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Cellular MicroRNA and P Bodies Modulate Host-HIV-1 Interactions

Robin Nathans, Chia-ying Chu, Anna Kristina Serquina, Chih-Chung Lu, Hong Cao, and Tariq M. Rana

Molecular Cell 34 (6): 696–709, June 2009.
doi:10.1016/j.molcel.2009.06.003

This week’s summary and scrupulous analysis by Anonymous:

The authors showed that a host microRNA (miRNA), mir-29a, targets the 3’ untranslated region (3’ UTR) of HIV-1 directly and negatively regulates viral expression. mir-29a has two other family members (with the same seed sequence) that are also able to repress viral expression. In addition, the paper suggested that this negative regulation contributes to the latency of HIV-1 via the following model: Upon integration into the host genome and transcription, viral mRNAs are transported out into the cytoplasm where translation of viral proteins and virus assembly usually takes place. If however, the HIV-1 3’ UTR is targeted by mir-29a, the viral mRNA is sequestered into P bodies, translation is suppressed and virus assembly is prevented. Activation could occur when viral mRNAs are released from P bodies after certain stimuli. If this model is true, then mir-29a-mediated regulation would be acting as a checkpoint from viral latency to activation.

While the authors convincingly demonstrated that mir-29a negatively regulates viral expression via a direct interaction with the HIV-1 3’ UTR, the evidence presented for P body sequestration is not as strong. The viral RNA is certainly sequestered into cellular foci but three of the four markers used to identify P bodies in the paper can also be found in stress granules. The authors made a point that the negative regulation is due to translational suppression and not mRNA destabilization but not much was done to probe that the latter was not taking place.

Still, the authors did a nice job tying the relevance of this miRNA-mediated regulation to viral latency. Aligning the 3’ UTRs of various HIV-1 subtypes, they found that the mir-29a target site in the 3’ UTR is highly conserved. This is true for most subtypes except the O group HIV-1 RNAs, in which the non-conserved nucleotides in the seed match region would abolish interaction with mir-29a. The authors highlight the fact that O group HIV-1 is endemic to certain parts of Africa and is typically 100-fold less infectious than the widely-circulating M group HIV-1, whose viral subtypes maintain the conserved nucleotides in the mir-29a seed match site. Hence it is plausible that mir-29a interaction and HIV-1 infection capability could be linked. If this is true, it is remarkable that the relatively recently-evolved HIV-1 is able to co-opt the more ancient mir-29a (conserved across humans, mice, rats, dogs and chickens) to modulate its own life cycle.

It is worth mentioning that while HIV-1 produces more than 30 mRNAs, almost all of them share the same 3’ UTR. Hence even a single miRNA-mediated downregulation would prevent other viral proteins, such as the viral transcription activator Tat, from being made. This, in turn, would reinforce latency. Having said that, mir-29a is not the first miRNA identified to target the 3’ UTR of HIV-1. A previous paper (ref.) found that several miRNAs (though mir-29a was not one of them) target the HIV-1 3’ UTR and contributes to latency in resting primary CD4+ T lymphocytes, which are the cells usually infected by HIV-1. In the subtype alignment described above, the 3’ UTR is well-conserved even beyond the mir-29a seed match site. It would be interesting to see if the seed matches of these miRNAs also coincide with these other highly-conserved segments.

Reference:
Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes
Huang et al., (2007) Nature Medicine 13: 1241-1247.