HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites

Abstract

HIV subtypes not only predominate in different geographical regions but also differ in key phenotypic characteristics. To determine if genotypic and/or phenotypic differences in the Envelope (Env) glycoprotein can explain subtype related differences, we cloned 37 full length Envs from Subtype B and AE HIV infected individuals from Singapore. Our data demonstrates that CRF01_AE Envs have lower Potential N Glycosylation Sites and higher risk of X4 development. Phenotypically, CRF01_AE were less infectious than subtype B Envs in cells expressing low levels of CCR5. Moreover, the Maraviroc IC50 was higher for subtype B Envs and correlated with infectivity in low CCR5 expressing cells as well as PNGS. Specifically, the glycosylation site N301 in the V3 loop was seen less frequently in AE subtype and CXCR4 topic viruses. CRF01_AE differs from B subtype in terms of CCR5 usage and Maraviroc susceptibility which may have implications for HIV pathogenesis and virus evolution.

Rapid CD4 cell loss is caused by specific CRF01_AE cluster with V3 signatures favoring CXCR4 usage

“…A recent study found that in the Los Alamos HIV database, N301 glycan is present in as high as 99% of subtype B sequences with R5 phenotype and more than 80% of sequences with X4 phenotype. Differently, in CRF01_AE, 94% of R5 sequences and 39% of X4 sequences have the N301 glycan site (34). This again indicates that loss of the N301 glycan is an important pathway for coreceptor switch in CRF01_AE HIV-1, but is not a primary route among subtype B viruses.…”

Combination gene therapy for HIV using a conditional suicidal gene with CCR5 knockout

“…Cells were fixed at day 3 post infection and images acquired using the Nikon Eclipse Ti microscope expression [18]. Our lab has extensively studied the role of CCR5 expression levels in HIV pathogenesis [19][20][21][22][23][24][25] and believe that a reduction in CCR5 levels in mono allelic KO may reduce CCR5 levels and provide a CCR5delta32 heterozygous like phenotype in patients resulting in reduced HIV pathogenesis. However, the goal of CCR5 KO should be bi allelic KO in order to achieve HIV resistance/cure as seen in the Berlin patient.…”