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    A natural neuropeptide directs HIV-1 for degradation via the proteasome

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    A study conducted by Jonathan Ganor and Morgane Bomsel

    During its sexual transmission, HIV-1 is rapidly internalized by Langerhans cells (LCs),

    which subsequently transfer infectious virus to CD4+ T cells, in a process termed trans-infection. Scientists at the Cochin Institute show now that calcitonin gene-related peptide (CGRP), a natural neuropeptide secreted by peripheral neurons, increases the efficiency of HIV-1 degradation in LCs. In fact, CGRP directs HIV-1 towards the faster and more efficient process of intracellular degradation within the proteasome, which reduces the amount of virus available to trans-infect CD4+ T cells. Increasing HIV-1 proteasomal degradation in LCs might represent a novel and promising clinical strategy in the fight against HIV-1. This study was published on Dec 1st 2017 in the Journal of Virology.

    Upon contact of genital epithelia with HIV-1 during its sexual transmission, Langerhans cells (LCs) rapidly internalize and degrade incoming virus. Yet, infectious HIV-1 that escapes degradation can be subsequently transferred to CD4+ T-cells, during the first phase of a process termed trans-infection. Although HIV-1 productive infection of LCs is limited, some virus can be produced de novo and transferred to CD4+ T-cells at later steps, during the second phase of trans-infection. 

    LCs are in direct contact with peripheral neurons that innervate all mucosal epithelia. Upon mechanical, thermal and/or chemical noxious stimuli, these neurons are activated and secrete the neuropeptide calcitonin gene-relate peptide (CGRP), which can affect LCs function. In a previous study, the team headed by M Bomsel showed that CGRP strongly inhibits HIV-1 trans-infection, by modulating the early interactions between HIV-1 and LCs.

    In the present study, Y Ganor and M Bomsel report that CGRP increases the efficiency of HIV-1 intracellular degradation in LCs. In the absence of CGRP, HIV-1 is degraded in vitro via the endo-lysosmal machinery in LCs. In contrast, in the presence of CGRP, HIV-1 is diverted towards a faster and more effective degradation process, namely the proteasome. Such efficient proteasomal degradation limits the amount of virus available to trans-infect CD4+ T cells.

    CGRP is a potent vasodilator that plays an important role during the sexual response. The results of the present study suggest that CGRP could also control HIV-1 sexual transmission in vivo by diverting the virus for proteasomal degradation. Hence, developing strategies to enhance HIV-1 proteasomal degradation in LCs might turn out clinical useful in the fight against HIV-1.

     

    Legend figure

    HIV-1 degradation pathways in Langerhans cells (LCs) and their role during CD4+ T cell trans-infection. Upon its mucosal entry, HIV-1 is rapidly internalized by LCs and traffics along the endo-lysosomal pathway
    Left panel: LCs in-vitro, in the absence of CGRP. In these settings, a fraction of HIV-1 is degraded in lysosomes. Yet, virus that escapes such degradation is transferred from LCs to CD4+ T cells during trans-infection
    Right panel: LCs in-vivo, during sexual intercourse. In theses settings, peripheral neurons might secret CGRP, which binds to its surface receptor expressed by LCs. This interaction directs HIV-1 to proteasomal degradation, which is more efficient. Hence, the amount of virus available to trans-infect CD4+ T cells is markedly reduced.

     

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