Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle

Abstract

The p6 domain of HIV-1 Gag contains highly conserved peptide motifs that recruit host machinery to sites of virus assembly, thereby promoting particle release from the infected cell. We previously reported that mutations in the YPXnL motif of p6, which binds the host protein Alix, severely impair HIV-1 replication. Propagation of the p6–Alix binding site mutants in the Jurkat T cell line led to the emergence of viral revertants containing compensatory mutations not in Gag but in Vpu and the envelope (Env) glycoprotein subunits gp120 and gp41. The Env compensatory mutants replicate in Jurkat T cells and primary human peripheral blood mononuclear cells, despite exhibiting severe defects in cell-free particle infectivity and Env-mediated fusogenicity. Remarkably, the Env compensatory mutants can also rescue a replication-delayed integrase (IN) mutant, and exhibit reduced sensitivity to the IN inhibitor Dolutegravir (DTG), demonstrating that they confer a global replication advantage. In addition, confirming the ability of Env mutants to confer escape from DTG, we performed de novo selection for DTG resistance and observed resistance mutations in Env. These results identify amino acid substitutions in Env that confer broad escape from defects in virus replication imposed by either mutations in the HIV-1 genome or by an antiretroviral inhibitor. We attribute this phenotype to the ability of the Env mutants to mediate highly efficient cell-to-cell transmission, resulting in an increase in the multiplicity of infection. These findings have broad implications for our understanding of Env function and the evolution of HIV-1 drug resistance.

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

“…Interestingly, dominant non-synonymous mutations in env were observed in both selection groups (A541V, Q550H, and S144R in the Nelfinavir selection group, and N302Y, D547G, and Q550H in the PAV206 selection group in Fig 7A, B). One of these mutations, A541V (observed at Nelfinavir P29 in Fig 7A, B) was recently shown to confer broad escape from defects in virus replication defects caused by either virus mutations or antiretroviral drugs, most likely by increasing cell-to-cell transmission in T cell lines (45). The other dominant non-synonymous env mutations observed in our two selection groups are likely to also be in this general category.…”

“…Additionally, a second set of mutations was observed in PAV206 and Nelfinavir. These mutations were in env , are not drug-specific, and have been shown to confer global replication advantage most likely by increasing cell-to-cell transmission in T cell lines (45). The modest resistance observed in the PAV206 selection experiment (allowing virus replication in a PAV206 concentration 8X higher than the EC50) is likely explained by non-dominant cyclophilin A binding loop polymorphisms and the env mutations that may have been emerging.…”

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

“…Other changes outside of the IN coding region, including the HIV-1 env gene, can confer resistance to DTG (150). HIV-1 can infect cells through fusing directly with the cellular plasma membrane or through the virological synapse that forms between an infected cell and an uninfected cell (151) (reviewed in Ref.…”

In Vivo Emergence of a Novel Protease Inhibitor Resistance Signature in HIV-1 Matrix

“…The HIV-1 envelope (Env) has been reported in two studies to impact PI susceptibility (18,19), with a number of reports of diverse env sequence changes during PI failure (20,21). Gag is highly polymorphic across HIV-1 subtypes, and existing literature reports diverse mutations occurring both within and outside cleavage sites following treatment with older PI such as indinavir, saquinavir and nelfinavir in subtype B infections (14,(20)(21)(22)(23)(24).…”