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IDSA 2011: CD4 Cell Regeneration Is Impaired in HIV Elite Controllers

Elite controllers -- the small proportion of HIV positive people who maintain undetectable viral load without antiretroviral therapy (ART) -- may still experience CD4 T-cell depletion and eventual disease progression due to inadequate regeneration of naive T-cells, according to findings presented at the 49th Annual Meeting of the Infectious Diseases Society of America (IDSA 2011) this week in Boston.

Along with undetectable HIV RNA, most elite controllers also maintain a long-term stable CD4 cell count, leading many experts to assume they experience no significant progression of immune deficiency. But some researchers have reported changes in immune activation and inflammation even in this population.

Mathias Lichterfeld from Massachusetts General Hospital and colleagues conducted a study to learn more about immune response and progression in people who control HIV without ART.

The investigators compared elite controllers, ART-treated HIV positive patients, HIV progressors, and HIV negative individuals, looking at 15 people in each group. They used flow cytometry to measure proportions of naive (not yet committed to a specific pathogen), central memory, effector memory, and terminally differentiated CD4 T-cells. They also evaluated output of CD4 cells by the thymus (an organ in the chest where new T-cells mature).

Results

• Elite controllers and HIV progressors had similar relative proportions of naive CD4 cells, which were significantly lower than those of ART-treated patients and HIV negative individuals.
• In contrast, elite controllers and HIV progressors had significantly higher proportions of central memory, effector memory, and terminally-differentiated CD4 cells, compared with ART-treated and HIV negative people.
• Peripheral precursor CD4 cell populations were significantly elevated in elite controllers compared with all other groups.
• Homeostatic proliferation of naive CD4 cells -- cell multiplication to replace lost cells in an effort to maintain a stable level -- was also significantly greater in elite controllers than the other groups. 

"Despite severe depletion of naive CD4 T-cells, elite controllers are able to maintain adequate total CD4 T-cell counts by expanding peripheral precursor T-cells and through peripheral homeostatic proliferation of naive T-cells," the researchers concluded.

These findings, Lichterfeld explained at an IDSA press conference, suggest that elite controllers experience depletion of new naive T-cells as they are more rapidly recruited into action and become memory cells -- presumably somehow triggered by low-level HIV infection.

Initially, proliferation of CD4 cell precursors and homeostatic proliferation of naive cells can compensate and maintain their total CD4 count at a stable level, but controllers can develop AIDS even in the absence of detectable HIV as accelerated proliferation essentially wears out the immune system until it can no longer make up for deficient regeneration of new naive cells from the thymus.

"Elite controllers who do well have good thymus function, elite controllers who progress do not," Lichterfeld said. "Something is going on beyond HIV destruction of CD4 cells."

The findings raise the question of how to treat elite controllers, since they do not require currently available antiretroviral drugs to halt viral replication. An answer to this question would likely also benefit non-controllers who experience poor CD4 cell recovery or premature immune senescence.

"Elite controllers have been put off to the side because they were viewed as having no reason to treat -- they don't have detectable virus and there doesn't appear to be any damage," added moderator Michael Saag from the University of Alabama at Birmingham. "The message here is that maybe there is some ongoing damage."

Investigator affiliations: Massachusetts General Hospital, Boston, MA.

10/25/11

Reference

Y Yang, J Beamon, K Seiss, M Lichterfeld, et al. Peripheral mechanisms of CD4 T cell regeneration in HIV-1 elite controllers. 49th Annual Meeting of the Infectious Diseases Society of America (IDSA 2011). Boston, October 20-23, 2011. Abstract 841.