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Journal of Virology, November 2009, p. 11715-11725, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.00649-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Heptad Repeat 2 Domain Is a Major Determinant for Enhanced Human Immunodeficiency Virus Type 1 (HIV-1) Fusion and Pathogenicity of a Highly Pathogenic HIV-1 Env{triangledown}

Vijay Sivaraman,1,2 Liguo Zhang,1,2 Eric G. Meissner,1,2,{ddagger} Jerry L. Jeffrey,2,3 and Lishan Su1,2,3*

Department of Microbiology and Immunology,1 Lineberger Comprehensive Cancer Center,2 Curriculum in Genetics and Molecular Biology, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599-72953

Received 30 March 2009/ Accepted 21 August 2009

Human immunodeficiency virus type 1 (HIV-1)-mediated depletion of CD4+ lymphocytes in an infected individual is the hallmark of progression to AIDS. However, the mechanism for this depletion remains unclear. To identify mechanisms of HIV-1-mediated CD4 T-cell death, two similar viral isolates obtained from a rapid progressor patient with significantly different pathogenic phenotypes were studied. One isolate (R3A) demonstrates enhanced pathogenesis in both in vivo models and relevant ex vivo lymphoid organ model systems compared to another isolate, R3B. The pathogenic determinants were previously mapped to the V5-gp41 envelope region, correlating functionally with enhanced fusion activity and elevated CXCR4 binding affinity. To further elucidate specific differences between R3A and R3B within the V5-gp41 domains that enhance CD4 depletion, R3A-R3B chimeras to study the V5-gp41 region were developed. Our data demonstrate that six residues in the ectodomain of R3A provide the major determinant for both enhanced Env-cell fusion and pathogenicity. Furthermore, three amino acid differences in the heptad repeat 2 (HR-2) domain of R3A determined its fusion activity and significantly elevated its pathogenic activity. The chimeric viruses with enhanced fusion activity, but not elevated CXCR4 affinity, correlated with high pathogenicity in the thymus organ. We conclude that the functional domain of a highly pathogenic HIV-1 Env is determined by mutations in the HR-2 region that contribute to enhanced fusion and CD4 T-cell depletion.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, CB#7295, Chapel Hill, NC 27599. Phone: (919) 966-6654. Fax: (919) 966-8212. E-mail: lsu{at}med.unc.edu

{triangledown} Published ahead of print on 2 September 2009.

{ddagger} Present address: University of Washington, Internal Medicine Residency Program, Seattle, WA.

Journal of Virology, November 2009, p. 11715-11725, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.00649-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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