reactivation of latent FeLV from myelomonocytic and lymphoid cells of cats immune to FeLV, cats bearing FeLV-negative tumours, and kittens congenitally exposed to FeLV. Furthermore, the reappearance of FeLV infection is suppressed by the host's immune system but this can be altered by adrenal corticosteroid hormones in vivo and in vitro.

Reactivation of latent feline leukaemia virus infection

The 15,000-molecular-weight polypeptide (p15) of feline leukemia virus (FeLV) was shown to impair normal lymphocyte function in vitro and to abrogate immunity to feline oncornavirus disease in vivo . FeLV p15 suppressed concanavalin A-induced blast transformation of normal feline lymphocytes by 68%, while other virion proteins had no effect. p15 suppression was not due to toxicity, nor was p15 a competitive inhibitor of concanavalin A binding. Capping of receptors for concanavalin A on normal feline lymphocytes also was inhibited by either inactivated FeLV or FeLV p15. Groups of cats were immunized with either killed feline oncornavirus-associated cell membrane antigen bearing tumor cells or tumor cells plus FeLV p15. After challenge with feline sarcoma virus, three of four p15-treated cats developed progressive fatal fibrosarcoma as compared to one of five non-p15-treated cats. The cats receiving p15 also had lower cytotoxic antibody titers against feline oncornavirus-associated cell membrane antigen (mean peak titer, 1:6) than did the non-p15 group (1:74). These data support the hypothesis that the immunosuppression in cats infected with FeLV is mediated by FeLV p15.

https://cancerres.aacrjournals.org/content/canres/39/3/950.full.pdf

Richard G. Olsen

Papers

Pathogenesis of Experimental Feline Leukemia Virus Infection

Abrogation of lymphocyte blastogenesis by a feline leukaemia virus protein.

Feline Leukemia Virus Infection: Age-Related Variation in Response of Cats to Experimental Infection

Reactivation of latent feline leukaemia virus infection

Immunosuppressive properties of a virion polypeptide, a 15,000-dalton protein, from feline leukemia virus.