Eva Maria Fenyö, 1Hanneke Schuitemaker, 2Birgitta Åsjö, 3Jane McKeating, 4Quentin Sattentau 5 and the EC Concerted Action HIV Variability, 6
1Microbiology and Tumorbiology Center, Karolinska Institute, 171 77 Stockholm, Sweden
2Department of Clinical Viro Immunology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands
3Center for Research in Virology, University of Bergen , 5020 Bergen, Norway
4Department of Microbiology, University of Reading, RG6 2AH Reading, UK
5Centre d'Immunologie de Marseille-Luminy, Case 906, 13288 Marseille, France
6Active participants of the EC Concerted Action HIV Variability: Karolinska Institute (Stockholm, Sweden: EM. Fenyö Coordinator; Chester Beatty laboratories (London, United Kingdom): Robin A. Weiss, A. McKnight; University of Liverpool (Liverpool, UK): Thomas Schulz; Centre d'Immunologie de Marseille-Luminy (Marseille, France): Q. Sattentau; University of Reading (Reading, United Kingdom): J. McKeating; Univ. College and Middlesex School of Medicine (London, United Kingdom): P. Balfe; University of Bergen (Bergen, Norway): B. Å sjö Natl.Public Health Intitute (Helsinki, Finland): P. Leinikki, M. Salminen; Inst. of Medical Microbiology and Hygiene (Freiburg, Germany): A. Meyerhans; Central Laboratory of the Netherlands Red Cross Blood Transfusion Service (Amsterdam, The Netherlands): F. Miedema, H. Schuitemaker; Swedish Inst. for Infections Disease Control (Stockholm, Sweden): J. Albert; Instituto Nacional de Saude (Lisboa, Portugal): F. Avillez, N. Taveira; University of Padova (Padova, Italy): L. Chieco Bianchi, A. De Rossi; University of Edinburgh (Edinburgh, United Kingdom): A. Leigh Brown.
HIV-1 primary isolates have been classified according to their behavior
in tissue culture into two distinct groups based on their growth kinetics,
cytopathology and cellular tropism. Classification by growth kinetics and
cytopathology is indicative of replication rate and syncytium induction in
activated peripheral blood mononuclear cells (PBMC). Accordingly, the terms
slow/low and rapid/high for replication pattern and non-syncytium inducing
(NSI) and syncytium inducing (SI) for cytopathology were introduced [1-3].
In general, the terms SI and NSI correspond broadly to the rapid/high and
slow/low phenotypes, respectively [4, 5]. A currently used method to
distinguish between these HIV-1 phenotypes is based on the ability of a
virus to infect and induce syncytia in the MT-2 T cell line [6]. These two
groups of viruses are also distinct at the genetic level, SI viruses
generally have a greater positive charge within the third variable region
of the envelope glycoprotein than NSI viruses [7-9]. A third phenotype is
defined by tropism and includes the terms T cell tropic, macrophage-tropic,
dual-tropic [10] and T cell line-adapted (TCLA, reviewed in [11, 12]).
Classification of primary HIV-1 isolates by tropism is, however, not as
clear a classification as by replicative capacity and cytopathology, since
conflicting data exist concerning macrophage tropism of several reported
HIV-1 isolates. Macrophage tropism, as defined by the ability of the virus
to infect and replicate in primary monocyte/macrophage cultures has been
described either as a feature of primary viruses that mostly lack T cell
line tropism [13] or as a general characteristic of HIV-1 isolates [10,
14]. Another report describes tropism as a continuous spectrum, ranging
from viruses that infect macrophages with high efficiency and T cell lines
with very low efficiency, to the converse [15]. Clearly, more experimental
data are required to clarify this point. Finally, adaptation to growth in T
cell lines changes the biological properties of primary HIV-1 isolates
resulting in a variety of phenotypic and genotypic changes leading to
altered cellular tropism and increased sensitivity to neutralization by
antibody and soluble receptor [12 ,16,17 ].
The classification of SI and NSI, which corresponds broadly to the
rapid/high and slow/low phenotypes, respectively, (see Table 1) is not as
simple as it first appears. For example, NSI (slow/low) viruses are able to
grow as rapidly as SI (rapid/high) viruses and form syncytia in primary
cultures of CD4+ T cells depleted of CD8+ T cells ([18,19 ] and unpublished
results). Rapid/high viruses are similar to SI viruses in that both are
able to replicate in CD4+ cell lines of monocytoid or T-cell origin, and
are usually isolated from late-stage, immunodeficient patients. Yet in
cases where NSI viruses are isolated from AIDS patients, these viruses grow
rapidly in PBMC cultures but do not infect monocytoid or T-cell lines.
However, it has to be remembered that in spite of these complicating
factors, the biological properties of HIV-1 have allowed the definition of
virulence markers [20-22]. A more precise definition of such phenotypic
traits associated with increased HIV-1 virulence will be of importance.
Table 1. Classification of HIV-1 biological phenotypes previous terminology based on Chemokine receptor New Classification cytopathology in replication rate tropism usage MT-2 cells in PBMC concept 1 concept 2 CXCR4 X4 syncytium- rapid/high T cell tropic dual-tropic* inducing T cell line -adapted CCR5 R5 non-syncytium- slow/low macrophage- dual-tropic* CCR3/CCR2b R3/R2b inducing tropic CXCR4&CCR5 X4R5 syncytium- rapid/high T cell tropic dual-tropic* and/or CCR3 X4R5R3 inducing X4R3 Bonzo, Bob unclass- yet to be unclassified unclassified unknown ified and others named *Dual tropism for macrophages and lymphocytes as defined by Valentin et al. [10].The discovery that HIV-1 uses members of the seven transmembrane domain chemokine receptor family as co-receptors for membrane fusion and entry (reviewed in [23]) has changed our perception about the properties of both T cell line-adapted and primary HIV-1 isolates. The two most well-defined HIV-1 co-receptors are CXCR4 and CCR5, members of the CXC and CC chemokine receptor subfamilies, respectively (reviewed in [24]). CXCR4 was the first HIV-1 co-receptor to be characterized, and was shown to be required for the fusion of T cell line-adapted viruses with non-human cells expressing human CD4 [25]. It is expressed on many cell types including transformed T cells, fibroblasts, primary T cells, and macrophages. Subsequently, CCR5 was shown to be the principal co-receptor for primary HIV-1 isolates with the NSI phenotype [26-3026-30], whereas the SI phenotype was associated with the use of CXCR4 alone or in combination with CCR5 [31-33]. Other members of the CC chemokine receptor family, such as CCR2b and CCR3, may also function as co-receptors for NSI virus entry, although generally in a less efficient manner than CCR5 [26 28 33]. The almost complete resistance to infection by slow/low, NSI-type viruses of individuals carrying a deletion of 32 base pairs in both alleles of the CCR5 gene confirms the importance of this molecule in HIV-1 transmission in vivo [34-36].
Acknowledgments This work was completed with help of EC grants from the Concerted Action ``HIV Variability'' and Programme EVA.
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