A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1

Abstract

At the cellular level, cells infected with human immunodeficiency virus type 1 (HIV-1) exhibit immunity to a second infection by the virus that initiated the first infection or by related viruses [superinfection resistance (SIR)]. In the case of HIV infection, SIR was basically attributed to downregulation of the CD4 receptors. We have recently reported on an interaction between HIV-1 Rev and integrase (IN) proteins, which results in inhibition of IN activity in vitro and integration of cDNA in HIV-1-infected cells. A novel function for the viral Rev protein in controlling integration of HIV cDNAs was thus proposed. The results of the present work suggest involvement of the inhibitory Rev in sustaining SIR. A single exposure to wild-type HIV-1 resulted in one to two integrations per cell. The number of integrated proviral cDNA copies remained at this low level even after double infection or superinfection. SIR was dependent on Rev expression by the strain used for the first infection and was eliminated by peptides that disrupt intracellular complex formation between IN and Rev. The same lack of resistance was observed in the absence of Rev, namely following first infection with a DRev HIV strain. The involvement of Rev, expressed from either unintegrated or integrated viral cDNA, in promoting SIR was clearly demonstrated. We conclude that SIR involves Rev-dependent control of HIV cDNA integration.

Transportin 3 and importin α are required for effective nuclear import of HIV-1 integrase in virus-infected cells

“…As shown in Figure 1B and C, these two peptides failed to promote dissociation of the IN-TNPO3 complex, indicating that different domains mediate the interaction of IN with these two nuclearimport receptors. The results in Figure 1 also show that neither peptide had any effect on the interaction between Rev and IN, shown by us previously to occur in virus-infected cells [40][41][42][43][44] and indicating specificity of function.…”

Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef

“…Such studies demonstrated that preintegration translation of nef variously downregulates CD4, CXCR4, and CCR5 (18,45), which may serve to limit signal transduction through these receptors (59) and possibly limit viral superinfection (31,45,49,50). Similar studies have also demonstrated that preintegration translation of rev might limit superinfection of cells at the level of integration (29,30). We therefore suspected that transcription of preintegrated cDNA could also result in modulation of cell surface MHC-I expression by Nef.…”

“…Transcription of preintegrated HIV-1 cDNA can yield all classes of viral RNA transcripts (25,37,52); however, only the accessory and regulatory proteins Nef (18,58), Tat (2,14,46), and Rev (22,29) are translated in readily detectable amounts, and the full extent of the function of these proteins needs to be further characterized. Differences in transcription between integrated and unintegrated HIV-1 may be due to the fact that unintegrated HIV-1 cDNA is organized into chromatin structures, with histone modifications typical of silenced chromatin (23).…”

Peptides derived from the HIV-1 integrase promote HIV-1 infection and multi-integration of viral cDNA in LEDGF/p75-knockdown cells

“…However, infection of LEDGF/p75 knockdown cells occurs only in the presence of INS [25] or INr [17,22,24] peptides which promote dissociation of the Rev-IN complex, formed in the infected cells [14,17,18,22,24]. Following Rev-IN dissociation viral cDNA integration as well as virus production can reach, in LEDGF/p75-knockdown cells, even higher levels than those obtained in WT cells.…”