AUTHOR=Picton Anabela C. P. , Paximadis Maria , Koor Gemma W. , Bharuthram Avani , Shalekoff Sharon , Lassauniere Ria , Ive Prudence , Tiemessen Caroline T. 

TITLE=Reduced CCR5 Expression and Immune Quiescence in Black South African HIV-1 Controllers

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.781263

DOI=10.3389/fimmu.2021.781263

ISSN=1664-3224

ABSTRACT=<p>Unique Individuals who exhibit either suppressive HIV-1 control, or the ability to maintain low viral load set-points and preserve their CD4+ T cell counts for extended time periods in the absence of antiretroviral therapy, are broadly termed HIV-1 controllers. We assessed the extent to which black South African controllers (n=9), differ from uninfected healthy controls (HCs, n=22) in terms of lymphocyte and monocyte CCR5 expression (density and frequency of CCR5-expressing cells), immune activation as well as peripheral blood mononuclear cell (PBMC) mitogen-induced chemokine/cytokine production. In addition, relative CD4+ T cell CCR5 mRNA expression was assessed in a larger group of controllers (n=20) compared to HCs (n=10) and HIV-1 progressors (n=12). Despite controllers having significantly higher frequencies of activated CD4+ and CD8+ T cells (HLA-DR+) compared to HCs, CCR5 density was significantly lower in these T cell populations (<italic>P</italic>=0.039 and <italic>P</italic>=0.064, respectively). This lower CCR5 density was largely attributable to controllers with higher VLs (&gt;400 RNA copies/ml). Significantly lower CD4+ T cell CCR5 density in controllers was maintained (<italic>P</italic>=0.036) when HCs (n=12) and controllers (n=9) were matched for age. CD4+ T cell CCR5 mRNA expression was significantly less in controllers compared to HCs (<italic>P</italic>=0.007) and progressors (<italic>P</italic>=0.002), whereas HCs and progressors were similar (<italic>P</italic>=0.223). The levels of soluble CD14 in plasma did not differ between controllers and HCs, suggesting no demonstrable monocyte activation. While controllers had lower monocyte CCR5 density compared to the HCs (<italic>P</italic>=0.02), significance was lost when groups were age-matched (<italic>P</italic>=0.804). However, when groups were matched for both CCR5 promoter haplotype and age (n=6 for both) reduced CCR5 density on monocytes in controllers relative to HCs was highly significant (<italic>P</italic>=0.009). Phytohemagglutinin-stimulated PBMCs from the controllers produced significantly less CCL3 (<italic>P</italic>=0.029), CCL4 (<italic>P</italic>=0.008) and IL-10 (P=0.028) compared to the HCs, which was largely attributable to the controllers with lower VLs (&lt;400 RNA copies/ml). Our findings support a hypothesis of an inherent (genetic) predisposition to lower CCR5 expression in individuals who naturally control HIV-1, as has been suggested for Caucasian controllers, and thus, likely involves a mechanism shared between ethnically divergent population groups.</p>