Chronic Morphine Treatment and Antiretroviral Therapy Exacerbate HIV-Distal Sensory Peripheral Neuropathy and Induce Distinct Microbial Alterations in the HIV Tg26 Mouse Model.

Distal Sensory Peripheral Neuropathy (DSP) is a common complication in HIV-infected individuals, leading to chronic pain and reduced quality of life. Even with antiretroviral therapy (ART), DSP persists, often prompting the use of opioid analgesics, which can paradoxically worsen symptoms through opioid-induced microbial dysbiosis. This study employs the HIV Tg26 mouse model to investigate HIV-DSP development and assess gut microbiome changes in response to chronic morphine treatment and ART using 16S rRNA sequencing. Our results reveal that chronic morphine and ART exacerbate HIV-DSP in Tg26 mice, primarily through mechanical pain pathways. As the gut microbiome may be involved in chronic pain persistence, microbiome analysis indicated distinct bacterial community changes between WT and Tg26 mice as well as morphine- and ART-induced microbial changes in the Tg26 mice. This study reveals the Tg26 mouse model to be a relevant system that can help elucidate the pathogenic mechanisms of the opioid- and ART-induced exacerbation of HIV-associated pain. Our results shed light on the intricate interplay between HIV infection, ART, opioid use, and the gut microbiome in chronic pain development. They hold implications for understanding the mechanisms underlying HIV-associated pain and microbial dysbiosis, with potential for future research focused on prevention and treatment strategies.

Sex-specific neurogenic deficits and neurocognitive disorders in middle-aged HIV-1 Tg26 transgenic mice.

Varying degrees of cognitive deficits affect over half of all HIV-1 infected patients. Because of antiretroviral treatment (ART) regimens, the HIV-1 patient population is increasing in age. Very few epidemiological studies have focused on sex-specific differences in HIV-1-associated neurocognitive disorders (HAND). The purpose of this study is to examine any possible differences between male and female mice in the progression of cognitive dementia during persistent low-level HIV-1 protein exposure, mimicking the typical clinical setting in the post-ART era. Eight to ten-month old HIV-1 Tg26(+/-) transgenic mice were utilized to assess for specific learning and memory modalities. Initial physiological screening and fear conditioning assessments revealed that Tg26 mice exhibited no significant differences in general behavioral function, contextual fear conditioning, or cued fear conditioning responses when compared to their wild-type (WT) littermates, regardless of sex. However, Barnes maze testing revealed significantly impaired short and long-term spatial memory in males, while females had impaired spatial learning abilities and short-term spatial memory. The potential cellular mechanism underlying these sex-specific neurocognitive deficits was explored with hippocampal neurogenic analysis. Compared to WT mice, both male and female Tg26(+/-) mice had fewer quiescent neural stem cells and neuroblasts in their hippocampi. Male Tg26(+/-) mice had a more robust reduction of the quiescent neural stem cell pool than female Tg26(+/-) mice. While female WT mice had a higher number of neural progenitor cells than male WT mice, only female Tg26(+/-) mice exhibited a robust reduction in the number of neural progenitor cells. Altogether, these results suggest that middle-aged male and female Tg26(+/-) mice manifest differing impairments in cognitive functioning and hippocampal neurogenesis. This study emphasizes the importance of understanding sex related differences in HAND pathology, which would aid in designing more optimized therapeutic regimens for the treatment of HAND.

Adult neurogenic deficits in HIV-1 Tg26 transgenic mice.

BACKGROUND: Even in the antiretroviral treatment (ART) era, HIV-1-infected patients suffer from milder forms of HIV-1-associated neurocognitive disorders (HAND). While the viral proteins Tat and gp120 have been shown to individually inhibit the proliferation and neural differentiation of neural stem cells (NSCs), no studies have characterized the effects of all the combined viral proteins on adult neurogenesis. METHODS: The HIV-1 Tg26 transgenic mouse model was used due to its clinical relevance to ART-controlled HIV-1-infected patients who lack active viral replication but suffer from continuous stress from the viral proteins. Quantitative RT-PCR analysis was performed to validate the expression of viral genes in the neurogenic zones. In vitro stemness and lineage differentiation assays were performed in cultured NSCs from HIV-1 Tg26 transgenic mice and their wild-type littermates. Hippocampal neurogenic lineage analysis was performed to determine potential changes in initial and late differentiation of NSCs in the subgranular zone (SGZ). Finally, fluorescent retroviral labeling of mature dentate granule neurons was performed to assess dendritic complexity and dendritic spine densities. RESULTS: Varying copy numbers of partial gag (p17), tat (unspliced and spliced variants), env (gp120), vpu, and nef transcripts were detected in the neurogenic zones of Tg26 mice. Significantly fewer primary neurospheres and a higher percentage of larger sized primary neurospheres were generated from Tg26 NSCs than from littermated wild-type mouse NSCs, implying that Tg26 mouse NSCs exhibit deficits in initial differentiation. In vitro differentiation assays revealed that Tg26 mouse NSCs have reduced neuronal differentiation and increased astrocytic differentiation. In the SGZs of Tg26 mice, significantly higher amounts of quiescent NSCs, as well as significantly lower levels of active NSCs, proliferating neural progenitor cells, and neuroblasts, were observed. Finally, newborn mature granule neurons in the dentate gyri of Tg26 mice had deficiencies in dendritic arborization, dendritic length, and dendritic spine density. CONCLUSIONS: Both in vitro and in vivo studies demonstrate that HIV-1 Tg26 mice have early- and late-stage neurogenesis deficits, which could possibly contribute to the progression of HAND. Future therapies should be targeting this process to ameliorate, if not eliminate HAND-like symptoms in HIV-1-infected patients.