CD8 T-cells are effective in controlling HIV during the early phase of the infection. However by the time, the virus mutates and develops an evasion mechanism against CD8 T-cells. Since cancer cells also develop immune evasion mechanisms, and scientists are using several technics to block those mechanism, i think it would also be possible to control "viral escape". I made some research regarding HIV immunotherapy, however the only thing i found was antibody based immunotherapy. My question is, would it be technically possible to engnieer custom CD8 T-cells which will targed HIV infected cells ?
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$\begingroup$ And drive the patient into AIDS even sooner?! The problem is that CD8 cells do their job and wipe out all of the infected CD4 positive cells. Once someone is infected, our current course of action is keep viremia low and don't allow for escape mutants, you do this by attacking multiple pathways using HAART. $\endgroup$– AMRCommented Jan 3, 2016 at 0:31
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$\begingroup$ If you have access to Janeway's Immunobiology 8th edition, read the Acquired Immune Deficiency Syndrome section in Chapter 13. It will give you a good feel for why you don't need better killers (CD8+), you need ways of blocking the virus from propagating, keeping as large a population of uninfected CD4+ cells as possible. There will always be a reservoir of the virus that has been integrated into the genome of cells that lays dormant, that's how lentiviruses behave; well except for the Berlin Patient. $\endgroup$– AMRCommented Jan 3, 2016 at 1:26
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$\begingroup$ @AMR , Since you are expert in immunology, my questions may sound too elementary. Sorry for this, but i have one more question if possible. Once patient is at a early stage of infection, Are all of the CD4+ T Cells infected ? As far as i know, we can't complately eradicate HIV from body because HIV drugs don't affect HIV hiding in resting CD4+ T cells. My Question is, assuming, the patient still have uninfected CD4+ T cells at the early stage of infection, May killing all infected CD4+ T by CD8+ T cells, and killing the virus itself with drugs may be an effective treatment method ? $\endgroup$– TeoFriendlyCommented Jan 4, 2016 at 15:41
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$\begingroup$ There are protocols that allow people like healthcare workers that have been accidentally infected, to go on HAART very soon after exposure. This will usually prevent the infection from taking hold. The way HAART does this is through 1)Entry inhibitors 2)Nucleoside Reverse Transcriptase inhibitors 3) Non Nucleoside Reverse Transcriptase inhibitors 4)Integrase inhibitors, and 5)Protease inhibitors. If you can keep the viral genome from integrating into the host genome, the virus will clear. Once the infection has integrated, you will never get rid of it; only happened once with Berlin Patient. $\endgroup$– AMRCommented Jan 4, 2016 at 17:47
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$\begingroup$ T-Cells aren't the only cells that have CD4. Macrophages, Dendritic Cells, Monocytes, Precursor T-cells, Natural Killer Cells. Let's say you have any of these infected cells encounter a cytotoxic T-Cell with specificity for the HIV amino acids, but the provirus is dormant and is not expressing its genes, then the CD8 cell will not identify any problems and will not kill the cell. Months, years, even decades after, the provirus can activate and start producing virons. The strategy currently is don't get it, block it ASAP if you are exposed, or suppress it with a multi drug regimen. $\endgroup$– AMRCommented Jan 4, 2016 at 17:58
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People in the comments suggest that this would "Drive the patient into AIDS sooner", or that this will be ineffective because of dormant virus. Neither is correct.
The question is asking about engineering CD8 with engineered T cell receptors specific for HIV. This is a logical approach, and multiple groups have tried it:
Development of CD8+ T cells expressing two distinct receptors specific for MTB and HIV-1 peptides
T-cell engineering by a chimeric T-cell receptor with antibody-type specificity for the HIV-1 gp120
A brief search on Pubmed will turn up many other articles. Some of these approaches have entered clinical trials; for example:
The problem with this approach is not that it will "drive the patient into AIDS sooner". A strong CD8 T cell response controls HIV well, and although it might be one contributor to CD4 T cell loss it's no longer believed that it's a major cause, especially in the early stages of HIV infection.
The general problem with CD8 control of HIV is that the virus is capable of mutation to avoid control by CD8s. Essentially, every case of HIV is effectively controlled by the CD8 T cell response in the early stage of infection, but the virus then mutates and escapes control, then the CD8 response adapts and controls the virus once again, and the virus mutates and escapes ... This can and has been tracked in many patients, showing repeated rebounds of the virus in the blood correlated with CD8 changes.
Better CD8 control of HIV is linked to a broader CD8 response -- that is, attacking many viral proteins, so that viral escape requires multiple simultaneous mutations (exponentially more difficult for the virus). (Alternatively, the CD8 response can attack a small number of proteins that are very constrained, so that the virus can't successfully mutate them. However, for reasons related to MHC restriction, that seems to only work in a small minority of people.)
An engineered CD8 T cell response will inevitably be to one or a small number of viral proteins. That's conceptually similar to the natural situation following HIV infection, meaning that the outcome could be the same -- viral mutation and immune escape.
Because engineering the TcR means you can pick your targets rationally, you might be able to do better than the natural situation, but it's not obvious. Overall, the fact that groups have been working on this approach for decades, without a breakthrough cure yet, suggests that it might be useful but isn't going to be a slam-dunk.
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$\begingroup$ You have three ways that HIV leads to AIDS: 1) Apoptosis: The cells recognizes it is infected or integrase messes up the cDNA insertion and the cell undergoes programmed cell death. 2) Lysis: Budding of HIV destroys the cell 3) CD8 targets and kills infected CD4 cells. Escape mutants are much more of a problem for Immunoglobulin neutralization than CD8 cells because CD8 is only "looking" at the primary amino acid sequence of the viral proteins that the infected cells are presenting. and if viral reservoirs weren't a problem then we could cure people with HAART and time or BMT. We can't. $\endgroup$– AMRCommented Jan 3, 2016 at 19:04
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$\begingroup$ Escape mutants are much more of a problem for Immunoglobulin neutralization than CD8 cells because CD8 is only "looking" at the primary amino acid sequence - this makes no sense, and is immediately proven wrong by the frequency of HIV CD8 escape mutants (rapid and repeated) vs immunoglobulin escape mutants. Very basic HIV biology here. $\endgroup$– iayorkCommented Jan 3, 2016 at 19:55
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$\begingroup$ Love the downvotes. Want to explain? $\endgroup$– iayorkCommented Jan 3, 2016 at 22:07