Date Published: March 6, 2017
Publisher: Public Library of Science
Author(s): David Beauparlant, Peter Rusert, Carsten Magnus, Claus Kadelka, Jacqueline Weber, Therese Uhr, Osvaldo Zagordi, Corinna Oberle, Maria J. Duenas-Decamp, Paul R. Clapham, Karin J. Metzner, Huldrych F. Günthard, Alexandra Trkola, David T. Evans.
A hallmark of HIV-1 infection is the continuously declining number of the virus’ predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.
The infection cycle of HIV-1 is intimately linked with the CD4 receptor on target cells. Entry is initiated by the binding of the viral envelope glycoprotein gp120 to CD4, necessitating a high conservation of the CD4 binding site (CD4bs) on the viral envelope . At the same time, the virus faces a humoral immune response targeting the CD4bs [1–4] and disease progression decreases the pool of available CD4 expressing target cells [5–8]. During disease progression multiple forces are therefore acting on the envelope glycoprotein and its interplay with CD4. How these factors shape envelope functional adaptation, and which combination of selective forces is responsible for giving rise to viral phenotypes observed at late disease stages remains unclear. A particular conundrum is the capacity of HIV-1 to maintain high level virus production at late disease stages, even when the classical target cells, CD4+ T cells, are heavily depleted [9–12]. Because of this, it was suggested for some time that HIV-1 resolves to replicate in other cell types at later stages [13, 14], which can be linked with use of alternative coreceptors (reviewed in [15–17]). Differential receptor usage most commonly includes varying the capacity of Env to bind CD4 or CCR5, and switching coreceptor use to CXCR4. All of these phenotypes have been observed in late disease states in vivo [18–22].
During disease progression HIV-1 must overcome the decreasing supply of activated CD4+ T cells, which express high levels of CD4 and the CCR5 coreceptor [10, 35, 115, 116]. The transition of the virus to altered receptor usage and the ensuing changes in cell tropism at later disease stages have been extensively studied over the past 30 years, yet many details remain elusive [14, 20, 36, 65, 69–71, 117–120]. The observed transitions during the course of the infection are thought to be needed to allow the virus to infect a broader range of host cells. This may require altered coreceptor usage [15, 77, 121], or modifications to allow infection of cells that express lower CD4 levels. Low CD4 usage in particular is exemplified by R5 viruses exhibiting macrophage tropism [63, 65–67, 74, 77, 78, 98, 122–124]. Development of increased CD4 binding capacity by gp120 has been implicated in high macrophage tropism [125–127], which may have relevant consequences in disease progression (reviewed ), however the forces that lead to this phenotype have not been clearly defined. One clue has been provided by the frequent association of highly macrophage-tropic envelopes with CNS infection in late disease  suggesting features of this compartment particularly favor or facilitate the development of envelopes with high CD4 affinity. Adaptation of the HIV-1 envelope to CD4low conditions warrants study to elucidate potential intermediate evolutionary states, CD4low associated phenotypes, and to improve our understanding of the forces driving development of this niche phenotype at the high end of the continuum of CD4 use.