title: 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.
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-1C 1084i), a HIV-1C isolate (HIV-1 IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1 ADA) 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-1C 1084i 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-1C 1084i 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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Vasudev R
authors.initials: VR
authors.lastname: Rao
authors.forename: Ujjwal
authors.initials: U
authors.lastname: Neogi
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Talboom
authors.forename: Ligia
authors.initials: L
authors.lastname: Padilla
authors.forename: Mustafizur
authors.initials: M
authors.lastname: Rahman
authors.forename: Cari
authors.initials: C
authors.lastname: Fritz-French
authors.forename: Sandra
authors.initials: S
authors.lastname: Gonzalez-Ramirez
authors.forename: Anjali
authors.initials: A
authors.lastname: Verma
authors.forename: Charles
authors.initials: C
authors.lastname: Wood
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
authors.forename: Udaykumar
authors.initials: U
authors.lastname: Ranga
authors.forename: Tasnim
authors.initials: T
authors.lastname: Azim
authors.forename: John
authors.initials: J
authors.lastname: Joska
authors.forename: Eliseo
authors.initials: E
authors.lastname: Eugenin
authors.forename: Anita
authors.initials: A
authors.lastname: Shet
authors.forename: Heather
authors.initials: H
authors.lastname: Bimonte-Nelson
authors.forename: William R
authors.initials: WR
authors.lastname: Tyor
authors.forename: Vinayaka R
authors.initials: VR
authors.lastname: Prasad
mesh_terms: D015526:AIDS Dementia Complex / Q000453:epidemiology* / Q000821:virology*; D000328:Adult; D000353:Africa, Southern / Q000453:epidemiology; D000818:Animals; D001210:Asia, Southeastern / Q000453:epidemiology; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D015995:Prevalence; D017422:Sequence Analysis, DNA; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus