Following up on several recent studies suggesting that multi-functional or polyfunctional T cells may be important in controlling HIV replication, a new paper by Sunil Kannanganat from Rama Rao Amara's group at Emory University reports that HIV-specific CD4 T cells capable of making three cytokines simultaneously (IL-2, TNF-alpha and interferon gamma) are abundant in individuals controlling HIV replication and show an inverse correlation with viral load.
The researchers compared three groups of individuals:
- Fourteen people who had maintained viral loads less than 1,000 copies for at least a year in the absence of any prior or current antiretroviral therapy (ART), this group were dubbed "controllers"
- Eight people who had never received ART with viral loads above 7,000 copies ("non controllers")
- Fifteen people who had been on effective ART for at least a year
HIV-specific CD4 T cell responses were measured and the proportion of these cells capable of making one, two or all three cytokines was calculated (cells were classified as either single producers, double producers or triple producers). Of the total HIV-specific CD4 T cell response in the controllers, 24% of the cells were triple producers, 34% double producers and 42% single producers. In contrast, 75% of the HIV-specific CD4 T cells from non controllers were single producers (mostly making only interferon gamma). Among ART recipients, 6% of HIV-specific CD4 T cells were triple producers, a lower proportion than that seen in the controllers but higher than in the non controllers (1%). One other difference noted in the ART recipients was that IL-2-producing cells were mainly single cytokine producers, whereas in controllers IL-2 producing cells were evenly distributed among single, double and triple producers.
The researchers also found that double and triple producing CD4 T cells made more cytokine on a per cell basis than single producers, and were more likely to upregulate the important co-stimulatory molecule CD40L after stimulation. Looking at correlations with viral load levels, there was a strong inverse correlation between the percentage of triple producing HIV-specific CD4 T cells and viral load (r=-0.8, p=<0.001) and also a positive correlation between the percentage of HIV-specific CD4 T cells that could only make interferon gamma and viral load (r=+0.6, p=0.03). The researchers also evaluated the correlation between the absolute numbers of HIV-specific CD4 T cells that were single, double or triple producers; this analysis showed a strong inverse relationship between the number of triple producers and viral load (r=-0.8, p=<0.001) and the number of double producers and viral load (r=-0.7, p=0.007) but no relationship with single producing cells (r=-0.2, p=ns).
The researchers conclude that, in their view, the most likely explanation for their findings is skewed maturation and/or exhaustion of HIV-specific CD4 T cells resulting from persisting high levels of viral antigen, as has been observed in mouse models of viral infection with LCMV. They also argue that their results strongly suggest that therapeutic vaccination strategies for HIV should aim to induce virus-specific CD4 T cells capable of making more than one cytokine.
JVI Accepts, published online ahead of print on 29 August 2007
J. Virol. doi:10.1128/JVI.01261-07
HIV-1 Controllers but not Non-Controllers Maintain Triple Cytokine Co-expressing CD4 T Cells
Sunil Kannanganat, Bill G. Kapogiannis, Chris Ibegbu, Lakshmi Chennareddi, Paul Goepfert, Harriet L. Robinson, Jeffrey Lennox, and Rama Rao Amara
Here, we evaluate the cytokine co-expression profiles of human immunodeficiency virus (HIV)-specific CD4 T cells for the expression of cytokines IFN-gamma, IL-2 and TNF-alpha. In controllers, CD4 T cells producing three or two cytokines (triple producers and double producers) represented >50% of the total response. In contrast, in non-controllers ~75% of responding cells produced only one cytokine (single producers), mostly IFN-gamma. Triple producers were functionally superior to single producers and showed an inverse correlation (p<0.001) with viral load. These results demonstrate a strong association between the maintenance of highly functional triple producing CD4 T cells and control of HIV-1.
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