Why does HIV-1 have to integrate?

Posted by ERV on September 30, 2010
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Awesome reader question time!

Hi ERV,

I’ve got a question about retroviruses that is probably simple, but none of my virology/micro lecturers have been able to answer it (they aren’t HIV researchers) – why is integration of the retroviral genome necessary for productive infection? It’s got the LTR promoter and all of the genes still, so after reverse transcription, why can’t it just hang around outside the chromosome making virus babies, like the DNA viruses? Obviously it’s not the case, or else integrase inhibitors and the like would do jack all, but I can’t see why.

Thats a good question! And Im not sure I (or anyone) completely knows the answer. Not that that is going to stop me from guessing!

Heres the deal– HIV-1, after it has been reverse transcribed into DNA, and has been translocated into the host cell nucleus, has everything it ‘needs’ to be infectious. There are lots of DNA viruses, like HPV and HSV-1 and 2, that replicate in the nucleus, but they dont integrate. Why does HIV-1 have to integrate?

Well, while HPV and HSV do not integrate into the host genome (or, when they do, its a mistake and a dead-end for the virus), they are not just floating around the nucleus, replicating willy-nilly. Transcription is not happening everywhere in the nucleus. We think ‘nuclei’ are tiny, but they are HUUUUUUUUUGE from the perspective of the virus and all the transcription machinery. So there end up being subnuclear domains, and some of those domains are more transcriptionally active than others.

Think of it this way– Chicago has a subway system. There are subways in Chicago. But you cant just stand anywhere in ‘Chicago’ and get on the subway, you have to go to specific parts of ‘Chicago’. Likewise, DNA cant just hang out in the nucleus and expect to be transcribed.

So viruses dont just twiddle their thumbs in the suburbs and hope to get transcribed. They have figured out different ways of getting to the subway. DNA viruses snuggle up to actively transcribing DNA by interacting with the nuclear matrix as an episome. HIV-1 DNA has no way of doing that.

HIV-1s ‘trick’ for getting transcribed is to insert itself into actively transcribing DNA. Once that happens, the transcription machinery already in the vicinity will notice the HIV-1 promoter, and make a ton of viral mRNA and viral genomic RNA because it thinks its supposed to (its in active DNA, right?).

So while, technically, occasionally, HIV-1 DNA might be able to be transcribed even if its not integrated, that event is probably rare and inefficient. If you block HIV-1 DNAs ability to integrate via integrase inhibitors, youve made the production of viral mRNA and genomic RNA rare and inefficient, thus, integrase inhibitors work as antiretrovirals.

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Comments

  1. #1 divalent
    September 30, 2010

    An analogous question (at least if you view the question more generally) might be: why do woodpeckers have to drill into tree bark to get insects, when so many insects can be found elsewhere?

    One answer to that question is that there are many ways to make a living as an insectivore, and many organisms are specialists; the physical and behavioral features of woodpeckers have evolved to perfect exploitation of one source of food in one particular way, at the expense of limiting or precluding their ability to exploit others in other ways (e.g., such as bats exploiting nocturnal flying insects).

    So for viruses you can make a living (at least) two general ways (as Abbie outlined), but you gotta be a specialist for one or the other.

  2. #2 Matt
    October 1, 2010

    Abbie and divalent, thanks for the responses – whether or not this is actually the case, I think it’s definitely a plausible answer. I will pass these nuggets of wisdom on to my lecturers (the more you know…) :)

  3. #3 Anon
    October 10, 2010

    I think you’ve hit on a good point, but there’s also the “phasmid” gambit, or cellular camoflage. HIV is so dad-gummed hard to defeat once integrated because it looks just like genomic DNA. It uses host repair machinery (important because it has a sleazy RT that misincorporates nucleotides), host replication, host transcription, and even host transcription factors.

    In short, hiding among the sheep is the best place for a “wolf in sheep’s clothing”. It’s an optimal strategy for very long periods of subclinical infection and slow expression of virions. It’s part of the reason we test blood for HIV, but not Ebola. One of those two is a self-limiting epidemic virus, the other is a silent, chronic virus.

    There’s a reason some of the retros are called LENTI viruses. LENTI = SLOW