Mini Review
Accelerated immune senescence and HIV-1 infection

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Abstract

A recent consensus has emerged regarding the association between chronic immune activation and poor outcome in HIV-1 infection. However, its basis remains unclear. Accumulating evidence suggests that the cells of the immune system may have a limited replicative lifespan in vivo. In this context, persistent activation during chronic HIV infection may lead to an exhaustion of immune resources. This may occur at two levels: Clonal and Global. Some HIV-1-specific CD8+ T-cells start expressing the senescence marker CD57 soon after primary infection. Persistently activated HIV-1-specific T-cell clones may eventually reach stages of replicative senescence and disappear, resulting in the specific loss of CD8+ T-cell populations important to control viral replication. In addition, HIV-1 infected individuals are characterized by the accumulation of highly differentiated CD8+ and CD4+ T-cells overtime. Together with the decline of T-cell renewal capacities, this may reflect a general ageing of the lymphocyte population. Similar observations have been done in HIV non-infected elderly individuals, which suggests that premature immunosenescence occurs in HIV-1 infection, as a result of persistent immune activation.

Section snippets

The course of HIV-1 infection

Over the past 40 years, from isolated case reports, the scale of the HIV-1 epidemic has become a global pandemic, and HIV-1 has become the most extensively studied pathogen in history. The clinical course of HIV-1 infection can be divided into three distinct stages (Fig. 1). The acute HIV-1 infection stage is characterised by widespread viral dissemination, which is generally halted within 1–4 weeks with the induction of host cellular immune response. However, while the immune system is able to

Immune activation and decline of immunity in HIV-1 infection

As HIV-1 persists in its host, the immune system continues to be challenged overtime, and immune activation and inflammation become generalized. This has long been characterized, with the observation of elevated levels of activated CD4+ and CD8+ T-cells, high CD8+ T-cell counts, increased T-cell apoptosis as well as increased levels inflammatory cytokines (like IL-6, TNF-α and IL-1β). In recent years, a consensus has been reached in the sense that this phenomenon of chronic immune activation

Exhaustion of HIV-specific CD8+ T-cell clonal populations

Accumulating evidence suggests that the cells of the immune system may have a limited replicative lifespan and can reach a state of replicative senescence in vivo (Pawelec et al., 1999). The occurrence of replicative senescence is primarily related to the number of cell divisions. For viral infections where the pathogen is eliminated by the cellular immune response during primary infection, the host is left with a population of memory cells, that should retain a good replicative potential in

Systemic exhaustion

Nonetheless, it is important to appreciate that activation driven immune exhaustion in HIV-1 infection may go far beyond the simple loss of virus specific CD8+ T-cell clones. HIV-1 infected donors are characterized by increasing proportions of highly differentiated CD8+ or CD4+ T-cells (CD27−/CD28−) over the different stages of the HIV-1 infection course ((Papagno et al., 2004) and VA, unpublished data) (Fig. 3). In order to gain further insight into the significance of increased T-cell

Concluding remarks

Loss of HIV replication control and progression towards HIV disease may the consequence of immune resources exhaustion due to persistent immune activation. This may happen at two levels: clonal exhaustion of HIV-specific CD8+ T-cells important to control HIV replication and systemic exhaustion of primary resources resulting in the decline of T-cell renewal capacities and a general ageing of the lymphocyte population, alike the natural process of immunosenescence taking place with age.

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