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. 2019 Sep 30;93(20):e01077-19.
doi: 10.1128/JVI.01077-19. Print 2019 Oct 15.

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Yanling Wu #  1 , Jing Xue #  2 , Chunyu Wang  3 , Wei Li  4 , Lili Wang  3 , Weizao Chen  4 , Ponraj Prabakaran  5 , Desheng Kong  6 , Yujia Jin  3 , Dan Hu  3 , Yulu Wang  3 , Cheng Lei  3 , Diao Yu  3   7 , Chao Tu  7 , Ariola Bardhi  8   9 , Igor Sidorov  10 , Liying Ma  6 , Harris Goldstein  8   9 , Chuan Qin  2 , Lu Lu  3 , Shibo Jiang  3 , Dimiter S Dimitrov  4 , Tianlei Ying  1
Affiliations

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Yanling Wu et al. J Virol. .

Abstract

Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections.IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

Keywords: HIV-1; acute SHIV infection; broadly neutralizing antibodies.

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Figures

FIG 1
FIG 1
Suppression of plasma viremia after LSEVh-LS-F monotherapy in rhesus macaques chronically infected with SHIVSF162P3. Four macaques were inoculated with 1,000 TCID50 of SHIVSF162P3 and treated with LSEVh-LS-F (orange) or PBS (purple) on day 106 after infection. Plasma viral RNA was measured by the RT-qPCR assay.
FIG 2
FIG 2
Therapeutic efficacy of LSEVh-LS-F in rhesus macaques during SHIV acute infection. (A) Experimental design of therapy experiment during the acute phase of SHIV infection. Eight rhesus macaques were challenged intravenously with SHIVSF162P3 (1,000 TCID50) and treated with 10 mg/kg of LSEVh-LS-F or PBS (n = 4 per group) on days 7, 9, 16, and 18. Plasma was collected at different time points (days 0, 7, 9, 16, 18, 21, 25, and 30). The orange arrows indicate the day of LESVh-LS-F administration. (B) Comparison of normalized plasma viral load (pVL) change at each time point, as determined by an unpaired two-tailed t test on log-transformed data. The error bars represent SDs for each group. (C) Data fitting for untreated macaques with mathematical models. Four constants were defined by data fitting: ku, k, T, and SHIV0. Initial SHIV0 load values and time of the viremia peak are shown by dashed lines. (D) Data fitting for treated macaques. Five constants were defined for each macaque by data fittings: kt, k7, k9, k16, and k18. SHIV0 was fixed as the average value for untreated macaques.
FIG 3
FIG 3
Pharmacokinetics of LSEVh-LS-F in uninfected macaques. A single intravenous administration of LSEVh-LS-F (10 mg/kg) was given to uninfected rhesus macaques (n = 3). Plasma levels of LSEVh-LS-F were measured by ELISA using gp140sc as the antigen and quantified by a standard curve drawn with known LSEVh-LS-F concentrations. The error bars indicate SDs.
FIG 4
FIG 4
Plasma viral loads (black) and LSEVh-LS-F concentrations (orange) in two chronically (A) or four acutely (B) SHIV-infected rhesus macaques.
FIG 5
FIG 5
Host humoral responses to bnAb and SHIV challenge. The plasma reactivities to LSEVh-LS-F in uninfected (A) and SHIV-infected (B) animals were determined by using an ELISA-based approach. Arrows indicate the timing of LSEVh-LS-F infusion. (C) Endogenous antibodies against SHIV gp140 in macaques C3 and C4. The anti-SHIV antibodies in serum were measured by ELISA, and peroxidase-labeled anti-macaque IgG was used as the detecting antibody.
FIG 6
FIG 6
Representative mechanism for the decay of infused bnAbs in different SHIV infection groups: uninfected (A) and chronically (B) and acutely (C) infected macaques. The SHIV particles are shown in blue. The infused bnAbs are shown in orange, and endogenous SHIV-specific antibodies are shown in green.
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