Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype

Abstract

The biological phenotype of primary human immunodeficiency virus type 1 (HIV-1) isolates varies according to the severity of the HIV infection. Here we show that the two previously described groups of rapid/high, syncytium-inducing (SI) and slow/low, non-syncytium-inducing (NSI) isolates are distinguished by their ability to utilize different chemokine receptors for entry into target cells. Recent studies have identified the C-X-C chemokine receptor CXCR4 (also named fusin or Lestr) and the CC chemokine receptor CCR5 as the principal entry cofactors for T-cell-line-tropic and non-T-cell-line-tropic HIV-1, respectively. Using U87.CD4 glioma cell lines, stably expressing the chemokine receptor CCR1, CCR2b, CCR3, CCR5, or CXCR4, we have tested chemokine receptor specificity for a panel of genetically diverse envelope glycoprotein genes cloned from primary HIV-1 isolates and have found that receptor usage was closely associated with the biological phenotype of the virus isolate but not the genetic subtype. We have also analyzed a panel of 36 well-characterized primary HIV-1 isolates for syncytium induction and replication in the same series of cell lines. Infection by slow/low viruses was restricted to cells expressing CCR5, whereas rapid/high viruses could use a variety of chemokine receptors. In addition to the regular use of CXCR4, many rapid/high viruses used CCR5 and some also used CCR3 and CCR2b. Progressive HIV-1 infection is characterized by the emergence of viruses resistant to inhibition by ␤-chemokines, which corresponded to changes in coreceptor usage. The broadening of the host range may even enable the use of uncharacterized coreceptors, in that two isolates from immunodeficient patients infected the parental U87.CD4 cell line lacking any engineered coreceptor. Two primary isolates with multiple coreceptor usage were shown to consist of mixed populations, one with a narrow host range using CCR5 only and the other with a broad host range using CCR3, CCR5, or CXCR4, similar to the original population. The results show that all 36 primary HIV-1 isolates induce syncytia, provided that target cells carry the particular coreceptor required by the virus.

IL-4 and a glucocorticoid up-regulate CXCR4 expression on human CD4+ T lymphocytes and enhance HIV-1 replication

“…Recent very unexpected findings have indicated that chemokines and their receptors play pivotal roles in HIV infection. In addition to CCR5 and CXCR4, at least nine other chemokine or orphan receptors, including CCR2b, CCR3, CCR8, GPR1, GPR15, STRL33, US28, V28, and ChemR23, can function as coreceptors to support the cellular entry of one or more HIV strains into various types of cells [12][13][14]. Chemokines, such as macrophage inflammatory protein 1␣ (MIP-1␣), MIP-1␤, RANTES, monocyte chemotactic protein 2 (MCP-2), eotaxin, and SDF-1, have been shown to block the entry of certain HIV strains into its target cells by the corresponding chemokine receptors [15][16][17][18][19][20].…”

Chemokine Receptors and their Crucial Role in Human Immunodeficiency Virus Infection: Major Breakthroughs in HIV Research

“…The conserved residues within the core of gp120 bind specifically to the coreceptors on different cell lines, an insight that offers us a way of viewing M-tropism versus T-tropism as being a mere matter of cells expressing CCR-5 or CXCR-4, respectively. Despite the previously mentioned controversies this approach is validated by the finding that for a variety of genetically diverse primary HIV-1 isolates, CCR-5 and CXCR-4 usage correlate with in vitro cytotropism for CD4 þ macrophages and T-cells [34][35][36]. In accordance with this a new consensus nomenclature has been proposed [37].…”

Complex positive selection pressures drive the evolution of HIV-1 with different co-receptor tropisms

“…HIV-1 R5 and X4 variants exhibit different phenotypic characteristics in cellular tropism and replication ability [5]. Two viral proteins Gp120 and RT are closely associated with HIV-1 phenotypes since the former determines cellular tropism by specifically recognizing co-receptors and the latter determines viral replication ability.…”

“…R5 and X4 have different viral characteristics, with R5 variants dominating the viral quasispecies early in and even throughout infection [1], whereas X4 variants classically emerge late in infection. X4 exhibits rapid replication and higher virulence in peripheral blood mononuclear cells (PBMCs) than R5 [5]. The emergence of X4 strains is usually accompanied by an accelerated decrease in CD4 + T cell counts, which leads to an accelerated disease progression [6].…”