HIV-1 clade promoters strongly influence spatial and temporal dynamics of viral replication in vivo

Abstract

Although the primary determinant of cell tropism is the interaction of viral envelope or capsid proteins with cellular receptors, other viral elements can strongly modulate viral replication. While the HIV-1 promoter is polymorphic for a variety of transcription factor binding sites, the impact of these polymorphisms on viral replication in vivo is not known. To address this issue, we engineered isogenic SIVmac239 chimeras harboring the core promoter/enhancer from HIV-1 clades B, C, and E. Here it is shown that the clade C and E core promoters/enhancers bear a noncanonical activator protein-1 (AP-1) binding site, absent from the corresponding clade B region. Relative ex vivo replication of chimeras was strongly dependent on the tissue culture system used. Notably, in thymic histocultures, replication of the clade C chimera was favored by IL-7 enrichment, which suggests that the clade C polymorphism in the AP-1 and NF-κB binding sites is involved. Simultaneous infection of rhesus macaques with the 3 chimeras revealed a strong predominance of the clade C chimera during primary infection. Thereafter, the B chimera dominated in all tissues. These data show that the clade C promoter is particularly adapted to sustain viral replication in primary viremia and that cladespecific promoter polymorphisms constitute a major determinant for viral replication.

Pertussis Toxin B-Oligomer Suppresses IL-6 Induced HIV-1 and Chemokine Expression in Chronically Infected U1 Cells via Inhibition of Activator Protein 1

“…Alternatively, PTX-B could downregulate AP-1 mediated activation of the intragenic gag enhancer (48,60), previously suggested to be induced by stimuli, such as IL-6, in combination with TNF-␣ or glucocorticoids (38,49). In this regard, our findings on the levels of luciferase expression driven by LTRs after IL-6 stimulation add to previous reports on biological differences among the different HIV clades, which are determined in part by differences in the composition of the LTR promoter (52,(77)(78)(79)(80). Thus, differences in the composition of transcription factor binding sites may provide each clade with a promoter responding in a unique matter to cellular activation pathways.…”

Molecularly Cloned SHIV-1157ipd3N4: a Highly Replication- Competent, Mucosally Transmissible R5 Simian-Human Immunodeficiency Virus Encoding HIV Clade Cenv

“…One to three NF-B binding sites may be present in the enhancer regions of SIV or different HIV-1 subtypes (9,38,46). We hypothesized that the number of such sites in the viral LTR may affect viral replication and virulence.…”

The HIV-1 clade C promoter is particularly well adapted to replication in the gut in primary infection

“…Two RhM, 97R0350 and 98R0026, were intravenously coinoculated with 100 50% tissue culture infectious doses (TCID 50 ) of each cell-free STR-B, STR-C and STR-E chimeras. CD4 and CD8 T lymphocytes were quantified by flow cytometry as described previously [17]. Faeces samples were placed in sterile tubes and immediately frozen at À808C.…”

“…We have previously shown that HIV-1 clade promoters strongly influence spatial and temporal dynamics of viral replication in vivo [17]. The SIVmac239 clone was engineered in which it was possible to freely exchange the viral promoter without altering nef (clone named STR for short terminal repeat).…”