HIV is a genetically unstable virus, and exists as a “quasispecies”, a cloud of variations surrounding a platonic ideal virus. Over time, selection pushes the cloud in various directions. What’s the main push behind that movement?
Because I’m interested in T cell immunity I tend to think of HIV mutation as being driven by, well, T cell immunity. This is the CTL escape I’ve mentioned before, and the paper that most dramatically reinforced that viewpoint for me was:
Constraints on HIV-1 evolution and immunodominance revealed in monozygotic adult twins infected with the same virus.
Draenert R, Allen TM, Liu Y, Wrin T, Chappey C, Verrill CL, Sirera G, Eldridge RL, Lahaie MP, Ruiz L, Clotet B, Petropoulos CJ, Walker BD, Martinez-Picado J.
J Exp Med. 2006 Mar 20;203(3):529-39.
This study found a pair of identical twins, infected with the same HIV strain at the same time, and tracked the appearance of new variants of HIV that popped up over time, correlating with immune responses. Remarkably, the mutations of HIV that appeared to be CTL escape variants were almost identical:
Of four responses that declined in both twins, three demonstrated mutations at the same residue. In addition, the evolving antibody responses cross-neutralized the other twin’s virus, with similar changes in the pattern of evolution in the envelope gene. These results reveal considerable concordance of adaptive cellular and humoral immune responses and HIV evolution in the same genetic environment, suggesting constraints on mutational pathways to HIV immune escape.
The conclusion I drew from this paper is that, in a particular genetic environment, the immune system shepherds HIV along a particular trail.
Now, this paper only tracked the twins for 3 years. Another paper had tracked a similar pair of twins over a much longer time, 17 years, and their findings were rather different:
Seventeen years after infection, their CTL targeting of HIV-1 was remarkably similar. In contrast, their overall TCR profiles were highly dissimilar, and a dominant epitope was recognized by distinctly different TCR in each twin. Furthermore, their viral epitopes had diverged, and there was ongoing viral phylogenetic divergence between the twins between 12 and 17 years after infection. These results indicate that while CTL targeting is predominately genetically determined, stochastic influences render the interaction of HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictable.
(The figure at right is the concluding figure from Yang et al., showing quite dramatically how each twin’s HIV had moved in different directions: “Phylogenetic relationships between pol (A), env (B), and nef (C) sequences from 1995 and 2000 are shown. Open and closed circles represent twin 1-05 sequences from 1995 and 2000, respectively; open and closed triangles represent twin 1-06 sequences from 1995 and 2000, respectively.“)
Still, even the Yang et al. paper don’t change my overall impression that HIV mutation is mainly CTL-driven; even if the viruses trotted down different paths, they were both (probably) being chivvied along those paths by CTL pressure.
What made me think about this today is an interesting variant on CTL escape variants, described in the latest issue of Journal of Virology:
A Rapid Progressor-Specific Variant Clone of Simian Immunodeficiency Virus Replicates Efficiently In Vivo Only in the Absence of Immune Reponses.
Takeo Kuwata, Russell Byrum, Sonya Whitted, Robert Goeken, Alicia Buckler-White, Ronald Plishka, Ranjini Iyengar, and Vanessa M. Hirsch.
Journal of Virology, Sept. 2007, p. 8891-8904 Vol. 81, No. 17
These guys were looking at monkeys infected with SIV, a subset of which were “rapid progressors” (RP). These monkeys show an early immune response, but lose their anti-HIV immunity very quickly — within 4 weeks. Worse than that, they also lose their ability to mount any new immune response, even to related antigens like tetanus toxoid. It turns out that these RP monkeys also contain a unique variant of SIV, with specific mutations in the env gene. Is this mutant virus responsible for the rapid progression of disease?
In fact, when they tried infecting monkeys with the new variant SIV, the recipients did not progress rapidly. If anything, the new variant virus was actually worse than wild-type virus at causing disease. And what’s more, when they took sampled the virus circulating in the newly-infected virus, what they found was that as immune responses to the virus developed, the RP variant disappeared and was replaced by … wild-type SIV, the parent of the RP variant. The only way the SIV could survive in their new hosts, in the face of an immune response, was to mutate back to the original wild-type sequence. It looks as if the causality was backwards; the RP variant didn’t cause the rapid progression, rather the rapid progression permitted these new viruses (that are very sensitive to immune responses) to be able to replicate.
These studies suggest that the SIV variants commonly selected in RP macaques are not the direct cause of rapid disease de novo in naive macaques. The evolution of RP-specific variants appears to be the result of replication in a severely immunocompromised host.
So perhaps this is an exception that proves the rule, and the major force behind HIV mutation and selection really is immune pressure: The virus doesn’t develop other variants until the immune system is completely screwed.
There’s at least one obvious exception to this: The change in receptor usage that HIV shows after infection. According to my primitive perception of this, the HIV types that are most readily spread between individuals (those that use the CCR5 receptor), are not the same type as most efficiently spread within an individual (those which can also use CXCR4); so the former are more likely to infect, but then mutants with the latter arise after infection. This is selection that’s not CTL-based. What other selection pressures on HIV, within a single individual, have been shown? I don’t know, I’m asking.