Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence

• Type of Material: Article
• Authors: Vasudev R. Rao, Albert Einstein College; Ujjwal Neogi, St. John's Medical College; Joshua S. Talboom, Arizona State University; Ligia Padilla, Atlanta VA Medical Center; Mustafizur Rahman, International Centre for Diarrhoeal Disease Research; Cari Fritz-French, Emory University; Sandra Gonzalez-Ramirez, University of Nebraska-Lincoln; Anjali Verma, Jawaharlal Nehru Centre for Advanced Scientific Research; Charles Wood, University of Nebraska-Lincoln; Ruth M. Ruprecht, Harvard; Udaykumar Ranga, Jawaharlal Nehru Centre for Advanced Scientific Research; Tasnim Azim, International Centre for Diarrhoeal Disease Research; John Joska, University of Cape Town; Eliseo Eugenin, Public Health Research Institute (PHRI); Anita Shet, St. John's Medical College; Heather Bimonte-Nelson, Arizona State University; William Tyor, Emory University; Vinayaka R. Prasad, Albert Einstein College
• Language: English
• Date: 2013-06-08
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Rao et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.retrovirology.com/content/10/1/61
• Title of Journal or Parent Work: Retrovirology
• ISSN: 1742-4690
• Volume: 10
• Issue: 61
• Start Page: 1
• End Page: 16
• Grant/Funding Information: The authors wish to thank the Einstein/Montefiore Center for AIDS Research (P30 AI051519) for the use of BSL3/Clinical Virology Core services.; The work was also supported by NIH P01 AI048240 (R.M.R.), NIH NS74903 & NIH GM103509 (to C.W.), NIH R01 MH096625 (to E.E.) and NIH T32 AI060547 (to S.G.).; This work was mainly supported by NIH R01 MH083579 (V.R.P.) and NIH D43 TW001403 (V.R.P.).
• Keywords: HIV-1 Tat; Neuropathogenesis; HIV-1 Tat C31S polymorphism; Neuroaids; HIV dementia; Tat dicysteine; SCID-HIVE mouse model; Clade C HIV-1; Subtype C HIV-1
• Research Categories: Biology, Microbiology; Biology, Virology; Health Sciences, Immunology

Abstract

Background HIV-1 Clade C (Subtype C; HIV-1C) is responsible for greater than 50% of infections worldwide. Unlike clade B HIV-1 (Subtype B; HIV-1B), which is known to cause HIV associated dementia (HAD) in approximately 15% to 30% of the infected individuals, HIV-1C has been linked with lower prevalence of HAD (0 to 6%) in India and Ethiopia. However, recent studies report a higher prevalence of HAD in South Africa, Zambia and Botswana, where HIV-1C infections predominate. Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. HIV-1 Tat protein is a viral determinant of neurocognitive dysfunction. Therefore, we focused our study on the variations seen in tat gene and its contribution to HIV associated neuropathogenesis. Results A phylogenetic analysis of tat sequences of Southern African (South Africa and Zambia) HIV isolates with those from the geographically distant Southeast Asian (India and Bangladesh) isolates revealed that Southern African tat sequences are distinct from Southeast Asian isolates. The proportion of HIV − 1C variants with an intact dicysteine motif in Tat protein (C30C31) was significantly higher in the Southern African countries compared to Southeast Asia and broadly paralleled the high incidence of HAD in these countries. Neuropathogenic potential of a Southern African HIV-1C isolate (from Zambia; HIV-1C1084i), a HIV-1C isolate (HIV-1IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1ADA) from the US were tested using in vitro assays to measure neurovirulence and a SCID mouse HIV encephalitis model to measure cognitive deficits. In vitro assays revealed that the Southern African isolate, HIV-1C1084i exhibited increased monocyte chemotaxis and greater neurotoxicity compared to Southeast Asian HIV-1C. In neurocognitive tests, SCID mice injected with MDM infected with Southern African HIV-1C1084i showed greater cognitive dysfunction similar to HIV-1B but much higher than those exposed to Southeast Asian HIV − 1C. Conclusions We report here, for the first time, that HIV-1C from Southern African countries is genetically distinct from Southeast Asian HIV-1C and that it exhibits a high frequency of variants with dicysteine motif in a key neurotoxic HIV protein, Tat. Our results indicate that Tat dicysteine motif determines neurovirulence. If confirmed in population studies, it may be possible to predict neurocognitive outcomes of individuals infected with HIV-1C by genotyping Tat.