Friday, October 22, 2010

Elite Controllers Display Higher Activation on Central Memory CD8 T Cells Than HIV Patients Successfully on HAART

AIDS Research and Human Retroviruses:: "Factors other than the size of the viral reservoir should explain the high level of activation of central memory CD8 T cells characteristically seen in HIV individuals with spontaneous control of viral replication."

Comment: It seems likely that this immune activation is helping these patients control HIV.

4 comments:

Rick Loftus, M.D. said...

Hmmm... I haven't seen the paper, and should, but: For so many of the immune activation markers, they're a side effect of the presence of HIV, rather than a sign of appropriate virus-controlling activity. I'm willing to believe that elite controllers are the "exception that proves the rule"...

Loreen Willenberg said...

@Rick Loftus, M.D. - I couldn't agree with you more. With each passing day, elite controllers are, indeed, proving to be an exception to the "rules", as far as we know them.
In reference to the higher activation levels on CD8 T-cells in ECs, in their recent paper for JAMA (cited below), Drs. Connors & Migueles (NIAID/NIH)state: "The CD8 T cells of LTNP (EC), compared with those of chronic progressors, do not appear to mediate control over HIV because larger numbers of HIV-specific CD8 T cells in the peripheral blood or because of a greater ability of these cells to recognize the patients' autologous viruses (58,59,60). Rather, accumulating evidence points to major differences between LTNPs (ECs) and patients lacking control over HIV in the functionality of their HIV-specific CD8 T cells. (5,14,61-63) More specifically, the HIV-specific CD8 T cells of LTNPs (ECs) compared with the cells of chronic progressors divide robustly when encountering an HIV-infected cell and simultaneously acquire increases in the major proteins contained within cytotoxic granules, the pore-forming protein perforin, and the serine protease granzyme B. (5,64-66) By forming pores within the target cell membranes, perforin permits granzyme B to gain access to the target cell interior, where it can induce apoptotic cell death (67). It has been further demonstrated in vitro that increases in these cytotoxic proteins after a period of stimulation confer a superior ability of the HIV-specific CD8 T cells of LTNPs (ECs), compared with those of viremic and ART-treated chronic progressors, to kill HIV-infected cells. (5,14) These results demonstrate HIV-specific CD8 T-cell functions that clearly correlate with immunologic control of HIV replication." (5,14)[Source: Migueles & Connors, "Long-term Nonprogressive Disease Among Untreated HIV-Infected Individuals - Clinical Implications of Understanding Immune Control of HIV", JAMA, July 14, 2010 - Vol 304, No 2].

With killing-capacity like this, it's no wonder we LTNP/ECs measure higher activation markers than treated patients!

Loreen Willenberg said...

@Rick Loftus, M.D. - I couldn't agree with you more. With each passing day, elite controllers are, indeed, proving to be an exception to the "rules", as far as we know them.
In reference to the higher activation levels on CD8 T-cells in LTNPs/ECs, in their recent paper for JAMA (cited below), Drs. Connors & Migueles (NIAID/NIH)lay out a clear definition of the cytotoxic abilities possessed by us that may explain higher activation levels. [Source: Migueles & Connors, "Long-term Nonprogressive Disease Among Untreated HIV-Infected Individuals - Clinical Implications of Understanding Immune Control of HIV", JAMA, July 14, 2010 - Vol 304, No 2].

Sorry for duplicate posting; received an error message that my first comment was too long.

rj said...

I think maybe the important thing here is that it's the central memory subset that seems to be working; in most people the absence of adequate HIV-specific CD4 T cell help is associated with a failure to generate a functional HIV-specific central memory CD8 T cell population. Elite controllers typically have much better HIV-specific CD4 T cell responses which associates with better HIV-specific CD8 T cell responses. Why HIV-specific CD4s are not so affected by HIV in these individuals is still uncertain, but increased expression of a protein called p21 (which has previously been shown to be protective in stem cells and macrophages) has recently emerged as a possible explanation:
http://www.medpagetoday.com/MeetingCoverage/IDSA/22916