CCR5 expression, haplotype and immune activation in protection from infection in HIV‐exposed uninfected individuals in HIV‐serodiscordant relationships

Abstract

Several host factors have been implicated in resistance to HIV infection in individuals who remain HIV-seronegative despite exposure. In a cohort of HIV-serodiscordant heterosexual couples, we investigated interactions between systemic inflammation and T-cell activation in resistance to HIV infection. Males and females in stable long-term relationships with either HIV-infected or uninfected partners were recruited, blood T-cell activation (CD38, HLA-DR, CCR5 and Ki67) and plasma cytokine concentrations were evaluated. The HIV-negative exposed individuals had significantly lower frequencies of CCR5 CD4 and CD8 T cells than unexposed individuals. Mean fluorescence intensity of CCR5 expression on CD4 T cells was significantly lower in HIV-negative exposed than unexposed individuals. Protective CCR5 haplotypes (HHA/HHF*2, HHF*2/HHF*2, HHC/HHF*2, HHA/HHA, HHA/HHC and HHA/HHD) tended to be over-represented in exposed compared with unexposed individuals (38% versus 28%, P = 0·58) whereas deleterious genotypes (HHC/HHD, HHC/HHE, HHD/HHE, HHD/HHD and HHE/HHE) were under-represented (26% versus 44%; P = 0·16). Plasma concentrations of interleukin-2 (P = 0·02), interferon-γ (P = 0·05) and granulocyte-macrophage colony-stimulating factor (P = 0·006) were lower in exposed compared with unexposed individuals. Activation marker expression and systemic cytokine concentrations were not influenced by gender. We conclude that the dominant signature of resistance to HIV infection in this cohort of exposed but uninfected individuals was lower T-cell CCR5 expression and plasma cytokine concentrations.

Genetic variations within the CCR5 promoter region among elite and viremic controllers in Uganda

“…This mutation has been associated with increased CCR5 expression on CD4+ T cells and thus could explain the rapid progression to AIDS among the NCs. This mutation has been found to be associated with rapid progression in other studies (33)(34)(35). This mutation was significantly associated with disease acceleration, particularly an accelerated progression to death in Caucasians (16).…”

Metabolomics as an Approach to Characterise the Contrasting Roles of CCR5 in the Presence and Absence of Disease

“…The authors concluded that the decreased frequencies of heterozygous CCR5∆32 in seropositive patients suggest partial resistance against HIV-1 infection thus affording protection [31]. In a South African-based study done by Jaumdally et al [33], the immune profiles of samples carrying protective and non-protective haplotypes were investigated. The authors investigated the interaction between systemic inflammation, immune activation of T-cells and CCR5 genotype in context to HIV-1 resistance.…”

“…These individuals when grouped thus expressed protective CCR5 haplotypes and presented with reduced inflammatory cytokines. The data obtained by Jaumdally and co-workers [33] provides important biological information regarding samples presenting differential CCR5 status even before actual infection. The terms used to describe CCR5 (i.e., genotype, levels, haplotype, etc.)…”

“…A protective haplotype will therefore take polymorphisms leading to lower CCR5 expression into account, while non-protective haplotypes are associated with increased CCR5. More recently, Jaumdally and colleagues [33] in their 2017 study investigated inflammation and T-cell activation in the plasma of uninfected participants, exposed and unexposed to human immunodeficiency virus type 1(HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS). Exposed uninfected individuals had lower frequencies of CCR5-positive (CCR5 + ) immune cells (protective against infection) than their unexposed counterparts.…”

Senescência e exaustão de células T e resposta vacinal em crianças infectadas perinatalmente pelo HIV

“…A dupla marcação de linfócitos com CD38+HLA-DR+ classicamente está associada com ativação e progressão da doença 52,53 . O receptor de membrana CCR5 está ligado à susceptibilidade à infecção pelo HIV, e também à progressão da doença em indivíduos infectados pelo HIV 54,55 . O receptor de membrana CD95 está envolvido na morte acelerada de linfócitos T no contexto de infecção pelo HIV, através da indução de apoptose, e é considerado marcador de exaustão e ativação celular [56][57][58][59] .…”