Aaron Diamond AIDS Research Center, New York, New York, USA.
J Virol. 2013 Jun;87(11):6137-49. doi: 10.1128/JVI.00178-13. Epub 2013 Mar 20.
Most human immunodeficiency virus (HIV) transmissions are initiated with CCR5 (R5)-using viruses across mucosal surfaces, with the majority in regions where HIV type 1 (HIV-1) clade C predominates. Mucosally transmissible, highly replication competent, pathogenic R5 simian-human immunodeficiency viruses (SHIVs) encoding biologically relevant clade C envelopes are therefore needed as challenge viruses in vaccine efficacy studies with nonhuman primates. Here we describe the generation of three lineage-related subtype C SHIVs through four successive rapid transfers in rhesus macaques of SHIVC109F.PB4, a molecular clone expressing the soluble-CD4 (sCD4)-sensitive CCR5-tropic clade C envelope of a recently infected subject in Zambia. The viruses differed in their monkey passage histories and neutralization sensitivities but remained R5 tropic. SHIVC109P3 and SHIVC109P3N were recovered from a passage-3 rapid-progressor animal during chronic infection (24 weeks postinfection [wpi]) and at end-stage disease (34 wpi), respectively, and are classified as tier 1B strains, whereas SHIVC109P4 was recovered from a passage-4 normal-progressor macaque at 22 wpi and is a tier 2 virus, more difficult to neutralize. All three viruses were transmitted efficiently via intrarectal inoculation, reaching peak viral loads of 10(7) to 10(9) RNA copies/ml plasma and establishing viremia at various set points. Notably, one of seven (GC98) and two of six (CL31, FI08) SHIVC109P3- and SHIVC109P3N-infected macaques, respectively, progressed to AIDS, with neuropathologies observed in GC98 and FI08, as well as coreceptor switching in the latter. These findings support the use of these new SHIVC109F.PB4-derived viruses to study the immunopathology of HIV-1 clade C infection and to evaluate envelope-based AIDS vaccines in nonhuman primates.
大多数人类免疫缺陷病毒 (HIV) 传播是通过黏膜表面的 CCR5（R5）利用病毒引发的，其中大多数发生在 HIV 1 型（HIV-1）C 型优势流行的地区。因此，需要具有黏膜传播能力、高度复制能力、致病性 R5 猴免疫缺陷病毒（SHIV），并编码具有生物学相关性的 C 型包膜，作为在非人类灵长类动物中进行疫苗功效研究的挑战病毒。在这里，我们描述了通过在恒河猴中连续进行四次快速转移，生成三种谱系相关的 C 型 SHIV 的过程，这些 SHIV 来源于表达来自赞比亚最近感染个体的可溶性-CD4（sCD4）敏感的 CCR5 趋化性 C 型包膜的分子克隆 SHIVC109F.PB4。这些病毒在猴子传代史和中和敏感性方面存在差异，但仍为 R5 嗜性。SHIVC109P3 和 SHIVC109P3N 分别从慢性感染（感染后 24 周 [wpi]）和终末期疾病（34 wpi）的第 3 次快速进展者动物中回收，被归类为 1B 级株，而 SHIVC109P4 则从第 4 次快速进展者正常进展者猕猴中回收，在 22 wpi 时是 2 级病毒，更难以中和。所有三种病毒均通过直肠内接种有效传播，达到 10(7)至 10(9) RNA 拷贝/ml 血浆的峰值病毒载量，并在不同的设定点建立病毒血症。值得注意的是，在感染 SHIVC109P3 和 SHIVC109P3N 的 7 只猕猴中的 1 只（GC98）和 6 只猕猴中的 2 只（CL31、FI08）分别进展为艾滋病，在 GC98 和 FI08 中观察到神经病理学，以及后者的核心受体转换。这些发现支持使用这些新的 SHIVC109F.PB4 衍生病毒来研究 HIV-1 C 型感染的免疫病理学，并在非人类灵长类动物中评估基于包膜的艾滋病疫苗。
