Date Published: March 27, 2018
Publisher: Lippincott Williams & Wilkins
Author(s): Thushan I. de Silva, Aleksandra Leligdowicz, Jonathan Carlson, Miguel Garcia-Knight, Clayton Onyango, Nicholas Miller, Louis-Marie Yindom, Stephane Hué, Assan Jaye, Tao Dong, Matthew Cotten, Sarah L. Rowland-Jones.
Supplemental Digital Content is available in the text
HIV-specific cytotoxic T-lymphocyte (CTL) responses are thought to play an important role in HIV-1 control [1–4]. A hallmark of HIV-1 evolution, however, is the rapid appearance of mutations within CTL epitopes, leading to loss of CTL recognition and immune control . HIV-2 differs from HIV-1 in that a substantial proportion of infected people maintain undetectable plasma viral loads for decades with no signs of immunodeficiency. Many others have viral loads 30-fold lower than HIV-1 at equivalent disease stages [6–9]. We have previously demonstrated a strong correlation between the presence of high frequency HIV-2 Gag-specific CTLs and viral control [10–12]. As HIV-2 is able to generate resistance mutations akin to HIV-1 under antiretroviral pressure , HIV-2 should also have the capacity to adapt to immune responses similar to HIV-1.
We report the first analysis of HLA-associated viral polymorphisms in HIV-2 p26, including a codon substitution within a known immunodominant HLA-B∗5801-restricted epitope. This may represent CTL-driven adaptation by HIV-2 and allows direct comparison with what is known about the equivalent HLA-B57/B∗5801-restricted epitope in HIV-1. In contrast to HIV-1, wherever a mutation at position 3 of the epitope (T242N) occurs in 63–93% of HLA-B∗5801-positive individuals , a mutation at position 5 (E245D) is found in 65% of HLA-B58 ST-positive patients. The HIV-1 TW10 epitope lies within a region essential for capsid formation  and residue 242 is thought to be critical to stabilizing the electrostatic charge along helix 6 . A T242N mutation reduces this stabilizing effect , consistent with viable virus with significantly reduced fitness. It is possible that for HIV-2, with much lower in-vivo viral titres than HIV-1, the fitness costs of such a mutation are too severe, leading to an alternative pathway of immune adaptation. Further functional studies are required to explore this hypothesis.
We thank Tim Vincent and the Caió team, as well as the Caió cohort participants, for their invaluable contribution to this study.