Persistent HIV-1 replication maintains the tissue reservoir during therapy

• Published in: Nature (London) Vol. 530; no. 7588; pp. 51 - 56
• Main Authors: Lorenzo-Redondo, Ramon, Fryer, Helen R., Bedford, Trevor, Kim, Eun-Young, Archer, John, Kosakovsky Pond, Sergei L., Chung, Yoon-Seok, Penugonda, Sudhir, Chipman, Jeffrey G., Fletcher, Courtney V., Schacker, Timothy W., Malim, Michael H., Rambaut, Andrew, Haase, Ashley T., McLean, Angela R., Wolinsky, Steven M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2016; Nature Publishing Group
• Subjects: 631/181/757; 631/326/596/1787; 631/326/596/2564; Analysis; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antiretroviral agents; Antiretroviral drugs; Care and treatment; Carrier State - blood; Carrier State - drug therapy; Carrier State - virology; Development and progression; Drug resistance; Drug Resistance, Viral - drug effects; Haplotypes; Haplotypes - drug effects; Health aspects; Highly active antiretroviral therapy; HIV; HIV (Viruses); HIV infection; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - growth & development; HIV-1 - isolation & purification; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Infection; Infections; Lymph Nodes - drug effects; Lymph Nodes - virology; Lymphatic system; Models, Biological; Molecular Sequence Data; multidisciplinary; Patient outcomes; Phylogenetics; Phylogeny; Physiological aspects; Science; Selection, Genetic - drug effects; Sequence Analysis, DNA; Spatio-Temporal Analysis; Time Factors; Tissues; Viral Load - drug effects; Virus Replication - drug effects
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature16933

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy. By examining viral sequences in lymphoid tissue from three HIV-1-infected individuals receiving drug therapy, the authors find phylogenetic evidence for ongoing virus replication, suggesting that the antiretroviral drug concentration in the lymphoid tissue is insufficient to fully suppress the virus; using a mathematical model, they further explain why drug resistance does not necessarily arise as a result. HIV-1 persistence during drug therapy Combinations of antiretroviral drugs can reduce viral replication and reduce viral RNA to undetectable levels in blood in HIV-1 infection, but it is not clear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Steven Wolinsky and colleagues examined viral sequences in lymphoid tissue from three HIV-1 infected individuals receiving drug therapy. They find phylogenetic evidence for ongoing virus replication, suggesting that the antiretroviral drug concentration in the lymphoid tissue is insufficient to fully suppress the virus. They explain using a mathematical model why drug resistance does not necessarily arise under conditions where drug concentrations are insufficient to fully block virus replication.