HIV (Wellcome Images)“All politics is local” may be a cliche; but “All evolution is local” is at least equally true, and is a more interesting concept to geeks like me. A mutated virus may spread through a population, but it starts somewhere. What are the bottlenecks, what are the resources that evolution can draw on, what are the checks or drivers of transmission and spread?

It’s only relatively recently, though, that the techniques to properly measure microevolution of viruses have become generally available; genomic sequencing of reasonably large chunks of virus has become fast and cheap enough that very small changes in virus sequence can be used to track evolution over short times and distance. I talked about using this to track the foot and mouth disease outbreak in England in 2007. Two recent studies look at microevolution to analyze bottlenecks and transmission, in quite different contexts: Dengue virus circulation in schools, and HIV transmission between individuals. I’ll talk about the dengue study some other time; here I only have room for the Keele et al paper.1

I’ve talked a fair bit (like here and here) about the evolution in situ that HIV undergoes in each of its hosts, evolving rapidly in response to local conditions such as immune responses. Much of the variation in the infected individual is selected, of course; selected in response to local conditions — those local conditions being the genetics of the host, and to a large extent the host’s immune system. The immune system puts tremendous pressure on the virus, and the only way it can escape from the prison is to cripple itself. HIV immune escape variants are usually relatively defective viruses, because the mutations that allow them to become invisible to the immune system, damage the virus’s ability to replicate and spread.

HIV assembling in a macrophage
HIV infecting a macrophage2

Immune systems are idiosyncratic; yours is different than mine. When HIV is transmitted from one person to another the virus moves from one selection immune landscape to a very different one. The mutations that saved it in the first person are now probably no longer protective, yet the damage that those mutations were doing is still very much present – a double whammy. Fortunately for HIV (less so for humanity) it is still able to mutate its way back to a functional virus. If you examine HIV in one individual and then in the next step in the transmission chain, the new host’s virus will probably have started to revert back to the platonic essence of HIV; less, of course, the mutations that the new host’s immune system imposes on it.

A question is: What does the virus have to work with in this process? We speak of HIV as a quasi-species, traveling around as a cloud of related but different viruses. Within that cloud is variation that can be immediately selected. But is that true in transmission? How many viruses actually take that gigantic leap from one host to the next?

This is important for a couple of reasons. The big one is vaccination. One of the huge obstacles to HIV vaccination is variation; not only within a population, but within an individual. Let’s say you are vaccinated and protected against the most common HIV variant. If you are infected only with a handful of viruses, you will probably shut them down. But if you’re infected with a cloud of many different viruses, somewhere in that cloud will be a resistant virus; the chance of protection have gone way down. Which of those is actually what happens?

Keele et al 2008 Fig 2That’s the question that Keele1 (and a cast of thousands, or at any rate another 36 authors; particle phsyics authorship on a biology paper) asked, examining thousands of virus samples (just one gene, not the whole genome; but based on single virus genomes, not pooled genomes from the virus cloud) from over 100 patients shortly after they were newly infected with HIV. They used a mathematical model (which I am for now going to accept on faith; with two grants due in the next two weeks, I don’t have time to sit down and work through the math) to consider three different possibilities:

  1. A cloud of viruses is transmitted;
  2. A limited number of viruses is transmitted out of the cloud;
  3. A cloud of viruses is transmitted, but is rapidly thinned down to become a limited number of viruses, due to selection within the new host.

They concluded that in fact the second possibility was true: Only a very small number of viruses manage to establish a foothold in the hostile new terrain:

we found that 78 (76%) had evidence of infection by a single virus or virus-infected cell and that 24 others (24%) had evidence of infection by at least two to five viruses. Aside from early selection of CTL escape variants found in several subjects, there was no suggestion of virus adaptation to a more replicative variant or bottlenecking in virus diversity preceding peak viremia. … we interpret the findings of low multiplicity infection and limited viral evolution preceding peak viremia to suggest a crucial but finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses.1

(My emphasis)

They also noted particular characteristics of the successful viruses, though I think their study, not being specifically designed for this, wasn’t able to come up with any surprises. But of course this opens the door to this further question: What’s special about these tiny few viruses that are successful transmitters, compared to the thousands or millions of other variants circulating in the original host? Are they just lucky little viruses, or are these the only ones that have some unique qualification for spread? And if so, can we take advantage of that quality to block spread?

  1. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H et al. (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A doi:10.1073/pnas.0802203105[][][]
  2. Gross, L., 2006. Reconfirming the Traditional Model of HIV Particle Assembly. PLoS Biology, 4(12), p.e445 EP []