Hypogonadism is a common comorbidity associated with HIV-1 that is more prevalent among infected individuals over the age of 45. The underlying mechanisms are unknown, but both combined antiretroviral therapeutics and HIV-1 proteins, such as trans-activator of transcription protein (Tat), dysregulate steroid-synthetic mechanisms including lipid storage/synthesis and mitochondrial function. Thus, Tat expression may accelerate age-related comorbidities partly by impairing endocrine function. Few studies exist of Tat-mediated behavioral deficits in aged animals and effects of endocrine status have not been investigated. Accordingly, we tested whether conditional Tat expression in aged (~ 1.5 years old), female, Tat-transgenic [Tat(+)] mice increases anxiety-like behavior, impairs cognition, and augments mechanical allodynia, when compared to age-matched controls that do not express Tat protein [Tat(−)]. We further tested whether aged mice that maintained their endocrine status (pre-estropausal) were more resilient to Tat/age-related comorbidities than peri- or post-estropausal mice. Tat and endocrine aging status exerted separate and interacting effects that influenced anxiety-like and cognitive behaviors. Peri- and post-estropausal mice exhibited greater anxiety-like behavior in the elevated plus-maze and impaired learning in the radial arm water maze compared to pre-estropausal mice. Irrespective of estropause status, Tat(+) mice demonstrated impaired learning, reduced grip strength, and mechanical allodynia compared to Tat(−) mice. Tat exposure reduced circulating estradiol in post-estropausal mice and increased the estradiol-to-testosterone ratio in pre-estropausal mice. Changes in circulating estradiol, testosterone, and progesterone correlated with grip strength. Thus, endocrine status is an important factor in age-related anxiety, cognition, neuromuscular function, and allodynia that can be accelerated by HIV-1 Tat protein.

性腺机能减退是一种与 HIV-1 相关的常见合并症，在 45 岁以上的感染者中更为普遍。其潜在机制尚不清楚，但联合抗逆转录病毒疗法和 HIV-1 蛋白，如转录蛋白的反式激活因子 (Tat )，类固醇合成机制失调，包括脂质储存/合成和线粒体功能。因此，Tat 表达可能部分通过损害内分泌功能来加速与年龄相关的合并症。很少有关于 Tat 介导的老年动物行为缺陷的研究，并且尚未研究内分泌状态的影响。因此，我们测试了老年（~ 1.5 岁）、雌性、Tat 转基因 [Tat(+)] 小鼠的条件性 Tat 表达是否会增加焦虑样行为、损害认知和增加机械异常性疼痛，与不表达 Tat 蛋白 [Tat(-)] 的年龄匹配对照相比。我们进一步测试了维持其内分泌状态（绝经前）的老年小鼠是否比绝经期前后的小鼠对 Tat/年龄相关的合并症更具弹性。Tat 和内分泌衰老状态分别产生影响焦虑样和认知行为的相互作用。与绝经前小鼠相比，绝经前和绝经后小鼠在高架十字迷宫中表现出更大的焦虑样行为，并且在桡臂水迷宫中表现出学习障碍。无论绝经状态如何，与 Tat(-) 小鼠相比，Tat(+) 小鼠表现出学习障碍、握力降低和机械异常性疼痛。Tat 暴露减少了绝经后小鼠的循环雌二醇，并增加了绝经前小鼠的雌二醇与睾酮的比率。循环雌二醇、睾酮和孕酮的变化与握力相关。因此，内分泌状态是与年龄相关的焦虑、认知、神经肌肉功能和异常性疼痛的一个重要因素，可以被 HIV-1 Tat 蛋白加速。