Abstract
BackgroundHIV-1 infects a wide range of CD4+ T cells with different phenotypic properties and differing expression levels of entry coreceptors. We sought to determine the viral tropism of subtype C (C-HIV) Envelope (Env) clones for different CD4+ T cell subsets and whether tropism changes during acute to chronic disease progression. HIV-1 envs were amplified from the plasma of five C-HIV infected women from three untreated time points; less than 2 months, 1-year and 3-years post-infection. Pseudoviruses were generated from Env clones, phenotyped for coreceptor usage and CD4+ T cell subset tropism was measured by flow cytometry.ResultsA total of 50 C-HIV envs were cloned and screened for functionality in pseudovirus infection assays. Phylogenetic and variable region characteristic analysis demonstrated evolution in envs between time points. We found 45 pseudoviruses were functional and all used CCR5 to mediate entry into NP2/CD4/CCR5 cells. In vitro infection assays showed transitional memory (TM) and effector memory (EM) CD4+ T cells were more frequently infected (median: 46% and 25% of total infected CD4+ T cells respectively) than naïve, stem cell memory, central memory and terminally differentiated cells. This was not due to these subsets contributing a higher proportion of the CD4+ T cell pool, rather these subsets were more susceptible to infection (median: 5.38% EM and 2.15% TM cells infected), consistent with heightened CCR5 expression on EM and TM cells. No inter- or intra-participant changes in CD4+ T cell subset tropism were observed across the three-time points.ConclusionsCD4+ T cell subsets that express more CCR5 were more susceptible to infection with C-HIV Envs, suggesting that these may be the major cellular targets during the first 3 years of infection. Moreover, we found that viral tropism for different CD4+ T cell subsets in vitro did not change between Envs cloned from acute to chronic disease stages. Finally, central memory, naïve and stem cell memory CD4+ T cell subsets were susceptible to infection, albeit inefficiently by Envs from all time-points, suggesting that direct infection of these cells may help establish the latent reservoir early in infection.
Highlights
Human immunodeficiency virus type 1 (HIV-1) infects a wide range of CD4+ T cells with different phenotypic properties and differing expression levels of entry coreceptors
Establishment of a longitudinal bank of C‐HIV Envs To understand how virus tropism for different memory CD4+ T cell subsets changes during a Subtype C HIV-1 (C-HIV) infection, we obtained longitudinal env clones (Additional file 1: Table S1) from five C-HIV-positive individuals enrolled in the CAPRISA 002 Acute Infection Study [41]
Plasma viral load had reduced in three participants (CAP177, CAP255 and CAP257; decreasing by: 0.01 to 1.23 log10 copies per ml) and increased in two (CAP88 and CAP228; increased by: 0.59 to 0.69 log10 copies/ml) by 3-years post-infection (T3) compared to Enrolment/acute infection (T0)
Summary
HIV-1 infects a wide range of CD4+ T cells with different phenotypic properties and differing expression levels of entry coreceptors. We sought to determine the viral tropism of subtype C (C-HIV) Envelope (Env) clones for different CD4+ T cell subsets and whether tropism changes during acute to chronic disease progression. Pseudoviruses were generated from Env clones, phenotyped for coreceptor usage and CD4+ T cell subset tropism was measured by flow cytometry. Longlived resting memory C D4+ T cells are less frequently infected [4, 5] and are primary targets for latent infection [6, 7]. Latently infected cells serve as the source of viral recrudescence when ART is interrupted. The latent reservoir represents a significant barrier to achieving HIV-1 cure using current therapeutic strategies
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