Trends in Immunology
Volume 23, Issue 12, 1 December 2002, Pages 580-585
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Opinion
Premature ageing of the immune system: the cause of AIDS?

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Abstract

The reasons for the failure of the immune system to control HIV-1 infection, and the resulting immunodeficiency, remain unclear. HIV-1 persists in its host despite vigorous immune responses, including a strong, and probably functional, HIV-specific cytotoxic T-lymphocyte response. Interestingly the immunological features of HIV-1-infected individuals show many similarities to those seen in elderly people without HIV infection. We propose that, through a process of continuous immune activation, HIV-1 infection leads to an acceleration of the adaptive immune system ageing process, resulting in premature exhaustion of immune resources, which participates in the onset of immunodeficiency. This hypothesis might shed new light on HIV-1 pathogenesis and could suggest the need to reconsider current immunotherapeutic strategies to fight the virus.

Section snippets

HIV-specific CD8+ T-cell response: impaired or fully functional?

Primary HIV-1 infection is characterized by rapid expansions of HIV-specific ‘effector’ CD8+ T cells, resulting in substantial reduction of viraemia. The dynamics of this response are similar to those observed in mouse models of other virus infections, which suggests that the primary CD8+ T-cell response to HIV-1 is not abnormal [4]. However, the virus is never cleared, and significant viraemia can often be detected in patients during chronic infection. It is intriguing that HIV-specific CD8+ T

Parallels between HIV-1 pathogenesis and human ageing

Regardless of the success or otherwise of immune control, HIV-1 infection almost invariably leads ultimately to rising viral loads and the onset of immunodeficiency. HIV is unique in that it induces CD4+ T-cell depletion, considered to be the best marker of disease progression to date. However, HIV-1-infected individuals also show several dramatic immunological alterations (Table 1), some or all of which probably also contribute to the development of AIDS. Although there has been considerable

Exhaustion of immune resources by HIV-1 leads to AIDS

Some of the damage directly related to HIV replication (e.g. CD4+ T-cell depletion) can be limited through therapeutic viral suppression. However, those defects that are common to both HIV infection and ageing, presumably resulting from successive rounds of T-cell activation, could be irreversible and affect the entire immune system. In HIV-1 infection, huge demands are placed on the immune resources of the infected person. During primary infection there is massive immune activation, in part to

Concluding remarks: implications for strategies to fight HIV-1

We hypothesize that HIV-1 infection, through a continuous process of both direct and indirect immune activation, might accelerate the ageing or decay of the adaptive immune system; so that a 25-year-old person with HIV-1 might exhibit some of the immune characteristics displayed by an uninfected person four times his age (Fig. 1). This hypothesis is consistent with models proposed in previous reports 45., 46.. Multiparameter studies to compare the immune characteristics of HIV-infected

Acknowledgements

We gratefully acknowledge Peter Beverley and Paul Moss for helpful comments and discussion.

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