HLA-DR+CD38+CD4+T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo
- 1 October 2011
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 85 (19), 10189-10200
- https://doi.org/10.1128/jvi.02529-10
Abstract
Percentages of activated T cells correlate with HIV-1 disease progression, but the underlying mechanisms are not fully understood. We hypothesized that HLA-DR+ CD38+ (DR+ 38+) CD4+ T cells produce the majority of HIV-1 due to elevated expression of CCR5 and CXCR4. In phytohemagglutinin (PHA)-stimulated CD8-depleted peripheral blood mononuclear cells (PBMC) infected with HIV-1 green fluorescent protein (GFP) reporter viruses, DR− 38+ T cells constituted the majority of CCR5 (R5)-tropic (median, 62%) and CXCR4 (X4)-tropic HIV-1-producing cells (median, 61%), although cell surface CCR5 and CXCR4 were not elevated in this subset of cells. In lymph nodes from untreated individuals infected with R5-tropic HIV-1, percentages of CCR5+ cells were elevated in DR+ 38+ CD4+ T cells (median, 36.4%) compared to other CD4+ T-cell subsets (median values of 5.7% for DR− 38− cells, 19.4% for DR+ 38− cells, and 7.6% for DR− 38+ cells; n = 18; P < 0.001). In sorted CD8− lymph node T cells, median HIV-1 RNA copies/105 cells was higher for DR+ 38+ cells (1.8 × 106) than for DR− 38− (0.007 × 106), DR− 38+ (0.064 × 106), and DR+ 38− (0.18 × 106) subsets (n = 8; P < 0.001 for all). After adjusting for percentages of subsets, a median of 87% of viral RNA was harbored by DR+ 38+ cells. Percentages of CCR5+ CD4+ T cells and concentrations of CCR5 molecules among subsets predicted HIV-1 RNA levels among CD8− DR/38 subsets (P < 0.001 for both). Median HIV-1 DNA copies/105 cells was higher in DR+ 38+ cells (5,360) than in the DR− 38− (906), DR− 38+ (814), and DR+ 38− (1,984) subsets (n = 7; P ≤ 0.031). Thus, DR+ 38+ CD4+ T cells in lymph nodes have elevated CCR5 expression, are highly susceptible to infection with R5-tropic virus, and produce the majority of R5-tropic HIV-1. PBMC assays failed to recapitulate in vivo findings, suggesting limited utility. Strategies to reduce numbers of DR+ 38+ CD4+ T cells may substantially inhibit HIV-1 replication.This publication has 60 references indexed in Scilit:
- Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymphoid TissueCell, 2010
- Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV InfectionJournal of Virology, 2010
- The Effect of Leflunomide on Cycling and Activation of T-Cells in HIV-1-Infected ParticipantsPLOS ONE, 2010
- HIV-1 sexual transmission: early events of HIV-1 infection of human cervico-vaginal tissue in an optimized ex vivo modelMucosal Immunology, 2010
- HIV-1 Nef Promotes Endocytosis of Cell Surface MHC Class II Molecules via a Constitutive PathwayThe Journal of Immunology, 2009
- SDF-1α Is a Potent Inducer of HIV-1-Specific CD8+T-Cell Chemotaxis, But Migration of CD8+T Cells Is Impaired at High Viral LoadsAIDS Research and Human Retroviruses, 2008
- HIV-1–induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivoBlood, 2008
- Relationship between T Cell Activation and CD4+T Cell Count in HIV‐Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of TherapyThe Journal of Infectious Diseases, 2008
- Low Immune Activation despite High Levels of Pathogenic Human Immunodeficiency Virus Type 1 Results in Long-Term Asymptomatic DiseaseJournal of Virology, 2007
- Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1Blood, 2007