Early ReportFrequent infection of peripheral blood CD8-positive T-lymphocytes with HIV-1
Introduction
The principal immunological defect occurring with progression of HIV-1 infection is the loss of CD4 T-helper cells, which have a central role in the immune response to pathogens. Theories about the causes of this loss of CD4 cells range from their destruction or dysfunction directly caused by viral infection to apoptosis resulting from defects in antigen presentation.1 Whether the defects in many immune pathways, including the cytotoxic T-cell response mediated by CD8 lymphocytes, are secondary to the destruction of T-helper lymphocytes is similarly unclear. For example, Macatonia and colleagues suggested that infection of reticulodendritic cells with HIV contributes to the defects in antigen processing and presentation to T-helper cells found in AIDS patients.2
In this study, we used standard separation methods to isolate subsets of cells involved in the immune response and thereby to investigate the extent to which each cell type is infected with HIV. It has hitherto been generally accepted that the cellular tropism of HIV is determined almost exclusively by the distribution of CD4, the cell-surface receptor for HIV-1.1, 2, 3 After virus attachment, high-affinityinteractionsbetweenCD4 and the external envelope glycoprotein (gp120) of HIV-1 initiate conformational changes, resulting in exposure of a fusogenic domain of the transmembrane envelope protein (gp41) which allows entry of the virus into the cytoplasm.1 CD4 is expressed on T-helper cells, monocytes, and peripheral-blood dendritic cells6, 7 but not on B cells or mature cytotoxic T cells.
Although monocytes express CD4 and the activation marker HLA-DR,1, 8, 9 there is little evidence for extensive infection of these cells with HIV. Estimates of the frequency of infected monocytes in the peripheral circulation have ranged from zero to 100 per million of total cells.10, 11, 12, 13, 14 Previous reports have found little evidence for in-vivo infection of mature cytotoxic T cells with HIV,10, 15 although infection of CD8 T lymphocytes has been achieved in vitro.6
Peripheral-blood dendritic cells, like monocytes, are a heterogeneous population at different stages of maturation.6 They are extremely potent antigen-presenting cells and their infection by HIV could be critical in the generation of immune dysfunction. Various groups have isolated populations of these cells that can be infected in vitro2, 16, 17 and HIV-1 has been isolated directly from peripheral-blood cells with dendritic-cell characteristics.14, 18
It is not known whether strains of HIV exist with differences in tropism for different cell types found in peripheral blood mononuclear cell populations. In vitro, macrophage tropism is associated with a non-syncytium-inducing viral (NSI) phenotype. Changes in phenotype and tropism of virus isolates are known to occur during disease progression19, 20, although no change in the relative frequencies of the different cell types infected has been shown. Although in-vitro studies19, 20 suggest that HIV isolated from patients with advanced immunodeficiency is unable to replicate in the monocyte lineage, we have found that disease progression is associated with the spread of HIV from cells of the lymphoid system to peripheral sites such as lung, brain, and gut,21 where many of the target cells in these tissues are of the macrophage/monocyte lineage, such as microglia in the brain.22
In this study, whole blood from HIV-1-positive individuals was separated into component cell populations and nucleic acid was extracted from CD4 T cells, CD8 T cells, monocytes, B cells, and dendritic cells. Limiting-dilution PCR was then used to quantify the amounts of provirus in each cell type.
Section snippets
Blood samples
20 mL samples of whole blood were collected from 16 HIV-seropositive individuals in Edinburgh, UK. Immunological and virological information on disease progression was available for 13 of the participants, whose risk factors for infection included intravenous drug abuse and sexual contact with an HIV-positive individual. CD4 counts were available for the samples studied and for the same individuals every 1 or 2 months during the previous 6 months, so mean values could be calculated. These
Results
ER-positive cells contained a mean frequency (three measurements) of 82·8% CD3 cells (table 2). Contaminating cells included B lymphocytes (0·9% CD 19 cells) and natural killer cells (15·5% CD16 cells). Positive selection for CD4 cells was shown by a reduction of CD4-positive cells from a mean of 47·0% in the ER-positive population to 1·7% in the depleted cells. CD4-depleted T cells consisted of 54–5% CD8 cells, which were then positively selected on CD8-coated beads. Residual cells after CD8
Discussion
We found HIV infection of a range of cell types within the peripheral blood mononuclear cell populations. There was remarkable variation in the frequencies of infected cells within each subset, although there was some evidence for a consistent change in the predominant CD4 T-helper target cells upon disease progression.
A surprising finding was the frequent infection of CD8 lymphocytes from AIDS patients (as high as 400 provirus copies per 106 cells in one case). For methodological reasons we
References (31)
- et al.
The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain
Cell
(1986) - et al.
Detection of HIV DNA in peripheral blood dendritic cells of HIV-infected individuals
Res Virol
(1994) - et al.
HIV-induced thymocyte depletion is associated with indirect cytopathicity and infection of progenitor cells in vivo
Immunity
(1995) Pathogenesis of human immunodeficiency virus infection
MicrobiolRev
(1993)- et al.
Dendritic cell infection depletion and dysfunction in HIV-infected individuals
Immunology
(1990) - et al.
The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus
Nature
(1984) - et al.
T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV
Nature
(1984) - et al.
Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-conditioned medium
J Exp Med
(1993) - et al.
Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1
Proc Natl Acad Sci USA
(1995) - et al.
Macrophage-tropic strains of human immunodeficiency virus type 1 utilize the CD4 receptor
J Virol
(1990)
In vitro maturation of mononuclear phagocytes and susceptibility to HIV-1 infection
J Acquir Immune Defic Syndr
The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4
Science
HIV-1 in blood monocytes: frequency of detection of proviral DNA using PCR and comparison with total CD4 count
AIDS Res Hum Retroviruses
Human immunodeficiency virus type I provirus is demonstrated in peripheral blood monocytes in vivo–a study utilizing an in situ polymerase chain reaction
AIDS Res Hum Retroviruses
Mechanisms of immune activation of human immunodeficiency virus in monocytes/macrophages
J Virol
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