Cell-to-Cell Transmission of HIV-1 and HIV-2 from Infected Macrophages and Dendritic Cells to CD4+ T Lymphocytes

Abstract

Macrophages (Mø) and dendritic cells (DCs) are key players in human immunodeficiency virus (HIV) infection and pathogenesis. They are essential for the spread of HIV to CD4+ T lymphocytes (TCD4+) during acute infection. In addition, they constitute a persistently infected reservoir in which viral production is maintained for long periods of time during chronic infection. Defining how HIV interacts with these cells remains a critical area of research to elucidate the pathogenic mechanisms of acute spread and sustained chronic infection and transmission. To address this issue, we analyzed a panel of phenotypically distinct HIV-1 and HIV-2 primary isolates for the efficiency with which they are transferred from infected DCs or Mø to TCD4+. Our results show that infected Mø and DCs spread the virus to TCD4+ via cell-free viral particles in addition to other alternative pathways. We demonstrate that the production of infectious viral particles is induced by the co-culture of different cell populations, indicating that the contribution of cell signaling driven by cell-to-cell contact is a trigger for viral replication. The results obtained do not correlate with the phenotypic characteristics of the HIV isolates, namely their co-receptor usage, nor do we find significant differences between HIV-1 and HIV-2 in terms of cis- or trans-infection. The data presented here may help to further elucidate the cell-to-cell spread of HIV and its importance in HIV pathogenesis. Ultimately, this knowledge is critical for new therapeutic and vaccine approaches.

The spleen is the graveyard of CD4+ cells in patients with the immunological failure of visceral leishmaniasis and AIDS

“…[40] The macrophage-led spleen in ammatory status, as seen in one non-HIV infected patient, [41] may release signs of transactivation of proviruses infected CD4 + driven by the innate immune response to viscerotropic Leishmania, allowing viral replication and inducing infected and bystander T-cells apoptosis and pyroptosis. [20,53] Interestingly, while non-HIV VL shows a high level of IL-6-driven acute phase response, a cytokine linked to severe VL without HIV, [24,57] its marker, Creactive protein [58] was near normal among our coinfected patients, reinforcing the idea that instead of IL-6, it was IL-1a released by pyroptotic cells the leading cause of immunological failure of our coinfected patients.…”

“…[20,22] However, this mechanism of CD4 + loss appears minimal as compared to virologic failure, when HIV infection is productive. [51] A similar mechanism may have been through macrophages, since HIVinfected macrophages are able to transmit cell-free or quiescent HIV provirus to CD4+, as observed [52][53][54][55] and therefore contributing to its activation and depletion. This hypothesis will be investigated in our patients' stored samples.…”

Human immunodeficiency virus transmission—Mechanisms underlying the cell‐to‐cell spread of human immunodeficiency virus

“…[52][53][54][55][56] Recently, several reports have demonstrated that cell-to-cell transmission (i.e., proximal cell) is the primary mode of infection spread, accounting for approximately 60% of viral transmission, 57,58 revealing one clear advantage of cell-to-cell transmission: it appears to be unaffected by most cellular barriers, allowing for more efficient infection of target cells when in close contact with donor-infected cells, as recently demonstrated for HIV-1 and HIV-2 primary isolates. 59 One of these studies also showed that cell-to-cell transmission during treatment is less sensitive to drugs than cell-free infection. 60 However, these results are still controversial and further research is needed to better understand the mechanisms underlying cell-to-cell transmission.…”

The integrated stress response signaling during the persistent HIV infection

“…Macrophages and monocytes may play a role in spreading the viral infection to lymphocytes during reservoir formation and viral blips. 34 , 35 , 36 , 37 , 38 , 39 In the last decades, many groups have worked to decipher the mechanism behind HIV latency in the aforementioned resident immune cells but mainly focused on peripheral CD4 + T cells. Diverse mechanisms were addressed that may be responsible for HIV latency, such as the epigenetic and non-epigenetic regulation of HIV latency.…”