# 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

## TL;DR

This study examines how a common HIV treatment affects the immune system and brain in rhesus monkeys infected with SIV, showing early immune damage and potential biomarkers for CNS inflammation.

## Contribution

The study introduces extracellular free water volume fraction (FW-VF) as a novel biomarker for early CNS inflammation in SIV-infected rhesus macaques.

## Key findings

- Immune system compromise occurs within 7 days of SIV infection, with CD4/CD8 ratio dropping below 1 within 14 days.
- Extracellular FW-VF increases in parallel with immune decline, suggesting early CNS infiltration by SIV.
- The FTC+TDF+DTG regimen suppresses SIV replication and enhances immunity but fails to prevent viral rebound in some monkeys.

## Abstract

Understanding the specific timing of cART initiation, its effectiveness, and failures, as well as assessing how well the current cART regimens control viral replication and rebound, enhance immune function, and repair or curb early injury in the central nervous system (CNS), is crucial to improving the livelihood of people living with HIV.

Here, we use an animal model to provide controlled environments to understand how the bodies of Chinese-origin rhesus monkeys, both the immune system and CNS, respond to a combination of emtricitabine (EMTBL/FTC), dolutegravir (DTG), and tenofovir disoproxil fumarate (TDF) following the induction of Simian Immunodeficiency Virus (SIV). We injected the rhesus monkeys with a dose of SIVmac239 (i.e., TCID50—a 50-fold half-tissue culture infective dose) through brachial veins and conducted seven follow-ups at baseline, day 10, day 35, day 84, day 168, day 252, and day 336 for MRI imaging and blood/CSF assays of SIV copies and immunity levels.

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