Immunologic strategies for HIV-1 remission and eradication

Abstract

Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4(+) T cells and perhaps other long-lived cellular reservoirs. In this Review, we discuss the role of the immune system in the establishment and maintenance of the latent HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which may eventually contribute to a curative intervention.

Figure 1. “Shock and Kill” Strategies

Latent HIV-1 reservoirs in resting CD4+ T cells can be activated (“shocked”), which might make them more susceptible to be eliminated (“killed”) by immunologic effector mechanisms.

Figure 2. Immunotherapeutic Strategies

Homeostatic proliferation and low levels of virus production likely contribute to the long-term maintenance of the viral reservoir. When the viral reservoir is subject to sufficient immunologic or pharmacologic stimulation, these cells may be eliminated by immunotherapies such as therapeutic vaccines and broadly neutralizing monoclonal antibodies, and may be modulated by immune modulating drugs such as PD-1 blockade, sirolimus, type I interferon, and IL-7.

Figure 3. PrEP/PEP/Cure Continuum

ART initiated prior to exposure is termed pre-exposure prophylaxis (PrEP), whereas ART initiated shortly after exposure is post-exposure prophylaxis (PEP) and forms a continuum with efforts aimed at virus eradication (cure). Even if early ART is not curative, it may reduce the size of the viral reservoir and preserve immune function.