HIV controllers with different viral load cutoff levels have distinct virologic and immunologic profiles

Abstract

Background: The mechanisms behind natural control of HIV replication are still unclear, and several studies pointed that elite controllers (ECs) are a heterogeneous group.

Methods: We performed analyses of virologic, genetic, and immunologic parameters of HIV-1 controllers groups: (1) ECs (viral load, <80 copies/mL); (2) ebbing elite controllers (EECs; transient viremia/blips); and viremic controllers (VCs; detectable viremia, <5000 copies/mL). Untreated noncontrollers (NCs), patients under suppressive highly active antiretroviral therapy (HAART), and HIV-1-negative individuals were analyzed as controls.

Results: Total and integrated HIV-1 DNA for EC were significantly lower than for NC and HAART groups. 2-LTR circles were detected in EEC (3/5) and VC (6/7) but not in EC. Although EC and EEC maintain normal T-cell counts over time, some VC displayed negative CD4 T-cell slopes. VC and EEC showed a higher percentage of activated CD8 T cells and microbial translocation than HIV-1-negative controls. EC displayed a weaker Gag/Nef IFN-γ T-cell response and a significantly lower proportion of anti-HIV IgG antibodies than EEC, VC, and NC groups.

Conclusion: Transient/persistent low-level viremia in HIV controllers may have an impact on immunologic and virologic profiles. Classified HIV controller patients taking into account their virologic profile may decrease the heterogeneity of HIV controllers cohorts, which may help to clarify the mechanisms associated to the elite control of HIV.

Figure 1

Quantification of total (A) and integrated (B) viral DNA and 2-LTR circles (C) for HIV controllers, HAART and NC groups. Relationship between plasma viral load and total HIV DNA (D), integrated HIV DNA (E), and 2-LTR circles (F). Negative 2-LTR PCR results are represented by open symbols. The number of positive 2-LTR PCR /number patients tested were as follows: EC=0/7, EEC=3/5, VC=6/7, HAART=9/13 and NC=18/19 (the percentages are indicated in the graph). The horizontal lines denote median values. P values for comparison between two groups were calculated using a 2-tailed Mann-Whitney test. Correlations were calculated using a nonparametric Spearman test. Data from EC, EEC, VC and NC were used to calculate correlations.

Figure 2

Evaluation of peripheral CD4⁺ (A) and CD8⁺ (B) T cell populations, CD4⁺ T cell slope (C) and CD4/CD8 ratio among Elite Controllers (EC), Ebbing Elite Controllers (EEC), Viremic Controllers (VC) and Non-controllers (NC). The horizontal bars denote median values. P values for comparison between two groups were calculated using a 2-tailed Mann-Whitney test.

Figure 3

Percentages of activated (CD38⁺HLA-DR⁺) CD8⁺ T cells (A) and level of sCD14 (pg/mL) in the plasma (B) among HIV-uninfected participants, Elite Controllers (EC), Ebbing Elite Controllers (EEC), Viremic Controllers (VC) and Non-Controllers (NC). The horizontal bars denote median values. P values for comparison between two groups were calculated using a 2-tailed Mann-Whitney test.

Figure 4

Evaluation of HIV-1 specific responses. Proportion of anti-HIV-1 IgG determined by BED-CEIA found in Elite Controllers (EC), Ebbing Elite Controllers (EEC), Viremic Controllers (VC) and Non-Controllers (NC) (A). Gag- (B) and Nef- (C) specific PBMC responses among Elite Controllers (EC), Ebbing Elite Controllers (EEC), Viremic Controllers (VC) and Non-Controllers (NC) by IFN-γ ELISpot (SFC/10⁶ PBMC). Open circles represent patients with B*57 and open squares represent patients with B*27 alelles. Horizontal dashed line represents the conventional cut-off value (0.8) below which a sample is classified as recent infection (153-day window period) based on the low proportion of HIV-specific IgG in the serum/plasma. The horizontal bars denote median values. P values for comparison between two groups were calculated using a 2-tailed Mann-Whitney test.