Is HIV-1 RNA dimerization a prerequisite for packaging? Yes, no, probably?

Abstract

During virus assembly, all retroviruses specifically encapsidate two copies of full-length viral genomic RNA in the form of a non-covalently linked RNA dimer. The absolute conservation of this unique genome structure within the Retroviridae family is strong evidence that a dimerized genome is of critical importance to the viral life cycle. An obvious hypothesis is that retroviruses have evolved to preferentially package two copies of genomic RNA, and that dimerization ensures the proper packaging specificity for such a genome. However, this implies that dimerization must be a prerequisite for genome encapsidation, a notion that has been debated for many years. In this article, we review retroviral RNA dimerization and packaging, highlighting the research that has attempted to dissect the intricate relationship between these two processes in the context of HIV-1, and discuss the therapeutic potential of these putative antiretroviral targets.

Figure 1

HIV-1 5' RNA Structural Elements. Illustration of a working model of the HIV-1 5' UTR showing the various stem-loop structures important for virus replication. These are the TAR element, the poly(A) hairpin, the U5-PBS complex, and stem-loops 1–4 containing the DIS, the major splice donor, the major packaging signal, and the gag start codon, respectively. Nucleotides and numbering correspond to the HIV-1 HXB2 sequence. (Adapted from Clever et al. [73] and Berkhout and van Wamel [136])

Figure 2

The Kissing-Loop Model of HIV-1 RNA Dimerization. HIV-1 RNA dimerization is initiated by a Watson-Crick base-pairing interaction between two palindromes in the loops of SL1 on two monomeric genomic RNAs. This interaction forms the loose unstable kissing-loop complex. Coincident with virus particle maturation, this unstable dimer is rearranged to form a more stable extended duplex that involves a mechanism whereby the base-pairs in the stems melt and then re-anneal to their complementary sequences on the opposite strand. Nucleotides and numbering correspond to the HIV-1 HXB2 sequence. (Adapted from Skripkin et al. [26] and Laughrea and Jetté [27])