Purifying Selection in Human Immunodeficiency Virus-1 pol Gene in Perinatally Human Immunodeficiency Virus-1-Infected Children Harboring Discordant Immunological Response and Virological Nonresponse to Long-Term Antiretroviral Therapy

Ralph-Sydney Mboumba Bouassa; Helene Pere; Christian Diamant Mossoro-Kpinde; Pierre Roques; Jean Chrysostome Gody; Sandrine Moussa; David Veyer; Gerard Gresenguet; Charlotte Charpentier; Mohammad-Ali Jenabian; Joel Fleury Djoba Siawaya; Laurent Belec

doi:10.14740/jocmr4157

Purifying Selection in Human Immunodeficiency Virus-1 pol Gene in Perinatally Human Immunodeficiency Virus-1-Infected Children Harboring Discordant Immunological Response and Virological Nonresponse to Long-Term Antiretroviral Therapy

J Clin Med Res. 2020 Jun;12(6):369-376. doi: 10.14740/jocmr4157. Epub 2020 Jun 4.

Authors

Ralph-Sydney Mboumba Bouassa^{1

2}, Helene Pere^{1

3}, Christian Diamant Mossoro-Kpinde^{4

5}, Pierre Roques⁶, Jean Chrysostome Gody^{4

7}, Sandrine Moussa⁸, David Veyer¹, Gerard Gresenguet^{4

9}, Charlotte Charpentier¹⁰, Mohammad-Ali Jenabian¹¹, Joel Fleury Djoba Siawaya^{2

12}, Laurent Belec^{1

2

3}

Affiliations

¹ Laboratoire de Virologie, Hopital Europeen Georges Pompidou, Assistance Publique-Hopitaux de Paris (AP-HP) and Universite de Paris, Paris Sorbonne Cite, Paris, France.
² Ecole Doctorale Regionale en Infectiologie Tropicale, Franceville, Gabon.
³ Universite de Paris, Paris Sorbonne Cite, Paris, France.
⁴ Faculte des Sciences de la Sante, Universite de Bangui, Bangui, Central African Republic.
⁵ Laboratoire National de Biologie Clinique et de Sante Publique, Bangui, Central African Republic.
⁶ Commissariat a l'Energie Atomique (CEA)-Universite Paris-Saclay; INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, Institut de Biologie Francois-Jacob (IBJF), Fontenay-aux-Roses, France.
⁷ Complexe Pediatrique, Bangui, Central African Republic.
⁸ Institut Pasteur de Bangui, Bangui, Central African Republic.
⁹ Unite de Recherches et d'Intervention sur les Maladies Sexuellement Transmissibles et le SIDA, Departement de Sante Publique, Faculte des Sciences de la Sante de Bangui, Central African Republic.
¹⁰ IAME, UMR 1137, INSERM, Universite Paris Diderot, Sorbonne Paris Cite, AP-HP, Laboratoire de Virologie, Hopital Bichat, AP-HP, Paris, France.
¹¹ Departement des Sciences Biologiques et Centre de Recherche BioMed, Universite du Quebec a Montreal (UQAM), Montreal, QC, Canada.
¹² Laboratory Medicine, Mother and Child University Hospital Jeanne Ebori, Libreville, Gabon.

Abstract

Background: Biological monitoring of antiretroviral treatment (ART) in human immunodeficiency virus (HIV)-infected pediatric population remains challenging. The aim of the present study was to assess the long-term HIV-1 genetic diversity in pol gene in HIV-1-infected children in virological failure under antiretroviral regimen adapted according to the successive World Health Organization (WHO) guidelines for resource-constrained settings.

Methods: HIV-1 diversity in pol gene was assessed in HIV-1-infected children and adolescents born from HIV-infected mothers (median age at follow-up: 13.8 years) in virological failure (VF⁺) despite long-term regimen recommended by the WHO. The numbers of nonsynonymous substitutions per potential nonsynonymous site (dN) and of synonymous substitutions at potential synonymous sites (dS) in HIV-1 pol gene and the dN/dS ratios were used to estimate the selective pressure on circulating HIV-1.

Results: The immunological responses to ART basically corresponded to: 1) Full therapeutic failure with immunological (I^-) and virological nonresponses in one-quarter (24.6%) of study children ((I^-, VF⁺) subgroup); 2) Discordant immunovirological responses with paradoxical high CD4 T cell counts (I⁺) and high HIV-1 RNA load in the remaining cohort patients (75.4%) ((I⁺, VF⁺) subgroup). The mean dS was 1.8-fold higher in (I⁺, VF⁺) than (I^-, VF⁺) subgroup (25.9 ± 18.4 vs. 14.3 ± 10.8). In the (I⁺, VF⁺) subgroup, the mean dS was 1.6-fold higher than the mean dN. Finally, the mean dN/dS ratio was 2.1-fold lower in (I⁺, VF⁺) than (I^-, VF⁺) subgroup (0.6 ± 0.3 vs. 1.3 ± 0.7), indicating purifying selection in the immunovirological discordant (I⁺, VF⁺) subgroup and positive selection in the immunovirological failure (I^-, VF⁺) subgroup.

Conclusions: Children and adolescents in immunovirological therapeutic failure harbor positive selection of HIV-1 strains favoring diversifying in pol-encoded amino acids. In contrast, children with persistent discordant immunovirological responses show accumulation of mutations and purifying selection in pol gene sequences, indicating limited genetic evolution and likely suggesting genetic adaptation of viruses to host functional constraints.

Keywords: Adolescents; Children; HIV-1 pol gene; Immunovirological dissociation; Nonsynonymous mutations; Purifying selection; Synonymous mutations; Virological failure.