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Journal of Virology, March 2004, p. 2586-2590, Vol. 78, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.5.2586-2590.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tat Protein of Human Immunodeficiency Virus Type 1 Subtype C Strains Is a Defective Chemokine

Udaykumar Ranga,^1* Raj Shankarappa,^2,3, Nagadenahalli B. Siddappa,^1,4, Lakshmi Ramakrishna,¹ Ramalingam Nagendran,¹ Marthandan Mahalingam,¹ Anita Mahadevan,⁵ Narayana Jayasuryan,⁶ Parthasarathy Satishchandra,⁷ Susarla K. Shankar,⁵ and Vinayaka R. Prasad⁸

Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research,¹ Department of Neurovirology,⁴ Department of Neuropathology,⁵ Department of Neurology, National Institute of Mental Health and Neurosciences,⁷ Microtest Innovations Pvt. Ltd., Bangalore, India,⁶ Center for Genomic Sciences, Allegheny-Singer Research Institute, Drexel University School of Medicine, Pittsburgh, Pennsylvania 15212,² Department of Surgery and Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15216,³ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York⁸

Received 21 February 2003/ Accepted 13 November 2003

Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is correlated with increased monocyte migration to the brain, and the incidence of HAD among otherwise asymptomatic subjects appears to be lower in India than in the United States and Europe (1 to 2% versus 15 to 30%). Because of the genetic differences between HIV-1 strains circulating in these regions, we sought to identify viral determinants associated with this difference. We targeted Tat protein for these studies in view of its association with monocyte chemotactic function. Analyses of Tat sequences representing nine subtypes revealed that at least six amino acid residues are differentially conserved in subtype C Tat (C-Tat). Of these, cysteine (at position 31) was highly (>99%) conserved in non-subtype C viruses and more than 90% of subtype C viruses encoded a serine. We hypothesized a compromised chemotactic function of C-Tat due to the disruption of CC motif and tested it with the wild type C-Tat (CS) and its two isogenic variants (CC and SC) derived by site-directed mutagenesis. We found that the CS natural variant was defective for monocyte chemotactic activity without a loss in the transactivation property. While the CC mutant is functionally competent for both the functions, in contrast, the SC mutant was defective in both. Therefore, the loss of the C-Tat chemotactic property may underlie the reduced incidence of HAD; although not presenting conclusive evidence, this study provides the first evidence for a potential epidemiologic phenomenon associated with biological differences in the subtype C viruses.

R.S. and N.B.S. equally contributed to this work.

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