Shan Lu, Shixia Wang, Zhongming Mou, Sean McCauley, Maria Duenas-Decamp, Jeremy Luban, Robin Brody, Olivia O'Connell, Paul Clapham, Aaron Wallace, Maria Paz Gonzalez-Perez, Briana Quitadamo, Paul J Peters, Mohan Somasundaran, Matthew Koch, Alexander Repik, Katherine Luzuriaga
HIV-1 R5 viruses exploit CCR5 as a coreceptor to infect both T-cells and macrophages. R5 viruses that are transmitted or derived from immune tissue and peripheral blood are mainly inefficient at mediating infection of macrophages. In contrast, highly macrophage-tropic R5 viruses predominate in brain tissue and can be detected in cerebral spinal fluid, but are infrequent in immune tissue or blood even in late disease. These mac-tropic R5 variants carry envelope glycoproteins (Envs) adapted to exploit low levels of CD4 on macrophages to induce infection. However, it is unclear whether this adaptation is conferred by an increased affinity of the Env trimer for CD4 or is mediated by post-binding structural rearrangements in the trimer that enhance the exposure of the coreceptor binding site and facilitate events leading to fusion and virus entry. Here, we investigated CD4 binding to mac-tropic and non-mac-tropic Env trimers and show that CD4-IgG binds efficiently to mac-tropic R5 Env trimers, while binding to non-mac-tropic trimers was undetectable.Our data indicated that the CD4bs is highly occluded on Env trimers of non-mac-tropic R5 viruses. Such viruses may therefore infect T-cells via viral synapses where Env and CD4 become highly concentrated. This environment will enable high avidity interactions that overcome extremely low Env:CD4 affinities.ImportanceHIV R5 viruses bind to CD4 and CCR5 receptors on T-cells and macrophages to initiate infection. Transmitted HIV viruses infect T-cells but not macrophages and these viral strains persist in immune tissue even in late disease. Here, we show that the binding site for CD4 present on HIV's envelope protein is occluded on viruses replicating in immune tissue. This occlusion likely prevents antibodies binding to this site and neutralizing the virus, but makes it difficult for virus:CD4 interactions to occur. Such viruses probably pass from T-cell to T-cell via cell contacts where CD4 is highly concentrated and allows infection via inefficient envelope:CD4 binding. Our data is highly relevant for vaccines that aim to induce antibodies targeting the CD4 binding site on the envelope protein.