Both Memory and CD45RA+/CD62L+ Naive CD4+ T Cells Are Infected in Human Immunodeficiency Virus Type 1-Infected Individuals

ABSTRACT Cellular activation is critical for the propagation of human immunodeficiency virus type 1 (HIV-1) infection. It has been suggested that truly naive CD4+ T cells are resistant to productive HIV-1 infection because of their constitutive resting state. Memory and naive CD4+ T-cell subsets from 11 HIV-1-infected individuals were isolated ex vivo by a combination of magnetic bead depletion and fluorescence-activated cell sorting techniques with stringent criteria of combined expression of CD45RA and CD62L to identify naive CD4+ T-cell subsets. In all patients HIV-1 provirus could be detected within naive CD45RA+/CD62L+ CD4+ T cells; in addition, replication-competent HIV-1 was isolated from these cells upon CD4+ T-cell stimulation in tissue cultures. Memory CD4+ T cells had a median of fourfold more replication-competent virus and a median of sixfold more provirus than naive CD4+ T cells. Overall, there was a median of 16-fold more integrated provirus identified in memory CD4+ T cells than in naive CD4+ T cells within a given patient. Interestingly, there was a trend toward equalization of viral loads in memory and naive CD4+ T-cell subsets in those patients who harbored CXCR4-using (syncytium-inducing) viruses. Within any given patient, there was no selective usage of a particular coreceptor by virus isolated from memory versus naive CD4+ T cells. Our findings suggest that naive CD4+ T cells may be a significant viral reservoir for HIV, particularly in those patients harboring CXCR4-using viruses.

[1]  C. Mackay.  Migration pathways and immunologic memory among T lymphocytes. , 1992, Seminars in immunology.

[2]  D. Ho,et al.  HIV-1 dynamics in vivo. , 1995, Journal of biological regulators and homeostatic agents.

[3]  L. Bradley,et al.  T cell memory. , 1998, Annual review of immunology.

[4]  É. Oksenhendler,et al.  HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphocytes , 1994, Cell.

[5]  Marc Parmentier,et al.  A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors , 1996, Cell.

[6]  Martin A. Nowak,et al.  Viral dynamics in human immunodeficiency virus type 1 infection , 1995, Nature.

[7]  David C. Krakauer,et al.  Effect of Immune Activation on the Dynamics of Human Immunodeficiency Virus Replication and on the Distribution of Viral Quasispecies , 1998, Journal of Virology.

[8]  Robert F. Siliciano,et al.  In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency , 1995, Nature Medicine.

[9]  T. Folks,et al.  Loss of inducible virus in CD45RA naive cells after human immunodeficiency virus-1 entry accounts for preferential viral replication in CD45RO memory cells. , 1997, Blood.

[10]  H. Matsuda,et al.  Age‐related accumulation of LFA‐1high cells in a CD8+CD45RAhigh T cell population , 1993, European journal of immunology.

[11]  R. Doms,et al.  Unwelcomed guests with master keys: how HIV uses chemokine receptors for cellular entry. , 1997, Virology.

[12]  J. Justement,et al.  Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Stephen C. Peiper,et al.  Identification of a major co-receptor for primary isolates of HIV-1 , 1996, Nature.

[14]  R. Connor,et al.  Change in Coreceptor Use Correlates with Disease Progression in HIV-1–Infected Individuals , 1997, The Journal of experimental medicine.

[15]  M. Sanders,et al.  Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets. , 1988, Immunology today.

[16]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[17]  J. Moore,et al.  Expression patterns of the HIV type 1 coreceptors CCR5 and CXCR4 on CD4+ T cells and monocytes from cord and adult blood. , 1998, AIDS research and human retroviruses.

[18]  P H Harvey,et al.  Revealing the history of infectious disease epidemics through phylogenetic trees. , 1995, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[19]  M. Roederer,et al.  CD8 naive T cell counts decrease progressively in HIV-infected adults. , 1995, The Journal of clinical investigation.

[20]  A. Perelson,et al.  HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time , 1996, Science.

[21]  C. Mackay,et al.  Lymphocyte recirculation and life span in vivo. , 1993, Current topics in microbiology and immunology.

[22]  C. Broder,et al.  CC CKR5: A RANTES, MIP-1α, MIP-1ॆ Receptor as a Fusion Cofactor for Macrophage-Tropic HIV-1 , 1996, Science.

[23]  M. Roederer,et al.  HIV does not replicate in naive CD4 T cells stimulated with CD3/CD28. , 1997, The Journal of clinical investigation.

[24]  R. Siliciano,et al.  Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection , 1997, Nature.

[25]  L. McQuay,et al.  Dilution assay statistics , 1994, Journal of clinical microbiology.

[26]  D. Richman,et al.  Preferential replication of HIV-1 in the CD45RO memory cell subset of primary CD4 lymphocytes in vitro. , 1997, The Journal of clinical investigation.

[27]  R. Weiss,et al.  Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry , 1996, Journal of virology.

[28]  F. Lori,et al.  Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  C. Mackay,et al.  The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  L. Picker,et al.  Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition. , 1993, Journal of immunology.

[31]  D. Scott‐Algara,et al.  Differential requirements for HIV‐1 replication in naive and memory CD4 T cells from asymptomatic HIV‐1 seropositive carriers and AIDS patients , 1993, Clinical and experimental immunology.

[32]  C. Broder,et al.  CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. , 1996, Science.

[33]  Anthony S. Fauci,et al.  Host factors and the pathogenesis of HIV-induced disease , 1996, Nature.

[34]  Ying Sun,et al.  The β-Chemokine Receptors CCR3 and CCR5 Facilitate Infection by Primary HIV-1 Isolates , 1996, Cell.

[35]  M A Nowak,et al.  Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Virginia Litwin,et al.  HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 , 1996, Nature.

[37]  Paul E. Kennedy,et al.  HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor , 1996, Science.

[38]  G. Janossy,et al.  Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. , 1988, Journal of immunology.