It’s rapidly becoming accepted, if not quite dogma, that T cell quality (rather than, or as well as, quantity) is a critical factor in controlling HIV infection. (I’ve talked about T cell quality several times previously. What it means, simplified, is that antiviral cytotoxic T cells can have a range of different functions, and those CTL with multiple functions seem to do better at controlling HIV than those with only one or a handful of functions.) As a result, there’s a lot of interest in developing vaccines that induce multi-functional CTL, in the hope that those vaccines will better control the virus itself. A recent paper1 from Norm Letvin’s lab, though, supports the concept but doesn’t offer a lot of encouragement for the vaccine strategy.
Letvin’s group vaccinated monkeys against immunodeficiency virus using several different vaccine strategies, and evaluated the quality of the antiviral CTL elicited by those vaccines. As we have now come to expect, there were big differences in both the quantity and the quality of T cells with the various approaches. No surprises so far.
Next, they challenged the vaccinated monkeys with virus. Again, as expected, those monkeys who controlled the virus best, had the largest and most multifunctional CTL response to the challenge (“both the magnitudes and functional profiles of the virus-specific CD8+ T cells generated by vaccination were associated with control of viral replication following SHIV-89.6P challenge“).
The unexpected part, though, was that the vaccine response didn’t tell you anything about the challenge response. That is, even though some vaccines gave lots of multifunctional T cells and others gave relatively little, that did not correlate with the eventual response after challenge; “Although the different vaccination regimens generated qualitatively different virus-specific T-cell populations, those differences were lost following the virus challenge.” Letvin’s group concluded that the similar levels of virus after challenge overrode the vaccine pattern.
The good news — kind of — is that any of the vaccines seemed to work relatively well. After challenge, “the profile of cytokine production by the virus-specific T lymphocytes in the control monkeys was heavily biased toward cells that produce only IFN-?, while the virus-specific T lymphocytes of all of the experimentally vaccinated monkeys following challenge were uniformly polyfunctional.” That is, even though the vaccines didn’t ultimately differ from each other, vaccination did lead to a different, and probably better quality, CTL response than in unvaccinated monkeys.
This might suggest that even testing CTL quality as well as quantity after vaccination may not be very predictive. However, it’s also possible that the monkey model is once again being deceptive. For example, if their suggestion that the challenge dose re-set the CTL quality is correct, this might be highly sensitive to both the number of infecting viruses and, even more, to the precise kinetics of early viral replication; and there are a myriad of other differences as well. The bottom line, though, is a reminder that we really don’t understand antiviral immunity very well in any system, let alone the baroque interactions between HIV and the immune system.