Differential utilization of CD4+ by transmitted/founder and chronic envelope glycoproteins in a MSM HIV-1 subtype B transmission cluster

Abstract

Objective: HIV-1 transmission leads to a genetic bottleneck, with one or a few variants of the donor quasispecies establishing an infection in the new host. We aimed to characterize this bottleneck in more detail, by comparing the properties of HIV envelope glycoproteins from acute and chronic infections within the particular context of a male-to-male transmission cluster. Design: We compared the genotypic and phenotypic properties of envelope glycoproteins from viral variants derived from five study participants from the same transmission cluster. Methods: We used single-genome amplification to generate a collection of full-length env sequences. We then constructed pseudotyped viruses expressing selected Env variants from the quasispecies infecting each study participant and compared their infectivities and sensitivities to various entry inhibitors. Results: The genotypic analyses confirmed the genetic bottleneck expected after HIV transmission, with a limited number of variants identified in four study participants during acute infection. However, the transmitted sequences harbored no evident common signature and belonged to various genetic lineages. The phenotypic analyses revealed no difference in infectivity, susceptibility to the CCR5 antagonist maraviroc, the fusion inhibitor enfurvitide or type-I interferon between viruses from participants with acute and chronic infections. The key property distinguishing transmitted viruses was a higher resistance to soluble CD4+, correlated with greater sensitivity to occupation of the CD4+ receptor by the anti-CD4+ antibodies LM52 and SK3. Conclusion: These results suggest that envelope glycoproteins from transmitted/founder viruses bind CD4+ less efficiently than those of viruses from chronic infections.

Identification of early-induced broadly neutralizing activities against transmitted founder HIV strains

“…Different studies have been performed to identify common features for T/F viruses. Shorter V1V2 regions [ 9 ], lower glycosylation sites [ 3 ] and less efficient binding to CD4 + [ 10 ] have been identified. These characteristics may increase infectivity and affinity to mucosal receptors or reduce sensitivity to neutralization [ 9 , 11 ].…”