A thorough understanding of the role of human immunodeficiency virus (HIV) intrahost evolution in AIDS pathogenesis has been limited by the need for longitudinally sampled viral sequences from the vast target space within the host, which are often difficult to obtain from human subjects. CD8⁺ lymphocyte-depleted macaques infected with simian immunodeficiency virus (SIV) provide an increasingly utilized model of pathogenesis due to clinical manifestations similar to those for HIV-1 infection and AIDS progression, as well as a characteristic rapid disease onset. Comparison of this model with SIV-infected non-CD8⁺ lymphocyte-depleted macaques also provides a unique opportunity to investigate the role of CD8⁺ cells in viral evolution and population dynamics throughout the duration of infection. Using several different phylogenetic methods, we analyzed viral gp120 sequences obtained from extensive longitudinal sampling of multiple tissues and enriched leukocyte populations from SIVmac251-infected macaques with or without CD8⁺ lymphocyte depletion. SIV evolutionary and selection patterns in non-CD8⁺ lymphocyte-depleted animals were characterized by sequential population turnover and continual viral adaptation, a scenario readily comparable to intrahost evolutionary patterns during human HIV infection in the absence of antiretroviral therapy. Alternatively, animals that were depleted of CD8⁺ lymphocytes exhibited greater variation in population dynamics among tissues and cell populations over the course of infection. Our findings highlight the major role for CD8⁺ lymphocytes in prolonging disease progression through continual control of SIV subpopulations from various anatomical compartments and the potential for greater independent viral evolutionary behavior among these compartments in response to immune modulation.

IMPORTANCE Although developments in combined antiretroviral therapy (cART) strategies have successfully prolonged the time to AIDS onset in HIV-1-infected individuals, a functional cure has yet to be found. Improvement of drug interventions for a virus that is able to infect a wide range of tissues and cell types requires a thorough understanding of viral adaptation and infection dynamics within this target milieu. Although it is difficult to accomplish in the human host, longitudinal sampling of multiple anatomical locations is readily accessible in the SIV-infected macaque models of neuro-AIDS. The significance of our research is in identifying the impact of immune modulation, through differing immune selective pressures, on viral evolutionary behavior in a multitude of anatomical compartments. The results provide evidence encouraging the development of a more sophisticated model that considers a network of individual viral subpopulations within the host, with differing infection and transmission dynamics, which is necessary for more effective treatment strategies.

对人类免疫缺陷病毒（HIV）宿主内部进化在AIDS发病机理中的作用的透彻了解已经受到了从宿主体内广泛的靶标空间中纵向采样病毒序列的需求的限制，而这通常很难从人类受试者中获得。猿猴免疫缺陷病毒（SIV）感染的CD8 ⁺淋巴细胞减少型猕猴由于其临床表现类似于HIV-1感染和AIDS的临床表现，并具有快速发病的特点，因此提供了越来越多的发病机理模型。将该模型与SIV感染的非CD8 ⁺淋巴细胞减少的猕猴进行比较，也提供了一个独特的机会来研究CD8 ⁺的作用在整个感染过程中病毒进化和种群动态中的细胞。使用几种不同的系统发育方法，我们分析了病毒gp120序列，该序列是从多个组织的广泛纵向采样以及SIVmac251感染的猕猴（有或没有CD8 ⁺淋巴细胞耗竭）的富集白细胞群体中获得的。非CD8 ⁺淋巴细胞减少的动物中SIV的进化和选择模式的特征是连续的种群更新和持续的病毒适应，这种情况很容易与没有抗逆转录病毒疗法的人类HIV感染期间的宿主内进化模式相比。或者，耗尽CD8 ^+的动物在感染过程中，淋巴细胞在组织和细胞群体之间的群体动态中表现出更大的变化。我们的发现强调了CD8 ⁺淋巴细胞通过持续控制来自各个解剖区室的SIV亚群在延长疾病进展中的主要作用，以及这些区室对免疫调节做出更大独立病毒进化行为的潜力。

重要性尽管联合抗逆转录病毒疗法（cART）策略的发展已成功延长了HIV-1感染者中AIDS发作的时间，但尚未找到功能性的治疗方法。对于能够感染多种组织和细胞类型的病毒，改善药物干预措施需要彻底了解目标环境中的病毒适应性和感染动态。尽管在人体宿主中很难完成，但在感染了SIV的猕猴的神经艾滋病模型中，很容易获得多个解剖位置的纵向采样。我们研究的意义在于通过不同的免疫选择压力来识别免疫调节对多种解剖区隔中病毒进化行为的影响。