tatExon 1 Exhibits Functional Diversity during HIV-1 Subtype C Primary Infection

Abstract

e 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.

Reactivation of latent HIV-1 by new semi-synthetic ingenol esters

“…Our results suggest that HIV subtype C viruses can potentially be more responsive to transcription activators compounds that target NF-kB interaction. This aspect should be considered in latency studies, since subtype C accounts for the majority of worldwide infections (Rossenkhan et al, 2013). …”

“…It is known that a single NF-κB binding site is present in the promoter of HIV-1 subtype E (HIV-1E), yet subtype B contains two, with subtype C containing at least three, but as many as four, NF-κB consensus sequences (Bachu et al, 2012; Roof et al, 2002; Rossenkhan et al, 2013). Moreover, Tat transactivation potential from different sub-types is not uniform: for example, subtype E and C Tat are strong mediators of LTR transcription compared to subtype B, and this is thought to be due to a higher affinity for the TAR hairpin (Desfosses et al, 2005).…”

“…Moreover, Tat transactivation potential from different sub-types is not uniform: for example, subtype E and C Tat are strong mediators of LTR transcription compared to subtype B, and this is thought to be due to a higher affinity for the TAR hairpin (Desfosses et al, 2005). Tat half-life from subtype E is about twice as long as that from subtypes B and C, which may be a compensatory mechanism for the reduction in NF-κB binding sites (Desfosses et al, 2005; Rossenkhan et al, 2013). All these reports support the fact that prolonged high viremia has been shown in a subset of patients during primary HIV-1 subtype C infection.…”

The Evolving Profile of the Signature Amino Acid Residues in HIV-1 Subtype C Tat

“…In addition, different profiles of SAR could be identified between the primary and chronic phases of subtype C infection. 43 …”

“…The cysteine-rich domain (CRD, [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] of Tat plays a critical role in protein dimerization and recruiting P-TEFb, a complex consisting of Cyclin T1 and CDK 9, to the RNA pol complex thereby enhancing transactivation at the level of elongation. [12][13][14] The core domain (CD, [41][42][43][44][45][46][47][48] is rich in hydrophobic residues. The Tat regions, CRD and CD, collectively can interact with tubulin binding proteins leading to apoptosis.…”