Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters

Abstract

Background: Human immunodeficiency virus type 1 (HIV-1) elite controllers are able to control virus replication to levels below the limits of detection by commercial assays, but the actual level of viremia in these individuals is not well defined. Here, we quantify plasma HIV-1 RNA in elite controllers and correlate this with specific immunologic parameters.

Methods: Plasma HIV-1 RNA levels were quantified in 90 elite controllers with use of a real time reverse-transcriptase polymerase chain reaction assay with a sensitivity of 0.2 copies/mL. HIV-1-specific immune responses and longitudinal CD4(+) T cell counts were examined.

Results: The median plasma HIV-1 RNA level was 2 copies/mL (interquartile range, 0.2-14 copies/mL). A longitudinal analysis of 31 elite controllers demonstrated 2-5-fold fluctuations in viremia in the majority of individuals; 6 had persistent levels below 1 copy/mL. Viremia correlated directly with HIV-1-specific neutralizing antibodies and Western blot reactivity but not with CD8(+) T cell responses. Absolute CD4(+) T cell decrease was more common among individuals with detectable viremia (P = .04).

Conclusions: Low-level viremia is present in the majority of elite controllers and is associated with higher HIV-1-specific antibody responses. Absolute CD4(+) T cell loss is more common among viremic individuals, suggesting that even very low-level viremia has negative consequences over time.

Figure 1

Plasma HIV-1 RNA virus load distribution among 83 elite controllers. The cut-off level of 0.2 copies/ml is represented by the dotted red line. The median is indicated with the black horizontal bar. The arithmetic mean HIV-1 RNA virus load for each subject is shown. Open circles represent patients with longitudinal HIV-1 RNA values; filled circles represent subjects with single time point virus load determinations. (B) Longitudinal HIV-1 RNA virus load in 31 elite controllers. Each line represents one study subject. Subjects with all HIV-1 RNA determinations below 1 copy/ml are shown with asterisks (n = 6).

Figure 2

Antibody responses to HIV-1 in elite controllers. Mean plasma virus load is plotted against (A) the number of virion proteins recognized by HIV antibodies, as detected by Western blot; (B) the mean neutralizing antibody ID80 titer; and (C) the breadth of neutralizing antibody response as measured by number of heterologous HIV Env-pseudoviruses neutralized by patient plasma. Statistical analysis is based on non-parametric Spearman test.

Figure 3

CD8+ T cell responses in elite controllers. (A) Correlation between plasma virus load and total magnitude of the CD8+ T cell response measured by Elispot and given in spot forming cells (SFC)/10⁶ PBMC; (B) Total breadth of the CD8+ T cell response given in number of peptides targeted throughout the entire proteome. Statistical analysis was based on the non-parametric Spearman test.

Figure 4

The change in absolute CD4+ T cells per/year was calculated by linear regression. (A) The value of the slope is represented on the y-axis for subjects with HIV-1 RNA < 1 copy/ml (black circles) and HIV-1 RNA > or equal to 1 copy/ml (grey triangles). The median change in CD4+ T cell count per/year is indicated with horizontal black bars. The p value of the difference between the groups was calculated using a two-tailed Mann Whitney U test. (B) The proportion of individuals with stable CD4+ T cells/mm³ per year (shown in white bars) and with significant CD4+ T cell loss cells/mm³ per year (shown in black bars) is compared between subjects with HIV-1 RNA < 1 copy/ml and HIV-1 RNA equal or > to 1 copy/ml.