The HR2 polymorphism N140I in the HIV-1 gp41 combined with the HR1 V38A mutation is associated with a less cytopathic phenotype

Abstract

BackgroundResistance to the fusion inhibitor enfuvirtide (ENF) is achieved by changes in the gp41 subunit of the HIV envelope glycoprotein (Env). Specific ENF-associated mutational pathways correlate with immunological recovery, even after virological failure, suggesting that the acquisition of ENF resistance alters gp41 pathogenicity. To test this hypothesis, we have characterized the expression, fusion capability, induction of CD4+ T cell loss and single CD4+ T cell death of 48 gp41 proteins derived from three patients displaying different amino acids (N, T or I) at position 140 that developed a V38A mutation after ENF-based treatment.ResultsIn all cases, intra-patient comparison of Env isolated pre- or post-treatment showed comparable values of expression and fusogenic capacity. Furthermore, Env with either N or T at position 140 induced comparable losses of CD4+ T-cells, irrespective of the residue present at position 38. Conversely, Env acquiring the V38A mutation in a 140I background induced a significantly reduced loss of CD4+ T cells and lower single-cell death than did their baseline controls. No altered ability to induce single-cell death was observed in the other clones.ConclusionsOverall, primary gp41 proteins with both V38A and N140I changes showed a reduced ability to induce single cell death and deplete CD4+ T cells, despite maintaining fusion activity. The specificity of this phenotype highlights the relevance of the genetic context to the cytopathic capacity of Env and the role of ENF-resistance mutations in modulating viral pathogenicity in vivo, further supporting the hypothesis that gp41 is a critical mediator of HIV pathogenesis.

HIV-1 Induced Bystander Apoptosis

“…In a more recent study, Cunyat et al . showed that the presence of V38A mutation in combination with N140I polymorphism is associated with reduced HIV mediated cytopathic effects [109]. These findings are in agreement with above mentioned clinical findings showing an increase in CD4 counts even after virological failure in Enfuvirtide treated patients [105,106,107].…”

Host and Viral Factors in HIV-Mediated Bystander Apoptosis

“…Hemifusion is a process that involves transient interaction of cellular membranes characterized by mixing of the outer leaflets of the bilayers without progression to fusion pore formation [ 45 ]. Although hemifusion has been extensively studied in influenza, it has been demonstrated by multiple independent groups in HIV as well [ 35 , 44 , 46 , 47 , 48 ]. It is hypothesized that membrane damage mediated during this hemifusion process in part mediates bystander apoptosis; a phenomenon also referred to as the “kiss of death” [ 31 ].…”

“…Subsequently, Melby et al [ 82 ] reported that mutations at position V38 in gp41 are associated with increase in CD4 recovery in enfuvirtide treated patients after virological failure. Further evidence for a role of gp41 in this process was shown by Cunyat et al who found that the presence of V38A in combination with N140I mutation in gp41 was associated with reduced HIV associated cytopathic phenotype [ 48 ]. In vitro mutagenesis studies by our lab later confirmed that mutations at the V38 position, especially V38E, reduces bystander apoptosis activity in vitro [ 83 ].…”

HIV-1 gp41 genetic diversity and enfuvirtide resistance-associated mutations among enfuvirtide-naïve patients in southern China

“…The major ENF resistance-associated mutations were identi ed in amino acid position 36-45 of HR1 domain. Other secondary mutations including N126K, E137K, S138A, N140I also were demonstrated to reduce ENF susceptibility [17][18][19][20]. ENF resistance-associated mutations have been reported in patients who have accepted highly active antiretroviral therapy (HAART), but less data about the ENF resistance associated mutations among ENFnaïve patients.…”