Eradicating HIV-1 infection: seeking to clear a persistent pathogen

• Published in: Nature reviews. Microbiology 2014-11, Vol.12 (11), p.750-764
• Main Authors: Archin, Nancie M., Sung, Julia Marsh, Garrido, Carolina, Soriano-Sarabia, Natalia, Margolis, David M.
• Format: Article
• Language: English
• Subjects: 631/326/421; 631/326/596/2564; 692/699/255/1901; Animals; Anti-HIV Agents - therapeutic use; Antigens; Antiretroviral agents; Cell cycle; Cell Line; Deoxyribonucleic acid; Disease Eradication - methods; Disease Models, Animal; DNA; Drug therapy; Genomes; Highly active antiretroviral therapy; HIV infection; HIV Infections - immunology; HIV Infections - prevention & control; HIV Infections - therapy; HIV Infections - virology; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immune response; Immune system; Infection control; Infections; Infectious Diseases; Life Sciences; Medical Microbiology; Methods; Microbiology; Parasitology; Pathogens; review-article; Viral infections; Viremia; Virology; Virus Integration; Virus Latency - physiology; Viruses
• ISSN: 1740-1526; 1740-1534
• DOI: 10.1038/nrmicro3352

Key Points HIV-1 infection will remain an incurable disease until persistent, latent infection of long-lived memory CD4 + T cells is successfully targeted. Resting memory CD4 + T cells are the best characterized reservoir of latent HIV-1 infection, but other potential cellular reservoirs of persistent, latent HIV-1 infection, including CD4 + memory stem cells and γδ T cells, have recently been reported. In addition, macrophages may be a source of persistent infection, but whether these cells harbour true latent infection is still unclear. The mechanisms that control HIV-1 latency are multifactorial, and thus it will probably be necessary to combine complementary approaches to eradicate HIV-1 infection. Humanized mouse and non-human primate models of HIV-1 will continue to have an essential role in HIV-1 eradication research. Development of reliable primary cell models of HIV-1 latency will also help in the evaluation of novel approaches. Development of reliable, sensitive and tractable assays that are capable of measuring the in vivo impact of anti-latency compounds and eradication protocols in clinical trial evaluation is a key unmet need. Histone deacetylase inhibitors have emerged as the leading anti-latency candidates to advance into the clinics. However, latency-reactivating agents alone will not be sufficient to clear infection, and strategies to enhance the immune response will also have to be used. Recent efforts have focused on the development of therapies that could eradicate HIV-1 infection or achieve a durable remission of viraemia in the absence of antiretroviral therapy; however, targeting viral quiescence within specific cellular reservoirs so that residual infection can be cleared remains a challenge. In this Review, Margolis and colleagues explore new approaches to eradicate established HIV-1 infection. Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific