HIV modelThe immune system needs to be rigorously controlled, lest it break its banks and flood the body with destructive responses. Any immune stimulant carries its own brakes; a response to an antigen peaks and then crashes as fast as it accelerated. When the brakes fail, autoimmunity and immune-mediated damage can be more lethal than the pathogen.

This gets complicated with chronic infections. Is it better to shut down the immune response, and let the pathogen romp through your body unchecked, or to let the immune response continue, and risk autoimmune disease? In some cases, shutting down the immune response seems to work pretty well; rodents infected with Hantaviruses (see here, for example) don’t try to fight off these viruses very aggressively, and tolerate the persistent infection pretty well (though not perfectly).

In other cases, though, reducing the immune response may be harmful. Hepatitis C virus infection in humans is linked to high TReg levels and to reduced immune response, and that may be one reason why it persists.

(By the way, it’s worth spelling out what I mean by “reducing the immune response”. In many cases this is mainly a regulatory T cell (TReg) effect, meaning it’s actually an active suppression of the aggressive immune response. Saying that the immune response is “reduced” or “shut down” really isn’t accurate; there’s still a strong and specific immune response, it’s just that the response has been redirected from attacking the pathogen, to controlling the anti-pathogen response. But it’s easier to say that it’s reduced.)

What category is HIV in? Is disease linked to an overactive immune response, or would cranking up immunity suppress the virus and reduce disease?  It’s been unclear, but the consensus is gradually tipping to the idea that the TReg response in HIV infection is more harmful overall (see this paper1 and the commentary from the Treatment Action Group blog, for example). A recent paper2 from the Emory Vaccine Center in Atlanta answers this more directly for SIV in macaques, which may or may not be a valid model for HIV in humans.

Sleeping Salaryman
“Exhausted Salaryman” – Hiromy

Cytotoxic T lymphocytes (the antiviral killer cells) in chronic viral infections often are “exhausted”: After a certain period of attack, the CTL become dysfunctional, or at least have reduced function. (I believe, but do not know for sure, that this is related to the concept of “polyfunctional” CTL that has recently become popular — control of HIV is correlated with CTL that can produce many different antiviral reagents, while uncontrolled HIV is correlated with CTL that only have one or a few of these reagents. See this post for a little more on that.) This “exhaustion” concept is relatively new, and it’s only in the past couple of years that physical markers of exhaustion have been identified. One such marker is the PD-1 (Programmed-Death-1) molecule,3 and in fact PD-1 is upregulated on CTL during HIV infection.4

PD-1 is not a mere passive flag. It’s a receptor that actively drives cells into an inhibited state. If PD-1 is the major reason that CTL are dysfunctional in HIV infection, then perhaps suppressing PD-1 will regenerate the immune response and shut down HIV. Or, of course, it could crank up all the immune responses including those you want shut down, and could lead to a massive and fatal autoimmune attack.

With the SIV/macaque model — amazingly enough; there hasn’t been a lot of good news on the HIV front for a while — blocking PD-1 actually worked just as you’d want it to. After blocking PD-1, anti-SIV CTL frequency roared up,  doubling the pre-treatment levels within a couple of weeks.

After PD-1 blockade, the Gag-CM9 tetramer-specific CD8 T cells expanded rapidly and peaked by 7-21 days. At the peak response, these levels were about 2.5-11-fold higher than their respective levels on day 0.2

Velu et al, Fig 4e: Survival curveAnd these newly abundant CTL were polyfunctional; they were far more likely to express multiple cytokines than the CTL pre-treatment. Remembering that polyfunctional CTL are correlated with control of HIV, it wasn’t so surprising that after PD-1 treatment SIV levels dropped dramatically after treatment as well. Most impressively, all the treated monkeys survived for at least 150 days, while 4 of the 5 control-treated macaques had died by then (see the survival curve to the left here).

Critically, the PD-1 treatment didn’t cause any side-effects in these monkeys, so at least over this relatively short period autoimmunity wasn’t a problem. Of course, HIV in humans is not exactly like SIV in macaques, and if it turned out to be necessary to have long-term treatment it may be a different story. Even if autoimmunity doesn’t develop, we think that having too many activated CD4 T cells (as opposed to CD8 T cells, CTL) is a bad thing for HIV patients because it makes the CD4 cells more susceptible to infection; if blocking PD-1 increases CD4 activation it might end up being harmful after all.   On the third hand5 it’s conceivable that a short-term treatment might reverse the exhaustion and allow the immune system to control HIV, with no further help, for a long period.

Who knows what’s going to happen when it moves into humans;  but so far at least,  it’s one of the most encouraging anti-HIV findings I’ve seen for quite a while.

  1. Regulatory T Cell Expansion and Immune Activation during Untreated HIV Type 1 Infection Are Associated with Disease Progression. Weiwei Cao, Beth D. Jamieson, Lance E. Hultin, Patricia M. Hultin, and Roger Detels. AIDS Research and Human Retroviruses. February 2009, 25(2): 183-191. doi:10.1089/aid.2008.0140. []
  2. Velu, V., Titanji, K., Zhu, B., Husain, S., Pladevega, A., Lai, L., Vanderford, T., Chennareddi, L., Silvestri, G., Freeman, G., Ahmed, R., & Amara, R. (2008). Enhancing SIV-specific immunity in vivo by PD-1 blockade Nature, 458 (7235), 206-210 DOI: 10.1038/nature07662[][]
  3. Restoring function in exhausted CD8 T cells during chronic viral infection. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Nature. 2006 Feb 9;439(7077):682-7. []
  4. Among several other papers:
    PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD. Nature. 2006 Sep 21;443(7109):350-4. []
  5. Abuse of mutagenic drugs is a constant problem among scientists[]