Yi Y, Frank I, Sulcove J, Kolson DL, Collman RG; Conference on Retroviruses and Opportunistic Infections.

9th Conf Retrovir Oppor Infect Feb 24 28 2002 Wash State Conv Trade Cent Seattle Wash Conf Retrovir Oppor Infect 9th 2002 Seattle Wash. 2002 Feb 24-28; 9: abstract no. 190-M.

Univ. of Pennsylvania Sch. of Med., Philadelphia

BACKGROUND: HIV-1 mainly infects macrophages/microglia in the central nervous system (CNS). Virus isolates from the CNS have generally been thought of as restricted to CCR5 usage, with a macrophage-tropic and non-syncytia-inducing (NSI) phenotype. Recently, however, we and others demonstrated that macrophages and microglia express both CCR5 and CXCR4 and that both pathways can serve as co-receptors for entry. We therefore sought to explore the biological diversity among HIV-1 isolates from the CNS.METHODS: We isolated an HIV-1 strain (tybe) from the cerebrospinal fluid of an individual with AIDS that differed from prototype CNS strains in that it was syncytia-inducing (SI) in MT-2 cells. HIV-1/tybe replicated to high level in primary human macrophages, as expected for a CNS isolate but, unlike prototype CNS strains, tybe used CXCR4 exclusively to infect macrophages. We generated a full-length functional env clone from this isolate.RESULTS: The tybe Env mediated fusion with transfected cells expressing CD4 and CXCR4 but not with cells expressing CCR5, confirming that it was exclusively X4. The Env-predicted protein sequence displayed a highly charged V3 sequence typical of X4 strains. Finally, supernatant from primary human macrophages infected with HIV-1/tybe induced apoptosis of Nt.2 neurons in pure and mixed neuronal cell cultures.CONCLUSIONS: This primary isolate (tybe) represents a novel type of HIV-1 derived from the CNS that is X4 yet able to replicate efficiently in macrophages and induce neuronal injury. These results demonstrate a broader range of biological characteristics among HIV-1 strains from the CNS than generally appreciated, and raise the possibility that X4 strains may participate in the pathogenesis of neurological disease in AIDS.

Publication Types:

• Meeting Abstracts

Keywords:

• Antigens, CD4
• Apoptosis
• Central Nervous System
• Gene Products, env
• Genes, env
• Giant Cells
• HIV-1
• Humans
• Macrophages
• Neurons
• Nitric Oxide Synthase
• Receptors, CCR5
• Receptors, CXCR4
• genetics
• immunology

Other ID:

• GWAIDS0024509

UI: 102264133

From Meeting Abstracts