A Subset of Extreme Human Immunodeficiency Virus (HIV) Controllers Is Characterized by a Small HIV Blood Reservoir and a Weak T-Cell Activation Level

Abstract

Background: Human immunodeficiency virus controllers (HICs) form a heterogeneous group of patients with regard to formal definitions, immunologic characteristics, and changes over time in viral load.

Patients and methods: The HICs with undetectable viral load ([uHICs] ie, for whom a viral load had never been detected with routine assays; n = 52) were compared with 178 HICs with blips during the follow up (bHICs). Clinical characteristics, ultrasensitive HIV-ribonucleic acid (RNA) and HIV-deoxyribonucleic acid (DNA) loads, HIV1-Western blot profiles, and immune parameters were analyzed.

Results: Relative to bHICs, uHICs had significantly lower ultrasensitive plasma HIV-RNA loads (P < .0001) and HIV-DNA levels in peripheral blood mononuclear cells (P = .0004), higher CD4⁺ T-cell count (P = .04) at enrollment, and lower T-cell activation levels. Between diagnosis and inclusion in the cohort, the CD4⁺ T-cell count had not changed in uHICs but had significantly decreased in bHICs. Twenty-one percent of the uHICs lacked specific anti-HIV immunoglobulin G antibodies, and these individuals also had very low levels of HIV-DNA. Half of the uHICs had a protective human leukocyte antigen (HLA) allele (-B57/58/B27), a weak CD8⁺ T-cell response, and very small HIV-DNA reservoir.

Conclusions: We suggest that an interesting HIC phenotype combines protective HLA alleles, low level of HIV blood reservoirs, and reduced immune activation. Prospective studies aimed at evaluating the benefit of combined antiretroviral therapy in HICs might take into account the identification of uHICs and bHICs.

Keywords: HIV controllers; HIV-DNA in PBMC; HLA; immune activation; ultrasensitive plasma HIV-RNA load..

Figure 1.

Slopes of CD4⁺ T-cell counts in a linear mixed-effects model, as a function of undetectable human immunodeficiency virus controller (uHIC) or HIC with blip (bHIC) status.

Figure 2.

Immunologic characteristics of the study population, as a function of undetectable human immunodeficiency virus (HIV) controller (uHIC) or HIC with blip (bHIC) status. (A and B) Frequencies of HLA-DR⁺ CD38⁺-activated CD8⁺ T cells and CD4⁺ T cells, respectively, at enrollment in the cohort (n = 34 uHICs and 116 bHICs for CD4⁺ T cells, and n = 34 and 117 for CD8⁺ T cells) and then at month (M)2 (n = 28 uHICs and 98 bHICs for CD4⁺ T cells, and n = 28 and 98 for CD8⁺ T cells), M24 (n = 30 uHICs and 83 bHICs for CD4⁺ T cells, and n = 30 and 84 for CD8⁺ T cells), and M36 (n = 27 uHICs and 59 bHICs for CD4⁺ T cells, and n = 27 and 59 for CD8⁺ T cells). *P = .05; **P < .01. The area of immune activation in uHICs (between x-axis and the full line) in the time is depicted in the gray zone, whereas the area of immune activation in bHICs is comprised between the x-axis and the dotted line. (C and D) Correlations between HLA-DR⁺CD38⁺CD4⁺ (C) and CD8⁺ (D) T cells and ultrasensitive HIV ribonucleic acid (RNA) load (Spearman).

Figure 3.

(A) Heat map representation of serum human immunodeficiency virus (HIV) immunoglobulin (Ig)G status (Western blot [WB] analysis testing reactivity for gp160, gp110/120, p68/66, p55, p52/51, gp41, p40, p34/31, p24/25, p18/17) at enrollment for undetectable human immunodeficiency virus controllers (uHICs) (n = 47). (B) Repartition of proportion of undetectable HIV deoxyribonucleic acid (DNA) and ultrasensitive (us) HIV ribonucleic acid (RNA), among uHICs with weak or full serum HIV IgG responses. As defined in the text, patients with at least 1 absent band on semiquantitative analysis of the WB were defined as having weak IgG responses.