Interference with HIV infection of the first cell is essential for viral clearance at sub-optimal levels of drug inhibition

• Published in: PLoS computational biology Vol. 16; no. 2; p. e1007482
• Main Authors: Moyano, Ana, Lustig, Gila, Rodel, Hylton E, Antal, Tibor, Sigal, Alex
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.02.2020; Public Library of Science (PLoS)
• Subjects: Advantages; Analysis; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antiretroviral agents; Antiretroviral drugs; Atazanavir; Biology and Life Sciences; Burst size; Disease transmission; Drug dosages; Drugs; Exposure; Gene expression; Genomes; Health aspects; Highly active antiretroviral therapy; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - pathology; Human immunodeficiency virus; Humans; Hypotheses; Infections; Laboratories; Latency; Latent infection; Medical research; Medicine and Health Sciences; Model testing; Monkeys & apes; Replication; Research and Analysis Methods; Tenofovir; Viral infections; Virions; Virus Latency; Virus replication; Virus Replication - drug effects; South Africa; Africa
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1007482

HIV infection can be cleared with antiretroviral drugs if they are administered before exposure, where exposure occurs at low viral doses which infect one or few cells. However, infection clearance does not happen once infection is established, and this may be because of the very early formation of a reservoir of latently infected cells. Here we investigated whether initial low dose infection could be cleared with sub-optimal drug inhibition which allows ongoing viral replication, and hence does not require latency for viral persistence. We derived a model for infection clearance with inputs being drug effects on ongoing viral replication and initial number of infected cells. We experimentally tested the model by inhibiting low dose infection with the drug tenofovir, which interferes with initial infection, and atazanavir, which reduces the cellular virion burst size and hence inhibits replication only after initial infection. Drugs were used at concentrations which allowed infection to expand. Under these conditions, tenofovir dramatically increased clearance while atazanavir did not. Addition of latency to the model resulted in a minor decrease in clearance probability if the drug inhibited initial infection. If not, latency strongly decreased clearance even at low latent cell frequencies. Therefore, the ability of drugs to clear initial but not established infection can be recapitulated without latency and depends only on the ability to target initial infection. The presence of latency can dramatically decrease infection clearance, but only if the drug is unable to interfere with infection of the first cells.