title: tat Exon 1 exhibits functional diversity during HIV-1 subtype C primary infection.
abstract: Human immunodeficiency virus type 1 (HIV-1) Tat is a mediator of viral transcription and is involved in the control of virus replication. However, associations between HIV-1 Tat diversity and functional effects during primary HIV-1 infection are still unclear. We estimated selection pressures in tat exon 1 using the mixed-effects model of evolution with 672 viral sequences generated from 20 patients infected with HIV-1 subtype C (HIV-1C) over 500 days postseroconversion. tat exon 1 residues 3, 4, 21, 24, 29, 39, and 68 were under positive selection, and we established that specific amino acid signature patterns were apparent in primary HIV-1C infection compared with chronic infection. We assessed the impact of these mutations on long terminal repeat (LTR) activity and found that Tat activity was negatively affected by the Ala(21) substitution identified in 13/20 (65%) of patients, which reduced LTR activity by 88% (± 1%) (P < 0.001). The greatest increase in Tat activity was seen with the Gln(35)/Lys(39) double mutant that resulted in an additional 49% (± 14%) production of LTR-driven luciferase (P = 0.012). There was a moderate positive correlation between Tat-mediated LTR activity and HIV-1 RNA in plasma (P = 0.026; r = 0.400) after 180 days postseroconversion that was reduced by 500 days postseroconversion (P = 0.043; r = 0.266). Although Tat activation of the LTR is not a strong predictor of these clinical variables, there are significant linear relationships between Tat transactivation and patients' plasma viral loads and CD4 counts, highlighting the complex interplay between Tat mutations in early HIV-1C infection.
authors.affiliation: Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
authors.forename: Raabya
authors.initials: R
authors.lastname: Rossenkhan
authors.forename: Iain J
authors.initials: IJ
authors.lastname: MacLeod
authors.forename: Theresa K
authors.initials: TK
authors.lastname: Sebunya
authors.forename: Eduardo
authors.initials: E
authors.lastname: Castro-Nallar
authors.forename: Mary Fran
authors.initials: MF
authors.lastname: McLane
authors.forename: Rosemary
authors.initials: R
authors.lastname: Musonda
authors.forename: Berhanu A
authors.initials: BA
authors.lastname: Gashe
authors.forename: Vlad
authors.initials: V
authors.lastname: Novitsky
authors.forename: M
authors.initials: M
authors.lastname: Essex
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D018791:CD4 Lymphocyte Count; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology*; D016325:HIV Long Terminal Repeat / Q000502:physiology; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010949:Plasma / Q000821:virology; D012641:Selection, Genetic; D014158:Transcription, Genetic; D019562:Viral Load; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus