Divergent transcriptional regulation among expanding human immunodeficiency virus type 1 subtypes

Abstract

The current AIDS pandemic represents the uneven spread of multiple genetically related subtypes (A to J) of human immunodeficiency virus type 1 (HIV-1). Notably, HIV-1 E in southeast Asia and HIV-1 C in sub-Saharan Africa are expanding faster and are likely of greater global significance than the HIV-1 B subtype prevalent in the United States and Europe. While many studies have focused on genetic variation among structural genes, we chose to conduct a comparative analysis of the long terminal repeats of HIV-1 E and HIV-1 C isolates and report subtype-specific differences in enhancer copy numbers and sequences, as well as divergent activation in response to the cellular transcriptional activators Rel-p65 and NFATc and viral Tat. This study is the first to identify functional distinctions in promoter architecture between HIV-1 subtypes and raises the possibility that regulatory divergence among the subtypes of HIV-1 has occurred. Divergent transcriptional regulation may explain some of the epidemiologically observed differences in transmission and pathogenesis and underscores the need for further comparative analysis of HIV-1 regulation.

A stronger transcription regulatory circuit of HIV-1C drives the rapid establishment of latency with implications for the direct involvement of Tat

“…Although the fundamental constitution of the HIV-1 promoter is highly conserved among the various genetic subtypes of HIV-1, within this underlying structural theme, there exist many subtype-specific molecular features that may modulate gene expression considerably from the viral promoter. Such differences are evident in the copy-number and nucleotide sequences of different TFBS especially those of USF, c-Myb, LEF-1, Ets1, NF-AT, Ap-1, NF-κB, and Sp1 binding sites, and regulatory elements such as the TATA box and the TAR element (Jeeninga RE et al, 2000;Mbondji-Wonje C et al, 2018;Montano MA et al, 1997). The critical roles that most of these regulatory elements play in positively regulating the basal and inducible levels of viral transcription have been well documented (Garcia JA et al, 1987;Pereira LA et al, 2000).…”

Regulation of HIV-1 gene transcription: from lymphocytes to microglial cells

“…Some subtypes of HIV-1, such as C, E, and A, appear to be transmitted more efficiently than the B clade. Variations in the nucleotide sequence of the LTR isolated from different HIV-1 M subtypes and strains have been reported [13,[167][168][169][170]. This LTR variability may have resulted from adaptation to specific cellular backgrounds to optimize HIV-1 gene transcription.…”

HIV‐1 subtypes in Spain: a retrospective analysis from 1995 to 2003

“…Natural polymorphisms at the pol gene also may facilitate the selection of different pathways and/or a more rapid emergence of drug resistance and treatment failure. HIV-1 genetic variability could also lead to phenotypic differences among clades [31][32][33][34], although more studies are required to clarify whether viral infectivity or pathogenicity is influenced by the HIV-1 genetic subtype.…”