Year-end Sale % OFF 
Abstract
HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naïve subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an “Ile-Gly” insertion in the gp120 V3 loop and replacement of the V3 “Gly-Pro-Gly” crown with a “Gly-Arg-Gly” motif, but that the accumulation of additional gp120 “scaffold” mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.
Highlights
More than 33 million people are infected with human immunodeficiency virus (HIV) and around 20 million have died from AIDS
Amino acid alterations occurring in 1109-F-30 envelope glycoproteins (Envs) clustered at the crown and stem regions of the V3 loop, and included Arg318 resulting in substitution of the highly conserved ‘‘Gly-Pro-Gly’’ crown motif for ‘‘Gly-Arg-Gly’’, an Ile314-Gly315 insertion immediately proximal to the crown alteration, and Asp327, Val328, Arg329 and Asp331 in the descending strand of the V3 loop stem (Fig. 3A)
Since current models of gp120 binding to coreceptor suggest that the V3 loop crown interacts with the coreceptor extracellular loop 2 region and the V3 loop stem interacts with the coreceptor N-terminus to mediate HIV type 1 (HIV-1) entry [59,60,61,62], we hypothesized that combinations of these V3 crown/stem mutations contribute to the evolution of R5 to X4 variants in subject 1109, and in addition, that a subset of these alterations give rise to ‘‘transitional’’ R5X4 intermediates that most likely arose after the ‘‘intermediate’’ timepoint and disappeared before the ‘‘final’’ timepoint
Summary
More than 33 million people are infected with human immunodeficiency virus (HIV) and around 20 million have died from AIDS. 2.1 million new infections occur annually [1] and most of these individuals live in developing countries with limited access to potentially life saving antiretroviral therapies. HIV is predicted to become the leading burden of disease in middle and low-income countries by 2015 [2]. The spread of HIV-1 in humans has enabled the evolution of group M viruses into a number of distinct subtypes (A-D, F-H, J, K) and intersubtype recombinant forms. Subtype C HIV-1 (C-HIV) is spreading rapidly and accounts for .50% of infections worldwide and .95% of infections in southern Africa and central Asia (reviewed in [4]), which are regions of the world burdened with the overwhelming majority of HIV-1 infections
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
