Abstract
HIV subtypes distribution varies by geographic regions; this is likely associated with differences in viral fitness but the predictors and underlying mechanisms are unknown. Using in-vitro, in-vivo, and ex-vivo approaches, we found significantly higher transactivation and replication of HIV-1-CRF02_AG (prevalent throughout West-Central Africa), compared to subtype-B. While CRF02_AG-infected animals showed higher viremia, subtype-B-infected animals showed significantly more weight loss, lower CD4+ T-cells and lower CD4/CD8 ratios, suggesting that factors other than viremia contribute to immunosuppression and wasting syndrome in HIV/AIDS. Compared to HIV-1-subtype-B and its Tat proteins(Tat.B), HIV-1-CRF02_AG and Tat.AG significantly increased histone acetyl-transferase activity and promoter histones H3 and H4 acetylation. Silencing N-myrystoyltransferase(NMT)-1 and casein-kinase-(CK)-II-alpha prevented Tat.AG- and HIV-1-CRF02_AG-mediated viral transactivation and replication, but not Tat.B- or HIV-1-subtype-B-mediated effects. Tat.AG and HIV-1-CRF02_AG induced the expression of NMT-1 and CKII-alpha in human monocytes and macrophages, but Tat.B and HIV-1-subtype-B had no effect. These data demonstrate that NMT1, CKII-alpha, histone acetylation and histone acetyl-transferase modulate the increased replication of HIV-1-CRF02_AG. These novel findings demonstrate that HIV genotype influence viral replication and provide insights into the molecular mechanisms of differential HIV-1 replication. These studies underline the importance of considering the influence of viral genotypes in HIV/AIDS epidemiology, replication, and eradication strategies.
Highlights
The human immunodeficiency virus (HIV) is characterized by a very high genetic variability, due to lack of DNA proofreading activity of the reverse transcriptase enzyme and pharmacological selective pressure[1,2,3,4]
We demonstrate that Tat.AG and HIV-1 CRF02_AG increased N-myrystoyltransferase (NMT)-1 and casein kinase-II-alpha (CKIIα) expression in human monocytes and monocytes-derived macrophages (MDM), and silencing NMT1 and CKIIα genes blocked HIV-1 CRF02_AG infection of human macrophages
Comparative analyses of the replication capacity of HIV-1 subtype-B (4 different isolates) and CRF02_AG (5 different isolates) in human peripheral blood mononuclear cells (PBMC) and MDM showed that compared to PBMC infected with HIV-1 subtype-B, CRF02_AG-infected cells had significantly higher reverse transcriptase (RT) activity at day-12 (Fig. 1A,B) and day-15 (Fig. 1C,D) post-infection (p.i.) (P < 0.0001)
Summary
The human immunodeficiency virus (HIV) is characterized by a very high genetic variability, due to lack of DNA proofreading activity of the reverse transcriptase enzyme and pharmacological selective pressure[1,2,3,4]. We demonstrate that Tat.AG and HIV-1 CRF02_AG (but not Tat.B or HIV-1 subtype-B) increased N-myrystoyltransferase (NMT)-1 and casein kinase-II-alpha (CKIIα) expression in human monocytes and MDM, and silencing NMT1 and CKIIα (but not NMT2 or CKIIβ) genes blocked HIV-1 CRF02_AG (but not subtype B) infection of human macrophages. These mechanistic studies provide insights into the molecular mechanisms modulating the increased replication of CRF02_AG viruses, and have implications for the transmission, adaptation, and predominance of this recombinant virus in Sub-Saharan Africa
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