T cell lifespan during HIV infection

Scientists have long held the prevailing view that during HIV infection the depletion of T cells is the result of direct HIV virus–mediated killing. In the September 15 issue of the Journal of Clinical Investigation, Marc Hellerstein and colleagues at the University of California in Berkeley report that it is the chronic activation of the host immune system in response to HIV infection that primarily contributes to T cell loss.

A series of influential studies published in the mid-1990s described the rapid decay of viral load following administration of highly active antiretroviral therapy (HAART), and proposed that HIV infection was associated with a high rate of virus turnover and short lifespan of infected cells. This suggested that HIV infection of susceptible CD4+ T cells led to such high rates of cell death, that compensatory T cell proliferation was inadequate to maintain sufficient T cell numbers and therefore compromised the ability of the immune system to fight the virus.

This view was recently challenged by observations that not only were virus-infected cells dying, but a greater number of uninfected bystander T cells underwent programmed cell death that was not a direct result of HIV infection. Therefore, a new theory has been proposed in which high levels of T cell proliferation reflects a state of chronic immune activation following HIV infection as opposed to simple compensatory proliferation.

Hellerstein and colleagues used a highly innovative technique for measuring the dynamics of T cell turnover in 3 groups of individuals: (i) HIV-infected; (ii) HIV-infected HAART-treated; and (iii) uninfected. They authors found that most of the increased T cell turnover during HIV infection involved a subset of memory T cells – those cells which have encountered prior infection and can rapidly mobilize and clone themselves should the same foreign antigen be encountered during a subsequent infection. The authors concluded that the increased degree of proliferation of this T cell subset was the result of chronic immune activation and not the result of a mechanism striving to compensate for the loss of T cells directly killed by the virus. The increased degree of memory T cell turnover results in a lack of long-lived memory T cells available to assist newly infected cells. The authors did however demonstrate that HAART was able to ameliorate the defect in the production of these long-lived cells.

This identification of this fast-replicating but short-lived subset of T cells aids our understanding of how the body reacts to HIV infection and how HIV wields its destructive power. In an accompanying commentary Guido Silvestri and Mark Feinberg from the Emory Vaccine Center in Atlanta, Georgia, discuss how the dynamics of the T cell population effects the progression of HIV disease. These authors add that the present study “provides important clues as to how HIV infection leads to CD4+ T cell depletion and AIDS”. It is still not clear how HIV induces this chronic state of immune activation and why this is so disruptive to the proper overall functioning of the host immune system. Silvestri and Feinberg continue, “some of these questions can be resolved with future application of the innovative and informative labeling techniques pioneered by Hellerstein and colleagues”.

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TITLE: Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection

AUTHOR CONTACT:
Marc Hellerstein
University of California, Berkeley, California, USA.
Phone: (510) 642-0646
Fax: (510) 642-0535
E-mail: march@nature.berkeley.edu

ACCOMPANYING COMMENTARY:
Turnover of lymphocytes and conceptual paradigms in HIV infection

AUTHOR CONTACT:
Mark B. Feinberg
Emory Vaccine Center, Atlanta, Georgia, USA.
Phone: (404) 727-4374
Fax: (404) 727-8199
E-mail: mbf@sph.emory.edu