Viral complementation allows HIV-1 replication without integration

Abstract

Background: The integration of HIV-1 DNA into cellular chromatin is required for high levels of viral gene expression and for the production of new virions. However, the majority of HIV-1 DNA remains unintegrated and is generally considered a replicative dead-end. A limited amount of early gene expression from unintegrated DNA has been reported, but viral replication does not proceed further in cells which contain only unintegrated DNA. Multiple infection of cells is common, and cells that are productively infected with an integrated provirus frequently also contain unintegrated HIV-1 DNA. Here we examine the influence of an integrated provirus on unintegrated HIV-1 DNA (uDNA).

Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection

“…Aware of the fact that significant numbers of HIV-1-infected cells contain more than one viral genome (35), we demonstrate a viable crosstalk between integrated and episomal HIV-1 forms, which, similar to an earlier report, allowed recombination between integrase-deficient and wild-type viral genomes (7). Overall, this study demonstrates that chromatinized episomal HIV-1 genomes are subject to epigenetic silencing, which can be alleviated by HDACi, including SCFAs generated by the normal bacterial flora of the gut and thus, strongly indicates that episomal HIV-1 forms and SCFAs could play an important role in the early phases of HIV-1 infection, especially when the initial viral load is low.…”

“…These findings suggest that gene expression from nonintegrating HIV-1 forms can potentially affect the life cycle and pathogenesis of HIV-1. This notion was corroborated by a recent report showing the ability of integrated HIV-1 provirus to support packaging of episomally transcribed viral genomes into infectious particles (7).…”

“…These studies imply that altered viral gene expression from HIV-1 forms may be involved in the mechanism that renders nonintegrating HIV-1 replication-defective. In fact, the use of integrase-deficient, HIV-1-containing reporter genes in place of early or late proteins (nef, gag) demonstrated that episomal HIV-1 lacks the capability to express proteins encoded by either unspliced or fully spliced viral mRNAs in CD4-positive cells (7,8). Conversely, expression of env-, tat-, and nef-encoding mRNAs from nonintegrating HIV-1 was observed, although only the fully spliced mRNAs were translated to nef and tat proteins (9).…”

The human immunodeficiency virus type 1 Rev protein: ménage à trois during the early phase of the lentiviral replication cycle

“…Expression of the early HIV-1 tat, rev and nef genes after infection with integration-deficient HIV-1 has been detected repeatedly, but expression levels seem to be too low to promote lategene expression and production of infectious particles (reviewed by Wu, 2004). More recently, however, it has been demonstrated that integration-deficient mutants can be rescued by co-infection with wild-type HIV-1 (Gelderblom et al, 2008). Co-infection with wild-type virus led to late-gene expression from the unintegrated HIV-1 mutant DNA and even transfer of genomic RNA of the IN-deficient mutant into target cells at an unexpectedly high frequency.…”

“…However, in these experiments, replication of the second virus has not been analysed. If the only effect of Rev during the early phase of the replication cycle is to block integration to prevent genotoxicity, then the data of Gelderblom et al (2008) would actually indicate that the second virus can replicate without integration and therefore contribute to the development of sequence diversity.…”