Elite SuppressoraDerived HIV-1 Envelope Glycoproteins Exhibit Reduced Entry Efficiency and Kinetics

• Published in: PLoS pathogens Vol. 5; no. 4; p. e1000377
• Main Authors: Lassen, Kara G, Lobritz, Michael A, Bailey, Justin R, Johnston, Samantha, Nguyen, Sandra, Lee, Benhur, Chou, Tom, Siliciano, Robert F, Markowitz, Martin, Arts, Eric J, Trkola, Alexandra
• Format: Journal Article
• Language: English
• Published: 01-04-2009
• Subjects: Human immunodeficiency virus 1
• ISSN: 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000377

Elite suppressors (ES) are a rare subset of HIV-1ainfected individuals who are able to maintain HIV-1 viral loads below the limit of detection by ultra-sensitive clinical assays in the absence of antiretroviral therapy. Mechanism(s) responsible for this elite control are poorly understood but likely involve both host and viral factors. This study assesses ES plasma-derived envelope glycoprotein (env) fitness as a function of entry efficiency as a possible contributor to viral suppression. Fitness of virus entry was first evaluated using a novel inducible cell line with controlled surface expression levels of CD4 (receptor) and CCR5 (co-receptor). In the context of physiologic CCR5 and CD4 surface densities, ES envs exhibited significantly decreased entry efficiency relative to chronically infected viremic progressors. ES envs also demonstrated slow entry kinetics indicating the presence of virus with reduced entry fitness. Overall, ES env clones were less efficient at mediating entry than chronic progressor envs. Interestingly, acute infection envs exhibited an intermediate phenotypic pattern not distinctly different from ES or chronic progressor envs. These results imply that lower env fitness may be established early and may directly contribute to viral suppression in ES individuals. Author Summary The majority of HIV-1ainfected individuals experience high plasma viral loads and CD4 super(+) T cells loss in the absence of antiretroviral therapy. However, a very rare and important subset of individuals termed elite suppressors is able to maintain HIV-1 plasma viral loads below the limit of viral detection in the absence of treatment. The reasons behind this ability to control the virus are poorly understood, but they likely involve both an effective host immune response against HIV-1 and factors related to the virus itself. Here, we analyze the function of the HIV-1 coat protein or envelope glycoprotein from a group of elite suppressors. HIV-1 envelope mediates entry into the host cell via interaction with the cellular receptors CD4 and CCR5. Envelopes from elite controllers interacted with these receptors inefficiently compared to those from individuals with detectable viral loads. These inefficient interactions by elite suppressor envelopes led to slow rates of entry into host cells. Envelopes from acutely infected individuals were not significantly different from elite suppressors or chronically infected individuals. These findings suggest that the decreased envelope efficiency may contribute to viral control in elite suppressors.