Time Scales of CD4+ T Cell Depletion in HIV Infection

T he hallmark of HIV infection is the depletion of CD4 + T cells in peripheral blood, lymphoid organs, and mucosal tissues [1]. Since CD4 + T cells play an essential role in immune defenses against almost all pathogens, HIV-positive patients are subject to a variety of opportunistic infections. Despite decades of intensive research, the mechanisms underlying CD4 + T cell depletion remain widely debated. CD4 + T cells constitute the major target cells for HIV. David Ho and colleagues initially proposed that CD4 + T cells disappear by viral infection and subsequent cytolytic effects, and/or by the removal of infected CD4 + T cells by the immune response [2]. To account for the slow time scale of CD4 + T cell depletion, they suggested the " tap and drain " hypothesis [2], according to which CD4 + T cell production (a wide-open tap) is ultimately exhausted by the homeostatic response that is almost perfectly compensating for the large daily loss (the drain) of CD4 + T cells due to HIV infection. More recently the " immune activation " hypothesis has gained popularity [3]. HIV infection in humans, and simian immunodefi ciency virus (SIV) infection in rhesus macaques, is characterized by increased rates of cell division in CD4 + and CD8 + T cells, natural killer cells, and B cells [4], and by up-regulation of various activation markers [5]. Most strikingly, Sooty Mangabeys and African Green monkeys that become naturally infected with their own strain of SIV also have high viral loads, but have hardly any disease progression to AIDS, presumably because they maintain almost normal activation levels of their CD4 + and CD8 + T cells [6]. The apparently advantageous absence of immune activation in the host– pathogen relations that have coevolved over many generations raises the question, " Why would the immune system be so prominently activated in humans and macaques? " An intriguing possibility is that the virus has evolved strategies to increase the availability of suitable target cells by activating CD4 + T cells. Increasing target cell availability would be like " fueling the fire, " resulting in more infection and runaway depletion of CD4 + T cells. In a new study published in PLoS Medicine, Andrew Yates and his colleagues investigate whether such a runaway process would be compatible with the slow time scale of memory CD4 + T cell depletion in humans [7]. Immune …