Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells

Abstract

HIV-1 subverts antigen processing in dendritic cells (DCs) resulting in viral uptake, infection, and transfer to T cells. Although DCs bound monomeric gp120 and HIV-1 similarly, virus rarely colocalized with endolysosomal markers, unlike gp120, suggesting HIV-1 alters endolysosomal trafficking. Virus within DC intracellular compartments rapidly moved to DC-CD4 ؉ lymphocyte synapses when introduced to CD4 ؉ lymphocyte cultures.Although viral harboring and transfer from nonlysosomal compartments was transient, given DC-associated virus protein, nucleic acids, and infectious HIV-1 transfer to CD4 ؉ , lymphocytes decayed within 24 hours. However a second long-term transfer phase was apparent in immature DCs after 48 hours as a zidovudinesensitive rise in proviral DNA. Therefore, DCs transfer HIV-1 to CD4 ؉ lymphocytes in 2 distinct phases. Immature and mature DCs first divert virus from the endolysosomal pathway to the DC-T-cell synapse. Secondly, the later transfer phase from immature DCs is through de novo HIV-1 production. Thus, the controversy of DCs being infected or not infected for the mechanics of viral transfer to CD4 ؉ lymphocytes can be addressed as a function of time.

T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery

“…[17][18][19] Recent studies have indicated that HIV-1 may be more effectively transmitted during antigen presentation between CD4 + T cells and HIV-1 exposed or infected dendritic cells (DCs), termed an infectious immunological synapse, thus providing a means for increased local viral levels. [20][21][22][23][24] As it may be impossible to protect all susceptible cells in an individual through gene delivery, the delivered protection must function to allow a limited number of primary T cells to survive, enrich, and function in the face of a robust, widespread HIV-1 infection mediated via free virus and cell-to-cell interaction.…”

Dendritic cell activation and maturation induced by mucosal fluid from women with bacterial vaginosis

“…Langerhans Cells (LC), which are a subtype of DC found in tissues, have increased HIV uptake after stimulation [63]. This could parallel stimulation of DC by BV CVL samples leading to an increase in the macropinocytosis of virions [64].…”

Langerhans cells and viral immunity

“…These data imply that immature DC and LC in contrast to their mature forms are more important in HIV-1 transmission. Viral endocytosis leads to partial acid-proteolytic degradation in the late endosome, although some virus may be retained in its infectious state for longer periods [27,28]. The captured HIV-1 can be transferred to T cells and this process is called trans-infection or first phase transfer [26].…”

“…HIV-containing endosomes are diverted to the contact region, fuse with the cell membrane dumping their load of residual HIV into the synapse. Thus the amount of virus transferred declines over 12 h because of the endocytic degradation [28]. Conversely transfer of de novo produced virus which is also diverted to the contact region and in filopodia surrounding CD4 lymphocytes increases over 24-72 h [33].…”

“…These data imply that immature DC and LC in contrast to their mature forms are more important in HIV-1 transmission. Viral endocytosis leads to partial acid-proteolytic degradation in the late endosome, although some virus may be retained in its infectious state for longer periods [27,28] [26]. However, HIV entry via fusion leads to de novo productive infection first detectable at 24 h and with a plateau in vitro at 72 h. Recent studies suggest this de novo produced virus can re-enter the same or adjacent DC by endocytosis and the latter can also be infected de novo, thus mixing up the initial two distinct phases of viral endocytic degradation and de novo infection.…”