Correlation between SIV Tat evolution and AIDS progression in cerebrospinal fluid of morphine-dependent and control
Richard J Noel1, Ziomara Marrero-Otero, Rakesh Kumar
1AIDS Research Program, Ponce School of Medicine, Ponce, PR 00732, USA; Department of Biochemistry, Ponce School of Medicine, Ponce, PR 00732. rnoel@psm.edu
Abstract:
Morphine abuse has been associated with higher virus replication and accelerated disease progression in a non-human primate model of AIDS. In our previous report, we have shown that 50% of morphine-addicted macaques progress rapidly and that 2/3 of the rapid progressors exhibit severe neuropathogenesis. In this report, we examined the sequence evolution of the SIV Tat protein, known to participate in AIDS neuropathology, in the cerebrospinal fluid (CSF) of morphine-dependent and control macaques over the first 20 weeks of infection. The CSF SIV Tat evolution was found to be inversely related with disease progression, and the highly neuropathogenic inoculum clone sequence was the prevalent CSF form in rapid progressors. Divergence from the inoculum clone was significantly greater in both morphine-dependent normal progressors and control macaques than in the morphine-dependent rapid progressors. Furthermore, we also found evidence of a trend that morphine alters the type of mutation, resulting in an enhanced ratio of transitions to transversions (Ts:Tv). Rapid disease exacerbates this trend and appears to influence the distribution of nonsynonymous changes in the first exon of SIV tat, with a clear majority of mutations occurring in the C-terminal half of the protein where the known functionally important domains reside. Thus, morphine abuse may change the nature and extent of mutations that drive viral evolution.
Insights
Morphine abuse accelerates AIDS progression in macaques by altering Simian Immunodeficiency Virus (SIV) Tat protein evolution in cerebrospinal fluid. Rapid progressors showed less viral mutation, suggesting morphine impacts viral adaptation.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Morphine abuse is linked to increased Simian Immunodeficiency Virus (SIV) replication and faster disease progression in a non-human primate model of Acquired Immunodeficiency Syndrome (AIDS).
- Previous studies indicated that 50% of morphine-addicted macaques rapidly progress to AIDS, with two-thirds of these exhibiting severe neuropathogenesis.
Purpose of the Study:
- To investigate the sequence evolution of the SIV Tat protein in the cerebrospinal fluid (CSF) of morphine-dependent and control macaques during the initial 20 weeks of infection.
- To understand the role of SIV Tat evolution in AIDS neuropathology in the context of morphine dependence.
Main Methods:
- Analysis of SIV Tat protein sequence evolution in the CSF of morphine-dependent and control macaques.
- Comparison of viral evolution patterns between rapid progressors and normal progressors.
- Assessment of mutation types (transitions vs. transversions) and distribution of changes in the SIV tat gene.
Main Results:
- CSF SIV Tat evolution was inversely related to disease progression.
- The highly neuropathogenic inoculum clone sequence was prevalent in the CSF of rapid progressors.
- Divergence from the inoculum clone was significantly greater in morphine-dependent normal progressors and control macaques compared to morphine-dependent rapid progressors.
- Morphine appeared to alter mutation types, increasing the transitions to transversions ratio, an effect exacerbated by rapid disease progression.
Conclusions:
- Morphine abuse may alter the nature and extent of mutations driving SIV evolution, potentially influencing AIDS neuropathogenesis.
- The findings suggest a complex interplay between morphine, viral evolution, and disease progression in the central nervous system.
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