Bolton Diane L, Pegu Amarendra, Wang Keyun, McGinnis Kathleen, Nason Martha, Foulds Kathryn, Letukas Valerie, Schmidt Stephen D, Chen Xuejun, Todd John Paul, Lifson Jeffrey D, Rao Srinivas, Michael Nelson L, Robb Merlin L, Mascola John R, Koup Richard A
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA, and Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J Virol. 2015 Nov 18;90(3):1321-32. doi: 10.1128/JVI.02454-15. Print 2016 Feb 1.
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.
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.
1型人类免疫缺陷病毒（HIV-1）感染后不久给予联合抗逆转录病毒疗法（cART）可抑制病毒血症并限制病毒储存库的播种，但大多数患者需要终身治疗。高效广谱中和HIV-1单克隆抗体（MAb）在慢性HIV-1感染期间给药时可降低血浆病毒血症，但这些抗体在急性感染期间的治疗潜力尚不清楚。我们测试了HIV-1包膜糖蛋白特异性广谱中和MAb抑制恒河猴急性猿猴-人类免疫缺陷病毒（SHIV）复制的能力。四组猕猴感染了SHIV-SF162P3，并在第10天，即预期血浆病毒血症达到峰值之前接受了以下治疗：（i）CD4结合位点MAb VRC01；（ii）VRC01的一种更强效克隆变体（VRC07-523）和一种V3聚糖依赖性MAb（PGT121）的组合；（iii）每日cART；或（iv）不治疗。在给予MAb后11天开始每日cART，并在所有接受治疗的动物中持续13周。在单次给药后的11天内，与未治疗的对照组相比，MAb治疗显著降低了峰值病毒血症，加快了衰减斜率，并减少了总病毒复制。用双MAb治疗后，淋巴结CD4 T细胞中的前病毒DNA也减少了。这些数据证明了强效MAb的病毒学效应，并支持未来的临床试验，该试验将研究HIV-1中和MAb作为急性HIV-1感染期间cART辅助治疗的效果。
已证明用高效广谱中和HIV-1 MAb治疗慢性HIV-1感染可显著降低血浆病毒血症。然而，MAb治疗在急性HIV-感染期间的抗病毒作用尚不清楚。在这里，我们证明靶向HIV-1包膜糖蛋白的MAb既能抑制急性SHIV血浆病毒血症，又能限制CD4 T细胞相关的病毒DNA。这些发现为MAb作为急性HIV-1感染期间抗逆转录病毒疗法辅助治疗的临床试验提供了支持。
