Thursday, May 21, 2015

Snippet: T cell exhaustion in HIV


Let me start with an interesting question. It is now well known beyond challenge that HIV primarily infects CD4 T cells thus effecting one of the key immunological component. It also effects other immune cells but to a lesser degree. The key component of eliminating infected cell is CD8 T cells. But what gets the CD8 cells to not work, or function inefficiently. The immediate answer would be CD4 is an helper cell and effecting them leads to effects on CD8 cells. So If you could revive CD8 cell function by somehow interfering with interactions would that be helpful?

Fig 1: Changes in T cell
exhaustion. Source
The step-wise loss of cellular functionality leading to loss of the T cell is called as T cell exhaustion (TCE). T cell exhaustion was originally defined as clonal deletion of virus-specific CD8 T cells that occurs during high-grade chronic infections. Some of the well known examples of TCE include infections by HIV, Adenovirus, HBV, HCV, LCMV etc. For example In HIV infection CD8 T cells functionality drops, and begin to express markers such as Programmed death-1 (PD-1) which leads to loss of immune response capability. The exact mechanism of how a CD8 T cell is kept away from this self annihilating process is a separate post. At this time it would suffice to tell you that the CD4 is the helper via ligand interactions and secreting cytokines. Loss of CD4 can thus effect the functionality of the CD8 T cells.

Now let's think of this. If you could somehow stop the T cell exhaustion, would that in any way improve the Immune response against infections like HIV? To test this idea the ideal candidate was PD-1 for HIV. The hypothesis was that receptors like PD-1 function to inhibit T cells not only by reducing TCR signaling, but also by inducing the expression of genes that impair T cell function. With a series of experiments Porichis, was able to assert that PD-1 up regulation exhausted CD8 T cells and increase in BATF (Basic leucine zipper transcription factor) levels were seen in antigen-specific T cells with the greatest degree of dysfunction. Essentially, PD-1 blockade can enhance HIV-specific CD4 T-cell proliferation.

With this understanding, tests were further conducted to see if blocking the PD-1 could be of any good. By using samples from 45 patients blocking the PD-1 pathway boosted CD4+ T-cell function, even among people who had undetectable viral load. The story gets better. The next set of study looked at at the epigenetic regulation of the gene PD-1. The study showed that in HIV-positive people with low viral loads, the promoter region of the gene remained unmethylated.

CD8 TCE is a hallmark of HIV infection. This also provides a path of interest to be targeted in HIV. The complete pathway is yet to be deciphered. But several key features are known. For example, it has been shown that HIV-specific CD8+ T cells possess highly elevated levels of Eomes, CD160 and low T-bet expression. This differential expression leads to the up-regulation of several inhibitory receptors, impaired functional characteristic, which lead to TCE.

Quigley etal(2010). Integrative genomic analysis of HIV-specific CD8+ T cells reveals that PD-1 inhibits T cell function by upregulating BATF. Nature Medicine, 16(10), 1147. PMCID:3326577

Porichis F, Kwon DS, Zupkosky J, Tighe DP, McMullen A, Brockman MA, Pavlik DF, Rodriguez-Garcia M, Pereyra F, Freeman GJ.... (2011) Responsiveness of HIV-specific CD4 T cells to PD-1 blockade. Blood, 118(4), 965-74. PMID:21652684

Yi JS, Cox MA, & Zajac AJ (2010). T-cell exhaustion: characteristics, causes and conversion. Immunology, 129 (4), 474-81 PMID:20201977

Youngblood, Ben, Alessandra Noto, Filippos Porichis, Rama S. Akondy, Zaza M. Ndhlovu, James W. Austin, Rebeka Bordi et al. Cutting edge: Prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. The Journal of Immunology 191, no. 2 (2013): 540-544. PMCID:3702641

Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA, Michaƫlsson J, et al. (2014) T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection. PLoS Pathog 10(7): e1004251. doi:10.1371/journal.ppat.1004251

Peretz Y, He Z, Shi Y, Yassine-Diab B, Goulet J-P, Bordi R, et al. (2012) CD160 and PD-1 Co-Expression on HIV-Specific CD8 T Cells Defines a Subset with Advanced Dysfunction. PLoS Pathogens 8(8): e1002840.doi:10.1371/journal.ppat.1002840

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