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. 2014 Jan 15;9(1):e85371.
doi: 10.1371/journal.pone.0085371. eCollection 2014.

HIV-1 specific antibody titers and neutralization among chronically infected patients on long-term suppressive antiretroviral therapy (ART): a cross-sectional study

Johannes S Gach  1 , Chad J Achenbach  2 , Veronika Chromikova  3 , Baiba Berzins  2 , Nina Lambert  2 , Gary Landucci  4 , Donald N Forthal  4 , Christine Katlama  5 , Barbara H Jung  6 , Robert L Murphy  2
Affiliations

HIV-1 specific antibody titers and neutralization among chronically infected patients on long-term suppressive antiretroviral therapy (ART): a cross-sectional study

Johannes S Gach et al. PLoS One. .

Abstract

The majority of potent and broadly neutralizing antibodies against HIV-1 have been isolated from untreated patients with acute or chronic infection. To assess the extent of HIV-1 specific antibody response and neutralization after many years of virologic suppression from potent combination ART, we examined antibody binding titers and neutralization of 51 patients with chronic HIV-1 infection on suppressive ART for at least three years. In this cross-sectional analysis, we found high antibody titers against gp120, gp41, and the membrane proximal external region (MPER) in 59%, 43%, and 27% of patients, respectively. We observed significantly higher endpoint binding titers for gp120 and gp41 for patients with >10 compared to ≤ 10 years of detectable HIV RNA. Additionally, we observed higher median gp120 and gp41 antibody titers in patients with HIV RNA <50 copies/mL for ≤ 5 years. 22% of patients neutralized a HIV-1 primary isolate (HIV-1(JR-FL)) and 8% neutralized a HIV-2/HIV-1 MPER chimera. Significantly greater HIV-1(JR-FL) neutralization was found among patients with >10 years of detectable HIV RNA (8/20 [40.0%] versus 3/31 [9.7%] for ≤ 10 years, p = 0.02) and a trend toward greater neutralization in patients with ≤ 5 years of HIV RNA <50 copies/mL (7/20 [35.0%] versus 4/31 [12.9%] for >5 years, p = 0.08). All patients with neutralizing activity mediated successful phagocytosis of VLPs by THP-1 cells after antibody opsonization. Our findings of highly specific antibodies to several structural epitopes of HIV-1 with antibody effector functions and neutralizing activity after long-term suppressive ART, suggest continuous antigenic stimulation and evolution of HIV-specific antibody response occurs before and after suppression with ART. These patients, particularly those with slower HIV progression and more time with detectable viremia prior to initiation of suppressive ART, are a promising population to identify and further study functional antibodies against HIV-1.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Serum mapping against different HIV-1 epitopes.
Sera of HIV-1 patients were tested for binding against different HIV-1 antigens including recombinant gp120JR-FL, gp41JR-FL, and p24 (A). To check for MPER specific antibodies, serum binding against three different MPER peptides was evaluated (B). To gain better knowledge about the binding epitopes on gp120, sera were tested against the gp120 variable loop truncation variants ΔV1/V2 and ΔV3 (C). Endpoint titers of the patient samples were determined by calculating the highest serum dilution that gives a reading above the blank including three standard deviations.
Figure 2
Figure 2. Soluble CD4 competition assay.
Assay was performed with three HIV-1 positive serum samples and respective mAb controls (1F7, 2G12, and 17b) in the absence (A and C) or presence (B and D) of soluble CD4. The EC50 values (half maximal binding at reciprocal serum dilution or antibody concentration) were calculated and compared for significant differences.
Figure 3
Figure 3. Phagocytosis assay.
Phagocytic score of samples tested at different antibody concentrations is indicated. All purified IgG fractions and the positive control HIVIG revealed Fc-mediated effector functions compared to the negative control IVIG. The cut off value of confidence interval for IVIG has a phagocytic score of 194.77. All samples greater than the cut off are positive with 99% confidence.
Figure 4
Figure 4. Comparison of HIV-1 specific antibody endpoint titers and time with detectable HIV RNA categorized as ≤10 and >10 years.
Scatter plots of antibody endpoint titers to recombinant gp120JR-FL, gp120JR-FL ΔV1/V2, gp120JR-FL ΔV3, and gp41 categorized by time with detectable HIV RNA show significantly higher titers for patients with >10 years of detectable viremia.
Figure 5
Figure 5. Comparison of HIV-1 specific antibody endpoint titers and time with HIV RNA<50 copies/mL categorized as ≤5 and >5 years.
Median binding titers against gp120JR-FL (A) and gp41JR-FL (B) were both lower in patients with >5 years of undetectable viremia.
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