8th Conference on Retroviruses and Opportunistic Infections Chicago, IL - February 4 - 8, 2001

Conf Retroviruses Opportunistic Infect 2001 Feb 4-8; 8:44 (abstract no. 5)

P. Gorry¹, A. Ohagen¹, G. Holm¹, C. Birch², J. Bell³, K. Kunstman⁴, S. Wolinsky⁴, and D. Gabuzda^1
1Dana-Farber Cancer Inst., Boston, MA; ²VIDRL, Australia; ³Univ. of Edinburgh, UK; and ⁴Northwestern Univ. Med. Sch., Chicago, IL.

BACKGROUND: The viral determinants that underlie neurotropism and neurovirulence of HIV-1 are unknown, due in part to limited studies on primary brain isolates. To better understand neuropathogenic mechanisms of HIV-1, we isolated primary viruses from brain, CSF, spinal cord, spleen, and lymph node autopsy samples from 6/19 AIDS patients with HIV-1 encephalopathy and dementia.

METHODS: Phenotypic characterization was performed to determine coreceptor usage, replication capacity in PBMC, MDM and microglia, fusogenicity in MDM, and ability to induce neuronal apoptosis.

RESULTS: Brain-derived isolates exhibited heterogeneous coreceptor usage and consisted of R5, X4 and R5X4 variants. All primary isolates that replicated to high levels in microglia replicated to similar high levels in MDM. However, 6/11 R5 isolates and 1/5 R5 isolates that replicated in MDM and microglia were highly fusogenic in MDM and induced neuronal apoptosis in primary brain cultures. In other studies, R5X4 Envs cloned directly from brain were shown to be highly fusogenic and cytopathic, similar to the phenotype exhibited by the R5X4 isolates.

CONCLUSIONS: These findings suggest that M-tropism rather than CCR5 usage per se underlies neurotropism. Our results further suggest that neurotropic isolates which use CXCR4 and are highly fusogenic are more frequently associated with neuropathicity compared to R5 virus. Our data support the hypothesis that R5X4 viruses which emerge late during the course of HIV-1 infection invade the CNS and contribute to the neurodegenerative processes that occur in individuals with AIDS dementia. This may be a factor that underlies the discrepancy between early neuroinvasion by HIV-1 and the occurrence of dementia at late stages of AIDS.

2001-02-04
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