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Tesi etd-06202016-172131


Tipo di tesi
Tesi di specializzazione (5 anni)
Autore
GALLI, VERONICA
URN
etd-06202016-172131
Titolo
Human T-Lymphotrophic virus type 1 (HTLV-1) infection of the three monocyte subsets in HAM/TSP patients
Struttura
RICERCA TRASLAZIONALE E DELLE NUOVE TECNOLOGIE IN MEDICINA E CHIRURGIA
Corso di studi
PATOLOGIA CLINICA
Commissione
relatore Mingari, Maria Cristina
correlatore Dott.ssa Franchini, Genoveffa
Parole chiave
  • Human T-Lymphotrophic virus type 1 (HTLV-1)
  • Infection
  • viral load
  • virus spread
  • monocyte subsets
Data inizio appello
19/07/2016;
Consultabilità
parziale
Data di rilascio
19/07/2019
Riassunto analitico
Human T- Lymphotropic virus type 1 (HTLV-1) is an exogenous retrovirus that establishes a persistent infection in humans. HTLV-1 is the causative agent of two distinct pathologies: adult T-cell Leukemia/Lymphoma (ATLL), an aggressive malignancy of mature CD4+ T cells, and HTLV-1-associated myelopathy/tropic spastic paraparesis (HAM/TSP), a demyelinating neurodegenerative disease. An estimated 15-20 million of people worldwide with endemic regions in Japan, equatorial Africa, the Caribbean and SouthAmerica are infected with HTLV-1. While the majority of HTLV-1 infected individuals remain asymptomatic, a low percentage of patients develop either ATLL (2-3%) or HAM/TSP (2-3%) after a long period of clinical latency.
HTLV-1 primarly infects CD4+ T cells and has been detected in ex vivo CD8+ T cells, B cells, monocytes and dendritic cells (DC) from infected individuals. Although the major target of HTLV-1 is CD4+ lymphocytes, the virus has been shown to infect monocytes both in vitro and in vivo. Thus, monocytes represent a putative reservoir for the virus. Peripheral blood monocytes can be classified into three main subsets: CD14++CD16–(classical),CD14+CD16++(non-classical), and CD14++CD16+(intermediate) which exert important roles in innate and adaptive immunity. However, the contribution of the individual monocyte subsets to HTLV-1 disease and viral persistence has not been addressed.
Because viral DNA burden correlates with disease development, we investigated the contribution of monocyte subsets (classical, intermediate and non-classical) to the total viral burden in 22 HTLV-1 infected individuals by assessing their infectivity status, frequency, as well as chemotactic and phagocytic functions.
The three monocyte subsets sorted from HTLV-1 infected individuals were all positive for viral DNA and the frequency of classical monocytes in blood was lower while expression levels of the chemokine receptors CCR5, CXCR3 and CX3CR1 was higher; the percentage of intermediate monocytes and their chemokine receptor expression did not differ.
However, the migratory capacity of intermediate monocytes to CCL5, the ligand for CCR5, was higher and there was a higher proportion of non-classical monocytes that expressed CCR1, CXCR3 and CX3CR1. The level of viral DNA in the monocyte subsets correlated with the migration capacity to CCL2, CCL5 and CX3CL1 for classical monocytes, with lower phagocytosis for intermediate monocytes, and with the level of viral DNA in CD8+ and CD4+ T-cells for non-classical monocytes. These data suggest a model whereby
HTLV-1 infection augments the number of classical monocytes that migrate to tissues and become infected and the number of infected non-classical monocytes that transmit virus to CD4+ and CD8+ T-cells. These results, together with prior findings in a macaque model of HTLV-1 infection, support the notion that infection of monocytes by HTLV-1 is likely a requisite for viral persistence in humans.

Importance

Monocytes have been implicated in immune regulation and disease progression in patients with HTLV-1-associated inflammatory diseases. We detected HTLV-1 viral DNA in all three monocyte subsets and found that infection impacts surface receptor expression, migratory function and subset frequency. The frequency of non-classical patrolling monocytes is increased in HTLV-1-infected individuals and they have increased expression of CCR1, CXCR3 and CX3CR1. Viral DNA level in non-classical monocytes correlated with viral DNA level in CD4+ and CD8+ T-cells. Altogether, these data suggest an increased recruitment of classical monocytes to inflammation sites that may result in virus acquisition and, in turn, facilitates virus dissemination and viral persistence. Our findings thus provide new insight into the importance of monocyte infection in viral spread and suggest targeting monocytes for therapeutic intervention.
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