A Paradigm for Virus–Host Coevolution: Sequential Counter-Adaptations between Endogenous and Exogenous Retroviruses

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the host germline transmitted vertically from generation to generation. It is hypothesized that some ERVs are used by the host as restriction factors to block the infection of pathogenic retroviruses. Indeed, some ERVs efficiently interfere with the replication of related exogenous retroviruses. However, data suggesting that these mechanisms have influenced the coevolution of endogenous and/or exogenous retroviruses and their hosts have been more difficult to obtain. Sheep are an interesting model system to study retrovirus-host coevolution because of the coexistence in this animal species of two exogenous (i.e., horizontally transmitted) oncogenic retroviruses, Jaagsiekte sheep retrovirus and Enzootic nasal tumor virus, with highly related and biologically active endogenous retroviruses (enJSRVs). Here, we isolated and characterized the evolutionary history and molecular virology of 27 enJSRV proviruses. enJSRVs have been integrating in the host genome for the last 5–7 million y. Two enJSRV proviruses (enJS56A1 and enJSRV-20), which entered the host genome within the last 3 million y (before and during speciation within the genus Ovis), acquired in two temporally distinct events a defective Gag polyprotein resulting in a transdominant phenotype able to block late replication steps of related exogenous retroviruses. Both transdominant proviruses became fixed in the host genome before or around sheep domestication (∼ 9,000 y ago). Interestingly, a provirus escaping the transdominant enJSRVs has emerged very recently, most likely within the last 200 y. Thus, we determined sequentially distinct events during evolution that are indicative of an evolutionary antagonism between endogenous and exogenous retroviruses. This study strongly suggests that endogenization and selection of ERVs acting as restriction factors is a mechanism used by the host to fight retroviral infections.

内源性逆转录病毒（endogenous retroviruses, ERVs）是宿主生殖系曾发生的古代逆转录病毒感染的遗迹，可通过垂直传播在代际间传递。有假说提出，部分ERV可被宿主用作限制因子，以阻断致病性逆转录病毒的感染。事实上，部分ERV可有效干扰相关外源性逆转录病毒的复制。然而，能够证明此类机制影响了内源性和/或外源性逆转录病毒及其宿主共进化的相关数据，却较难获取。

绵羊是研究逆转录病毒-宿主共进化的极具价值的模型系统，原因在于该物种中共存两种外源性（即水平传播）致癌性逆转录病毒——绵羊肺腺瘤逆转录病毒（Jaagsiekte sheep retrovirus）与地方性鼻肿瘤病毒（Enzootic nasal tumor virus），且它们与活性极强的内源性绵羊肺腺瘤逆转录病毒（enJSRVs）具有高度同源性并具备生物学活性。

本研究共分离并鉴定了27株enJSRV前病毒的进化历史与分子病毒学特征。enJSRV已整合入宿主基因组达500万至700万年之久。其中两株enJSRV前病毒（enJS56A1与enJSRV-20）是在距今300万年以内（即绵羊属物种形成之前及物种形成过程中）整合进入宿主基因组的，它们先后在两次时间差异化的事件中获得了缺陷型Gag多聚蛋白，由此产生了可阻断相关外源性逆转录病毒晚期复制步骤的显性负表型。这两株显性负调控前病毒均在绵羊驯化前后（约9000年前）在宿主基因组中被固定下来。

值得注意的是，一种可逃逸此类显性负调控enJSRVs的前病毒在极近的时期出现，大概率是在距今200年以内。综上，本研究明确了进化过程中先后发生的多类事件，这些事件均指向内源性与外源性逆转录病毒之间的进化拮抗关系。本研究有力证实，作为限制因子的ERV的内源性整合与选择，是宿主对抗逆转录病毒感染的一种演化策略。