Dataset Information

Cytokines and T-Cell Homeostasis in HIV Infection.

ABSTRACT: Untreated human immunodeficiency virus (HIV) infection is characterized by progressive CD4(+) T-cell depletion and CD8(+) T-cell expansion, and CD4(+) T-cell depletion is linked directly to the risk for opportunistic infections and infection-associated mortality. With suppression of HIV replication by antiretroviral therapy, circulating CD4(+) Tcell numbers typically improve while CD8(+) T-cell expansion persists, and both CD4(+) T-cell cytopenia and CD8(+) T-cell expansion are associated with morbidity and mortality. In this brief review, we report on the role that selected homeostatic and inflammatory cytokines may play both in the failure of CD4(+) T-cell restoration and the CD8(+) T-cell expansion that characterize HIV infection.

SUBMITTER: Freeman ML

PROVIDER: S-EPMC6373575 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cytokines and T-Cell Homeostasis in HIV Infection.

Freeman Michael L ML Shive Carey L CL Nguyen Thao P TP Younes Souheil-Antoine SA Panigrahi Soumya S Lederman Michael M MM

The Journal of infectious diseases 20161001

Untreated human immunodeficiency virus (HIV) infection is characterized by progressive CD4(+) T-cell depletion and CD8(+) T-cell expansion, and CD4(+) T-cell depletion is linked directly to the risk for opportunistic infections and infection-associated mortality. With suppression of HIV replication by antiretroviral therapy, circulating CD4(+) Tcell numbers typically improve while CD8(+) T-cell expansion persists, and both CD4(+) T-cell cytopenia and CD8(+) T-cell expansion are associated with m ...[more]

PMID: 27625431

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.

Project description:Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p?=?0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that subset activation and skewed immune homeostasis determine the conditions of viral dissemination and early establishment of the HIV reservoir.

Dataset Information

Cytokines and T-Cell Homeostasis in HIV Infection.

Publications

Cytokines and T-Cell Homeostasis in HIV Infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets