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. 2015 Nov 18;90(3):1321-32.
doi: 10.1128/JVI.02454-15. Print 2016 Feb 1.

Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs

Diane L Bolton  1 , Amarendra Pegu  2 , Keyun Wang  2 , Kathleen McGinnis  2 , Martha Nason  3 , Kathryn Foulds  2 , Valerie Letukas  2 , Stephen D Schmidt  2 , Xuejun Chen  2 , John Paul Todd  2 , Jeffrey D Lifson  4 , Srinivas Rao  2 , Nelson L Michael  5 , Merlin L Robb  6 , John R Mascola  2 , Richard A Koup  2
Affiliations

Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs

Diane L Bolton et al. J Virol. .

Abstract

Combination antiretroviral therapy (cART) administered shortly after human immunodeficiency virus type 1 (HIV-1) infection can suppress viremia and limit seeding of the viral reservoir, but lifelong treatment is required for the majority of patients. Highly potent broadly neutralizing HIV-1 monoclonal antibodies (MAbs) can reduce plasma viremia when administered during chronic HIV-1 infection, but the therapeutic potential of these antibodies during acute infection is unknown. We tested the ability of HIV-1 envelope glycoprotein-specific broadly neutralizing MAbs to suppress acute simian-human immunodeficiency virus (SHIV) replication in rhesus macaques. Four groups of macaques were infected with SHIV-SF162P3 and received (i) the CD4-binding-site MAb VRC01; (ii) a combination of a more potent clonal relative of VRC01 (VRC07-523) and a V3 glycan-dependent MAb (PGT121); (iii) daily cART, all on day 10, just prior to expected peak plasma viremia; or (iv) no treatment. Daily cART was initiated 11 days after MAb administration and was continued for 13 weeks in all treated animals. Over a period of 11 days after a single administration, MAb treatment significantly reduced peak viremia, accelerated the decay slope, and reduced total viral replication compared to untreated controls. Proviral DNA in lymph node CD4 T cells was also diminished after treatment with the dual MAb. These data demonstrate the virological effect of potent MAbs and support future clinical trials that investigate HIV-1-neutralizing MAbs as adjunctive therapy with cART during acute HIV-1 infection.

Importance: Treatment of chronic HIV-1 infection with potent broadly neutralizing HIV-1 MAbs has been shown to significantly reduce plasma viremia. However, the antiviral effect of MAb treatment during acute HIV-1 infection is unknown. Here, we demonstrate that MAbs targeting the HIV-1 envelope glycoprotein both suppress acute SHIV plasma viremia and limit CD4 T cell-associated viral DNA. These findings provide support for clinical trials of MAbs as adjunctive therapy with antiretroviral therapy during acute HIV-1 infection.

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Figures

FIG 1
FIG 1
Experimental treatment schema and VRC01, VRC07-523, and PGT121 antibody levels in plasma. (A) Twenty-four rhesus macaques were challenged intravenously with SHIV-SF162P3 and treated on day 10 with either daily ART (n = 6), a single infusion of MAb VRC01 (n = 6), or a single infusion of two MAbs together (VRC07-523 and PGT121). Six control animals remained untreated. For those animals given MAb treatment, daily ART was initiated 21 days after infection. (B) Antibody levels in plasma of rhesus macaques after a single infusion of MAb VRC01 or a combination of MAbs VRC07-523 and PGT121 infused at 10 days post-SHIV challenge. Each line represents data for one animal, and error bars represent the 95% confidence intervals. The shaded areas correspond to the duration of daily ART treatment. The red dotted lines indicate the in vitro neutralization IC80s (micrograms per milliliter) against the SHIV-SF162P3 challenge stock. The black dotted lines indicate the limit of detection of plasma antibody levels. (C) Geometric mean antibody levels in plasma for the MAb treatment groups (n = 6 per group). The arrow indicates the time of antibody injection, and the shaded area represents the period of daily ART. (D) Measured plasma neutralization titers against the SHIV-SF162P3 challenge stock. Geometric mean plasma neutralization ID80 titers are shown for the MAb treatment groups (n = 6 per group) (solid red and blue lines) at the indicated times following infection. Predicted ID80 values calculated from the plasma MAb concentrations shown in panel B are overlaid as dotted lines. The predicted ID80 values for the group that received VRC07-523 and PGT121 were a sum of the predicted ID80 values for each MAb. (E) Anti-antibody responses after SHIV challenge. The geometric mean endpoint titer values for plasma reactivity to VRC01, VRC07-523, and PGT121 in infused animals were determined by using an ELISA-based approach. The error bars represent the 95% confidence intervals; the dotted line indicates the limit of detection for the assay. Arrows indicate the timing of MAb infusion.
FIG 2
FIG 2
SHIV loads in plasma. (A) Plasma viral loads in rhesus macaques that were left untreated (control) or treated as described in the legend of Fig. 1. Each animal is represented by a distinct line. The black arrows indicate the day of MAb administration, and the shaded areas correspond to the duration of daily ART treatment. (B) Geometric mean plasma viral loads (pVL) for the untreated group and the 3 treatment groups (n = 6 per group). The error bars represent the 95% confidence intervals at each time point. (C to E) Peak viremia (C), viremia area under the curve for days 10 to 21 (D), and slope of viremia decay from the peak to day 21 (E) for each animal by treatment group, with lines at the top indicating significant differences relative to untreated control animals (*, P < 0.05; **P < 0.01 [as determined by an unpaired two-tailed t test on log-transformed data]).
FIG 3
FIG 3
Anti-SHIV-specific adaptive immune responses elicited by SHIV-162P3 challenge. (A and B) Geometric mean endpoint titer values for plasma reactivity to SIV gag (anti-SIV gag) (A) or HIV-1 SF162 gp120 (anti-HIV Env) (B) were determined by an ELISA for each group (n = 6) at the indicated days postinfection. Error bars represent the 95% confidence intervals; the dotted lines indicate the limit of detection for the assay. (C and D) Numbers of antigen-specific T cells were measured in PBMC by in vitro stimulation with HIV-1 EnvB (C) and SIV Gag (D) peptide pools, followed by FACS detection of intracellular IFN-γ, IL-2, and TNF-α. Numbers of responding cells were summed across the cytokines within CD8 (top) and CD4 (bottom) T cell subsets and are reported as a percentage of each subset. Treatment groups were compared to untreated animals at each time point, and significant differences are indicated (as determined by a t test [+] or Wilcoxon rank test [#]). Gray bars depict the interquartile ranges. (E) Intracellular Th1 cytokine expression profile of HIV-1 Gag-specific CD4 (top) and CD8 (bottom) T cells measured in from PBMC as described above for panel D. The proportions of cells that express Boolean combinations of IL-2, IFN-γ, and TNF-α are depicted as a pie chart, averaged across each treatment group at the indicated weeks following SHIV infection. Significant differences (P < 0.05) between groups are indicated by lines above each row. (F) Fractions of the Gag-specific CD4 (top) and CD8 (bottom) T cell responses comprised of the indicated cytokines are shown for each animal.
FIG 4
FIG 4
Cell-associated viral DNA in CD4 T cells. (A) Flow cytometric staining and gating strategy used to sort CD4 T cell populations for cell-associated viral DNA by FACS analysis. Total, naive, central memory (CM), or T follicular helper (Tfh) CD4 T cells were identified with fluorescent antibodies by the indicated gates. (B and C) SIV gag DNA from lymph node mononuclear cells (day 18) (B) and PBMC (days 14 and 18 pooled) (C) following SHIV infection was measured by qPCR. Each animal is depicted by a unique symbol; open symbols represent undetected DNA. The geometric means and 95% confidence intervals are shown for each treatment group. Overall significant differences were determined by ANOVA and, if significant, followed by t test comparisons between individual groups, as indicated (*, P < 0.05). (D) Longitudinal cell-associated SIV gag DNA in lymph node (top) and PBMC (bottom). The dotted line indicates ART initiation in the MAb treatment groups; the dashed lines indicate MAb infusion or ART at day 10. Data points are nudged slightly along the x axis to prevent overlap.
FIG 5
FIG 5
SHIV loads in plasma following cART interruption. Shown is plasma viremia in treated rhesus macaques during the period after cessation of daily cART (day 112 postinfection). Treatment groups are indicated at the top. Line formatting for each animal is consistent with that described in the legend of Fig. 2A.
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