Dataset Information

Brain Microglial Cells Are Highly Susceptible to HIV-1 Infection and Spread.

ABSTRACT: Macrophages are a target of human immunodeficiency virus type 1 (HIV-1) infection and may serve as an important reservoir of the virus in the body, particularly after depletion of CD4⁺ T cells in HIV/AIDS. Recently, sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) was identified as the major restriction factor of HIV-1 infection in myeloid cells. SAMHD1 is targeted for proteolytic degradation by Vpx, a viral protein encoded by HIV-2 and many simian immunodeficiency viruses but not HIV-1. In this study, we assessed SAMHD1 restriction in in vitro differentiated macrophages and in freshly isolated macrophages from the lungs, abdomen, and brain. We found that infection and spread in in vitro cultured monocyte-derived macrophages were highly limited and that Vpx largely relieved the restriction to initial infection, as expected. We observed nearly identical infection and restriction profiles in freshly isolated peripheral blood monocytes, as well as lung (alveolar) and abdominal (peritoneal) macrophages. In contrast, under the same infection conditions, primary brain macrophages (microglia) were highly susceptible to HIV-1 infection despite levels of endogenous SAMHD1 comparable to the other macrophage populations. Addition of Vpx further increased HIV-1 infection under conditions of limiting virus input, and viral spread was robust whether or not SAMHD1 was depleted. These results suggest that HIV-1 infection of peripherally circulating macrophages is effectively restricted by SAMHD1; however, microglia are highly susceptible to infection despite SAMHD1 expression. These data may explain the long-standing observation that HIV-1 infection is often detected in macrophages in the brain, but seldom in other tissues of the body.

SUBMITTER: Cenker JJ

PROVIDER: S-EPMC5665495 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Brain Microglial Cells Are Highly Susceptible to HIV-1 Infection and Spread.

Cenker Jennifer J JJ Stultz Ryan D RD McDonald David D

AIDS research and human retroviruses 20170626 11

Macrophages are a target of human immunodeficiency virus type 1 (HIV-1) infection and may serve as an important reservoir of the virus in the body, particularly after depletion of CD4<sup>+</sup> T cells in HIV/AIDS. Recently, sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) was identified as the major restriction factor of HIV-1 infection in myeloid cells. SAMHD1 is targeted for proteolytic degradation by Vpx, a viral protein encoded by HIV-2 and many simian ...[more]

PMID: 28486838

Similar Datasets

Project description:Macrophages are susceptible to HIV infection and play an important role in viral dissemination through cell-cell contacts with T cells. However, our current understanding of macrophage-to-T cell HIV transmission is derived from studies that do not consider the robust migration and cell-cell interaction dynamics between these cells. Here, we performed live-cell imaging studies in 3-dimensional (3D) collagen that allowed CD4+ T cells to migrate and to locate and engage HIV-infected macrophages, modeling the dynamic aspects of the in situ environment in which these contacts frequently occur. We show that HIV+ macrophages form stable contacts with CD4+ T cells that are facilitated by both gp120-CD4 and LFA-1-ICAM-1 interactions and that prolonged contacts are a prerequisite for efficient viral spread. LFA-1-ICAM-1 adhesive contacts function to restrain highly motile T cells, since their blockade substantially destabilized macrophage-T cell contacts, resulting in abnormal tethering events that reduced cell-cell viral spread. HIV-infected macrophages displayed strikingly elongated podosomal extensions that were dependent on Nef expression but were dispensable for stable cell-cell contact formation. Finally, we observed persistent T cell infection in dynamic monocyte-derived macrophage (MDM)-T cell cocultures in the presence of single high antiretroviral drug concentrations but achieved complete inhibition with combination therapy. Together, our data implicate macrophages as drivers of T cell infection by altering physiological MDM-T cell contact dynamics to access and restrain large numbers of susceptible, motile T cells within lymphoid tissues.IMPORTANCE Once HIV enters the lymphoid organs, exponential viral replication in T cells ensues. Given the densely packed nature of these tissues, where infected and uninfected cells are in nearly constant contact with one another, efficient HIV spread is thought to occur through cell-cell contacts in vivo However, this has not been formally demonstrated. In this study, we performed live-cell imaging studies within a 3-dimensional space to recapitulate the dynamic aspects of the lymphoid microenvironment and asked whether HIV can alter the morphology, migration capacity, and cell-cell contact behaviors between macrophages and T cells. We show that HIV-infected macrophages can engage T cells in stable contacts through binding of virus- and host-derived adhesive molecules and that stable macrophage-T cell contacts were required for high viral spread. Thus, HIV alters physiological macrophage-T cell interactions in order to access and restrain large numbers of susceptible, motile T cells, thereby playing an important role in HIV progression.

Dataset Information

Brain Microglial Cells Are Highly Susceptible to HIV-1 Infection and Spread.

Publications

Brain Microglial Cells Are Highly Susceptible to HIV-1 Infection and Spread.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets