HIV and the T Cell Life Cycle

In an excellent review of a paper in the Journal of Biology (“Generalized immune activation as a direct result of activated CD4+ T cell killing“), Nienke Vrisekoop , Judith N Mandl, and Ronald N Germain discuss the life and death of the T lymphocyte.

T lymphocytes have a difficult existence. As mature cells, they are essential for immunity to infection, but in the early stages of their development in the thymus, more than 90% of them fail selection for the appropriate antigen receptors and die before export to the peripheral immune system. Those that achieve maturity spend weeks, months or even years circulating through the body, in constant search of a foreign antigen that their antigen-specific receptor can recognize, and needing continuously to compete for trophic signals necessary for their survival. Most fail to find an antigenic match and remain as small resting cells until death. A few encounter the right partner and undergo a transient bout of exponential clonal expansion, only for more than 90% of these progeny to be lost by apoptosis shortly after the antigen is cleared. The remaining 10% are maintained as memory cells (Figure 1), conferring lasting protection.

Understanding the mechanism of T cell death is a major concern when confronting HIV and its progression into full blown AIDS.

Although it is known that HIV kills activated CD4+ T cells, it is still a major unresolved question why these cells progressively decline after infection. It is clear that in infected individuals, the rate of loss of CD4+ T cells is greater than the rate of production so that the CD4+ T cell pool is gradually eroded over time, but it remains to be determined how the balance between these processes is impaired. It is unlikely that direct killing of infected target cells by HIV is sufficient to cause CD4+ T cell depletion. Natural hosts for simian immunodeficiency virus (SIV), such as sooty mangabeys, do not progress to AIDS and maintain near-normal levels of peripheral CD4+ T cell numbers despite high rates of viral replication [4]. In fact, the level of immune activation is a better predictor of disease progression than viral load. Consistent with this, HIV infection in humans leads to chronic generalized immune activation characterized by an increased rate of exit of CD4+ and CD8+ T cells and of natural killer (NK) cells from the resting state, increased T and NK cell turnover and death, polyclonal B cell activation with increased levels of gamma globulins, and elevated production of pro-inflammatory cytokines. Conversely, chronic immune activation is not seen following SIV infection in natural hosts that do not show progression to AIDS [4].

That is, there is a question as to what causes the autoimmune response that is so devastating to people with AIDS.  There are two proposed methods of activation.  The first is that chronic activation of the hosts immune system disrupts CD4+T cell homeostasis.  The second is the opposite, that HIV drops the CD4+T count out of homeostasis and the bodies over-active response is chronic immune activation.  The authors make the point that these two possibilities are not incompatible.

Clearly, the two possible causal relationships between chronic immune activation and CD4+ T cell loss are not mutually exclusive. In fact, chronic immune activation and the loss of CD4+ T cells may amplify each other in a loop that makes it difficult to establish which process underlies and drives the other.

The study in review attempted to induce this same response in mice.

Marques et al. [1] suggest that the OX40-DTA mouse is one approach to this issue and that the findings in these mice provide important insight into the control of lymphocyte dynamics in infected humans. Indeed, in the absence of exogenous infection, OX40-DTA mice do show features consistent with generalized immune activation (Table 1), including an expansion of effector CD8+ T cell numbers that inverts the usual CD4+:CD8+ T cell ratio, and increased serum levels of inflammatory cytokines. This generalized activation cannot be attributed to the release of microbial components into the circulation from the gut, because deletion of activated CD4+ T cells does not in itself lead to a breach in the gut epithelium. Notably, Marques et al. [1] show that the expansion of effector CD8+ T cells and increases in serum levels of inflammatory cytokines can be reversed following reintroduction of Tregs from normal mice, suggesting that the increased immune activation in OX40-DTA mice can in part be ascribed to a Treg insufficiency, which they propose is a key event in HIV-infected individuals leading to CD4+ T cell depletion.

There’s a lot more, and the review goes into much more detail.  But, I can see how this approach could be fruitful in illuminating the underlying causes of a disease that plagues such a large number of humans on the planet.


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