Relationship between CCR5(WT/Δ32) heterozygosity and HIV-1 reservoir size in adolescents and young adults with perinatally acquired HIV-1 infection

[Background] Several host factors contribute to human immunodeficiency virus (HIV) disease progression in the absence of combination antiretroviral therapy (cART). Among them, the CC-chemokine receptor 5 (CCR5) is known to be the main co-receptor used by HIV-1 to enter target cells during the early stages of an HIV-1 infection.
[Objective] We evaluated the association of CCR5(WT/Δ32) heterozygosity with HIV-1 reservoir size, lymphocyte differentiation, activation and immunosenescence in adolescents and young adults with perinatally acquired HIV infection receiving cART. [Methods] CCR5 genotype was analysed in 242 patients with vertically transmitted HIV-1 infection from Paediatric Spanish AIDS Research Network Cohort (coRISpe). Proviral HIV-1 DNA was quantified by digital-droplet PCR, and T-cell phenotype was evaluated by flow cytometry in a subset of 24 patients (ten with CCR5(Δ32/WT) genotype and 14 with CCR5(WT/WT) genotype). [Results] Twenty-three patients were heterozygous for the Δ32 genotype but none was homozygous for the mutated CCR5 allele. We observed no difference in the HIV-1 reservoir size (455 and 578 copies of HIV-1 DNA per million CD4+ T cells in individuals with CCR5(WT/WT) and CCR5(Δ32/WT) genotypes, respectively; p 0.75) or in the immune activation markers between both genotype groups. However, we found that total HIV-1 DNA in CD4+ T cells correlated with the percentage of memory CD4+ T cells: a direct correlation in CCR5(WT/Δ32) patients but an inverse correlation in those with the CCR5(WT/WT) genotype. [Conclusions] This finding suggests a differential distribution of the viral reservoir compartment in CCR5(WT/Δ32) patients with perinatal HIV infection, which is a characteristic that may affect the design of strategies for reservoir elimination.
We particularly acknowledge the Spanish HIV HGM BioBank supported by the Spanish Instituto de Salud Carlos III, which is integrated with the Spanish AIDS Research Network. We thank V. Urrea (AIDS Research Institute IrsiCaixa, Badalona) for statistical support. IrsiCaixa is supported by the CERCA programme from Generalitat de Catalunya. Work by the group of MAMF was supported by Instituto de Salud Carlos III (Subdirección General de Evaluación) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT13/0010/0028, Fondo de Investigacion Sanitaria (FIS) (grants PI13/02016, PI12/0014 and CD14/00320 to AGS), Comunidad de Madrid (grant S-2010/BMD-2332]. This work was (partially) funded by the RD12/0017/0037 project as part of the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011 (HGUGM) and by CYTED 214RT0482. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. This project was also supported by the Spanish Secretariat of Research (grant Red Temática de Investigación Cooperativa en SIDA [RD12/0017] and CPII014/00025 and PI12/02283 from Fondo de Investigación Sanitaria (FIS) to E.R.-M.) Work by the JM-P group is supported by the Spanish Secretariat of Research (grant SAF2013-49042-R), the Foundation for AIDS Research (amfAR), and the Spanish AIDS network ‘Red Temática Cooperativa de Investigación en SIDA’ (RD12/0017/0002). S.M-L. was supported by Agència de Gestió d’Ajuts Universitaris i de Recerca from Generalitat de Catalunya (2013FI_B 00275).