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

Abstract

A panel of primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates that infected several CD4 ؉ T-cell lines, including MT-2 and C8166, were tested for infection of blood-derived macrophages. Infectivity titers for C8166 cells and macrophages demonstrated that primary SI strains infected macrophages much more efficiently than T-cell line-adapted HIV-1 strains such as LAI and RF. These primary SI strains were therefore dual-tropic. Nine biological clones of two SI strains, prepared by limiting dilution, had macrophage/C8166 infectivity ratios similar to those of their parental viruses, indicating that the dual-tropic phenotype was not due to a mixture of non-SI/macrophage-tropic and SI/T-cell tropic viruses. We tested whether the primary SI strains used either Lestr (fusin) or CCR5 as coreceptors. Infection of cat CCC/CD4 cells transiently expressing Lestr supported infection by T-cell line-adapted strains including LAI, whereas CCC/CD4 cells expressing CCR5 were sensitive to primary non-SI strains as well as to the molecularly cloned strains SF-162 and JR-CSF. Several primary SI strains, as well as the molecularly cloned dual-tropic viruses 89.6 and GUN-1, infected both Lestr ؉ and CCR5 ؉ CCC/CD4 cells. Thus, these viruses can choose between Lestr and CCR5 for entry into cells. Interestingly, some dual-tropic primary SI strains that infected Lestr ؉ cells failed to infect CCR5 ؉ cells, suggesting that these viruses may use an alternative coreceptor for infection of macrophages. Alternatively, CCR5 may be processed or presented differently on cat cells so that entry of some primary SI strains but not others is affected.

Up‐regulation of HIV coreceptor CXCR4 expression in human T lymphocytes is mediated in part by a cAMP‐responsive element

“…Five major chemokine receptor classes (CC, CXC, CC/CXC, C, and CX 3 C) have been classified and 15 chemokine receptor subtypes within these five groups have been identified. Among the CC and CXC families are CCR5 and CXCR4, the principal coreceptors for entry of M-tropic (R5) and T-tropic (X4) HIV-1 virus into macrophages and T lymphocytes, respectively (8,26,27). The natural ligand for CXCR4, SDF-1␣ (CXCL12), was identified and found to be highly expressed in fetal liver and bone marrow stromal cells (5,25,28).…”

The effect of genetic variation in chemokines and their receptorson HIV transmission and progression to AIDS

“…Complicating any interpretation is the demonstration that R5 simian immunodeficiency virus (SIV) strains are certainly pathogenic and lethal without the X4 transition (as R5 HIV strains can be in people); SIV strains can actually increase their virulence over the course of infection without any switch in co-receptor usage (56). A clear rationale for the R5-X4 transition remains elusive, although the remarkable transition in tropism in a significant subset of individuals is firmly established (23)(24)(25)(26).…”

“…SIV is endemic among several small African monkey species, including mangabeys, and is thought to represent the origin of HIV-2, a phylogenetically divergent and less virulent strain of the AIDS virus which is restricted to west Africa (82). Genotypic sampling of the red capped mangabey revealed the presence of a CCR5 receptorinactivating ,24 deletion mutation with a frequency of 87%, meaning that 98% of individuals carried at least one copy of CCR5-, 24. SIV isolates from other monkey species all use CCR5, but the red capped mangabey SIV isolate does not; its primary entry receptor is CCR2.…”

“…Most patients infected with subtype B HIV strains (the predominant strains in the US and Europe) experience a mutational transition in their HIV envelope gene which alters the cell tropism to permit CXCR4 utilization (X4-or T-cell-tropic preference) so that the mutated virus can now replicate in CXCR4-bearing cells, including immortalized T-cell lines in vitro. This increase in the prevalence of T-tropic HIV strains usually precedes an abrupt decline in CD4-bearing lymphocytes, the hallmark of AIDS onset (23,24).…”

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

“…Transmission studies have shown that the initial infection is almost invariably established by NSI/ M-tropic strains. Thus, primary HIV-1 strains of the NSI type often use the CCR-5 coreceptor to gain entry in macrophage/ monocyte cell lines [18]. Strains, which rely on a broader range of coreceptors, may develop during the course of infection [19].…”