Cell proliferation may be responsible for CD4 T-cell level maintenance in elite controllers

BOSTON — HIV elite controllers can maintain sufficient counts of total CD4 T cells compared with highly active antiretroviral therapy-treated patients, HIV progressors and HIV-negative patients, despite severe depletion of naive CD4 T cells. According to data presented here, this is due to their ability to expand peripheral precursor T cells and through peripheral homeostatic proliferation of naive T cells.

"We show that you can develop AIDS even if you don't have detectable HIV replication," Mathias Lichterfeld, MD, PhD, instructor in medicine at Massachusetts General Hospital and Harvard Medical School, said during a press conference today. "And it looks like this is happening when mechanisms of CD4 cell regeneration are defective. We are investigating how that's possible. How can people have deficiencies CD4 cell regeneration even when HIV is not detectable?"

The current study included 15 patients in each of the following categories: elite controllers, HAART-treated, HIV progressors and HIV-negative. Using flow cytometry, the researchers measured proportions of naive, central memory, effector memory and terminally differentiated CD4 T cells. Surface staining for protein-tyrosine kinase 7 (PTK7+) and CD44 was used to identify precursor T-cell populations, and they quantified thymic output using ratios of sjTREC and bTREC levels.

Among elite controllers, relative proportions of naive T cells were similar to those in HIV progressors and significantly lower than in HAART-treated patients and HIV-negative patients (P<.01). However, elite controllers and HIV progressors had significantly higher levels of central-memory, effector-memory and terminally differentiated T cells compared with HAART-treated and HIV-negative patients (P<.01).

According to Lichterfeld, this suggests that the accelerated recruitment to the memory cell pool among elite controllers and HIV progressors may cause the depletion of naive T cells in these populations.

There was no significant difference in thymic output among elite controllers and HIV-negative patients; however, it was significantly lower among HIV progressors (P<.02) and HAART-treated patients. Compared with all other groups, elite controllers had significantly higher peripheral precursor T-cell populations, similar to thymus-dependent PTK7+ and thymus-independent CD44 T cells (P<.03). Similarly, homeostatic proliferation of naive T cells was significantly higher in elite controllers compared with all other groups (P<.02), as determined by Ki67 expression.

"An additional component of this is: What can we do from a treatment perspective for patients such as elite controllers who have CD4 cell losses? Currently, the conventional HIV drugs available are designed to suppress HIV replication, but these patients don't even have detectable HIV replication, so to what extent would they be likely to benefit from regular HIV treatment? That's an important question, and we're doing a clinical trial to investigate this further," Lichterfeld said. - by Stacey L. Fisher

For more information:

Lichterfeld M. #839. Presented at: IDSA 49th Annual Meeting; Oct. 20-23, 2011; Boston.

Disclosure: Dr. Lichterfeld reports no relevant disclosures.

To put this into a treatment perspective, there's a discussion about when to start treatment; elite controllers have always been put off to the side because they were viewed to have no reason to treat - they don't have detectable virus, and there doesn't appear to be any damage. The message here is that maybe there is some ongoing damage; even in elite controllers, that some of them are able to mask that from this regeneration and others have a drifting down because their thymus or peripheral mechanisms are repleting - CD4 T cells aren't there.

- Michael Saag, MD

Immediate Past Chair, HIV Medicine Association;
Director, Center for AIDS Research, University of Alabama at Birmingham

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Cell proliferation may be responsible for CD4 T-cell level maintenance in elite controllers