An Unusual Syncytia-Inducing Human Immunodeficiency Virus Type 1 Primary Isolate from the Central Nervous System that is Restricted to CXCR4, Replicates Efficiently in Macrophages, and Induces Neuronal Apoptosis

Abstract

Macrophage/microglia cells are the principal targets for human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS). Prototype HIV-1 isolates from the CNS are macrophage (M)-tropic, non-syncytia-inducing (NSI), and use CCR5 for entry (R5 strains), but whether syncytia-inducing (SI) CXCR4-using X4 strains might play a role in macrophage/microglia infection and neuronal injury is unknown. To explore the range of features among HIV-1 primary isolates from the CNS, the authors analyzed an HIV-1 strain (TYBE) from cerebrospinal fluid of an individual with acquired immunodeficiency syndrome (AIDS) that was unusual because it was SI. Like other CNS isolates, HIV-1/TYBE replicated to high level in primary human macrophages, but, in contrast to CNS prototypes, TYBE used CXCR4 exclusively to infect macrophages. A functional TYBE env clone confirmed the X4 phenotype and displayed a highly charged V3 sequence typical of X4 strains. Supernatant from TYBE-infected primary human macrophages induced apoptosis of neurons. Thus, TYBE represents a novel type of CNS-derived HIV-1 isolate that is CXCR4-restricted yet replicates efficiently in macrophages and induce neuronal injury. These results demonstrate that HIV-1 variants in the CNS may possess a broader range of biological characteristics than generally appreciated, raise the possibility that X4 strains may participate in AIDS neuropathogenesis, and provide a prototype clade B HIV-1 strain that replicates efficiently in primary macrophages through the exclusive use of CXCR4 as a coreceptor.

Biological Analysis of Human Immunodeficiency Virus Type 1 R5 Envelopes Amplified from Brain and Lymph Node Tissues of AIDS Patients with Neuropathology Reveals Two Distinct Tropism Phenotypes and Identifies Envelopes in the Brain That Confer an Enhanced Tropism and Fusigenicity for Macrophages

“…Analysis of the phenotypes of envelopes derived from brain tissue has been limited mainly to viruses isolated into bloodderived lymphocytes (15,16,42,51) or envelope fragments cloned into chimeric viruses (3). A recent report by Ohagen et al (28) described envelope genes that were amplified by PCR from brain tissue without culture.…”

Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology

“…Though typically the syncytiuminducing phenotype has been assigned to HIV strains that efficiently induce syncytia in transformed T cells in vitro (i.e., CXCR4-using strains), many R5 HIV-1 strains promote syncytia formation in primary macrophages albeit with variable efficacy, and their different ability in forming syncytia has been suggested to associate with their neuropathogenic potential (Gorry et al, 2002). On the other hand, although brain-derived viruses predominantly use CCR5, viruses that exclusively use CXCR4 for infection of microglia/macrophages have been identified (Gorry et al, 2005) and rarely reported in the CSF (Yi et al, 2003). Thus, both CXCR4 and CCR5-using viruses can potentially induce macrophage syncytia and contribute to HAD, though adaptive viral evolution appears to favor M-tropism of R5 HIV-1 strains (Gorry et al, 2005).…”

“…Brain-derived viruses generally use CCR5 for entry (Gonzalez-Scarano and Martin-Garcia, 2005), but viruses exploiting CXCR4 as co-receptor (or dual tropic viruses) are also found in the CNS and able to infect macrophages (Yi et al, 2003). These viruses are highly neurotoxic in vitro (Gabuzda and Wang, 2000) and generally predominate in the late stages of the disease.…”

Neuronal Apoptosis Is Mediated by CXCL10 Overexpression in Simian Human Immunodeficiency Virus Encephalitis

“…HIV-E is usually associated with infection with viruses that use the CCR5 coreceptor, although it has been demonstrated recently that viruses that use CXCR4 can also cause the disease. 41 SHIV-E has been clearly associated with viruses that use the CXCR4 co-receptor. 21,42,43 The common factor shared by these viruses was their tropism for macrophages.…”