Modulation and distribution of extracellular free water and tract deficits in rhesus macaques before and after the initiation of emtricitabine + tenofovir disoproxil fumarate + dotutegravir treatment

Our experimental data demonstrate that the immune system is compromised as early as 7 days after infection, with a rapid rise of <i>SIV</i> copies in <i>ml</i> and a significant drop of <i>CD4/CD8</i> ratio below ~1 within the first 14 days of infection. The alterations in the extracellular environments, manifesting as increased free water volume fraction (<i>FW-VF</i>) in MRI data and changes in the diffusivity properties of fiber tissues appearing in <i>FW</i>-corrected <i>FA</i> and <i>FW</i>-corrected <i>MD</i>, occur in parallel with an compromised immune system, suggesting that <i>SIV</i> enters the brain parenchyma in the early days of infection via a weakened brain defense system, causing inflammatory processes affecting the <i>CNS</i>. Our findings demonstrate that our current FTC+<i>TDF</i>+<i>DTG</i> regimen can enhance the immune system, suppress <i>SIV</i> replication, and slow damage to the intra- and extracellular environments. However, it is still ineffective in controlling viral rebound and experiences resistance in some rhesus monkeys, which may lead to further damage to the <i>CNS</i>. Our findings also provide the first SIVmac239-based evidence that extracellular <i>FW-VF</i> may be a more reliable biomarker of abnormal inflammatory processes, thus providing a better understanding of <i>SIV</i> disease progression than previously anticipated.