Research Article: Resisting Immune Exhaustion in HIV-1 Infection

Date Published: May 6, 2008

Publisher: Public Library of Science

Author(s): Sarah Rowland-Jones, Thushan de Silva

Abstract: Sarah Rowland-Jones and Thushan de Silva discuss a new study describing the fate of cytotoxic T lymphocytes responding to HIV-1 from very early through to chronic infection.

Partial Text: The human immune system is extraordinarily active against infection with HIV-1, yet never eliminates the virus and rarely controls viral replication for prolonged periods without the assistance of anti-retroviral therapy (ART). In order to harness the power of the human immune response in HIV therapy, we need a better understanding of the key elements of protective immunity against the virus and how and why these ultimately fail in chronic infection.

Most investigators would nominate cytotoxic T lymphocytes (CTLs) as key players in the control of HIV-1 infection, based on data accumulated over the two decades since they were first described. This evidence includes the appearance of CTLs very early in HIV-1 infection coinciding with a profound drop in plasma viral load and the dramatic rise in viraemia following CTL depletion in monkey models of both acute and chronic infection with simian immunodeficiency virus [1].

What are the clinical implications of this study? If polyfunctional HIV-specific CTLs need to be preserved long term for the fight against HIV-1 infection, then this study suggests that such preservation is best achieved by suppressing HIV-1 replication both early and efficiently. The question of whether or not to start ART in acute HIV-1 infection has been controversial.

Clinicians have been understandably reluctant to commit patients diagnosed with acute HIV-1 infection to lifelong ART. An alternative strategy was based on the hypothesis that preservation of HIV-specific immunity could be achieved by starting ART in acute infection, followed by structured treatment interruptions (STIs), thereby allowing “immune boosting” by exposure to autologous virus.

For clinicians to accept early and lifelong therapy for HIV-1 infection into routine practice, reliable data from controlled clinical trials are needed. To date, there have been no randomized and adequately powered studies addressing the issue of whether early ART can affect the risk of future HIV-1 disease progression.

Probably the best way forward would be to develop a therapeutic strategy that combines early viral suppression using ART with immunotherapy to augment HIV-specific immune responses in a way that does not expose the host immune system to the damaging consequences of continued HIV-1 replication (see Figure 1). Although both therapeutic vaccination and passive monoclonal antibody infusion in this setting have so far failed to show absolute benefit [22–24], there are some data to suggest that therapeutic vaccination in chronic HIV-1 infection can lead to a restoration of a broad and fully functional CTL response [25]. In Altfeld and colleagues’ study [3], a reliable marker of failing CTLs was expression of the molecule programmed death-1 (PD-1), which has been associated with “exhausted” and dysfunctional T cells in chronic infection [26]. Up-regulation of PD-1 on HIV-specific CTLs correlates with plasma viral load [27] and can be reversed when viral replication is controlled both in chronic and acute infection [3,28]. It has recently been shown in a murine model of lymphochoriomeningitis virus that a combination of therapeutic vaccination and blockade of PD-1’s interaction with its ligand, PD-L1, both enhanced the function of responding T cells and significantly improved viral control [29]. Perhaps a similar strategy may enhance the response to therapeutic immunisation in early HIV-1 infection and facilitate long-term viral control without resorting to lifelong drug therapy.



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