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Ian

Yang points out that the best test for CD8 T cells may be one that directly measures their ability to kill HIV-infected cells in a lab dish.

I don't think you can make this statement as a general rule, though; it's probably different for different viruses, and there may be no way of knowing if it's true for a specific virus without actually testing. For example, Frank Chisari and others have shown that hepatitis B virus can be suppressed without cell killing in what seemed to be an IFN-dependent manner. There are several other instances of viral suppression without killing.

That said, of course killing seems to be tremendously important in HIV in particular, and since there are strong clinical correlations with CTL killing and HIB suppression it does make sense to focus on that in this particular case.

Otto Yang

Kudos on your very nice summary of this topic (and I like the term "aficionado"!). I wanted to respond to the comment by Ian, which covers two important points about assays for CTL.

1. Activity against virus-infected cells probably is central to any good assay for vaccines (as the antibody researchers have taught us). The problem with ELISpot and ICS, as currently practiced, is that the target cells are loaded with excess epitopes compared to virus-infected cells. Thus, the hurdle for giving a signal by these assays is much lower than the hurdle for CTL recognition of infected cells. This means one will see many false positive "responses" as we saw in the cited JID paper. Note also that we were not doing ELISpots in that paper, but rather using chromium release assays, which are far less sensitive than ELISpot, yet we still had a very high false positive rate compared to measurements of activity against actual HIV-infected cells.

2. CTL may have multiple possible mechanisms against viruses, including IFN-gamma (the Chisari work pointed out by Ian is a nice example). Killing may or may not be the key activity against HIV (although my opinion is that it probably is), but a true gold standard for all viruses may be some direct measure of suppression of viral replication by the CTL (whatever the actual mechanism). We have shown both killing and direct assessment of viral inhibition, and found that they correlate well for HIV.

Thus, the ability of CTL to recognize infected cells, and the effect they have once they do recognize the cells, are two separate and important points for assay development.

Finally, I'd like to mention some brewing controversy about the polyfunctional assays (multiparameter ICS) mentioned. CTL in HIV-infected persons with excellent immune containment tend to be highly polyfunctional. The question has been raised whether polyfunctionality is the cause of good immune control (in which case these measurements are highly important for predicting vaccine efficacy), or vice-versa (in which case polyfunctionality is an epiphenomenon of good immune control or simply a healthy immune system). This remains unanswered, but so far most vaccines in HIV-seronegatives appear to have excellent polyfunctionality, including vaccines that are derivatives of strategies that have thus far not shown much promise (e.g. poxvirus-based constructs).

It will be fascinating to see what opinions are proposed at the upcoming HIV vaccine summit meeting called by NIH this Tuesday (3/25/08).

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