# Viral evolution in peripheral macrophages and brain during progression to AIDS

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $720,652

## Abstract

Project Summary:
An estimated 50% of HIV+ patients still exhibits central nervous system (CNS) viral infection, with 30% of
patients progressing to some form of HIV-associated neurocognitive disorder (HAND) despite combined anti-
retroviral therapy (cART). In the previously funded NIH R01 (NS063897-01A2) project – Viral evolution in
peripheral macrophages and brain during progression to AIDS – we used the SIV-infected macaque model of
neuroAIDS to show that in untreated animals SIV can enter the CNS multiple times, as early as 10 days post
infection, throughout the course of the disease. SIV subpopulations infecting the brain are evolutionarily related
to viral strains infecting myeloid cells in peripheral tissues, such as bone marrow and lung, which accumulate
in the meninges and choroid plexus in early infection, and in the perivascular space and SIV-associated
encephalitis (SIVE) lesions in late infection. Moreover, we found evidence that ongoing evolution in peripheral
tissues leads, late in infection, to the emergence of viral lineages adapted to enter and replicate in the CNS
microenvironment that may be linked to SIVE onset. However, the impact of cART on the timing and mode of
entry of virus into the CNS has yet to be analyzed, which is crucial to explain why HAND is present even in
virally suppressed patients. The present proposal for a competitive renewal seeks to extend the studies of the
original project by characterizing the evolutionary behavior of the virus leading up to CNS infection and
subsequent regulation of CNS-specific viral and host genes expression in the presence of cART. We seek to
evaluate, in particular, peripheral blood monocytes and monocyte/macrophage rich tissues as potential source
of CNS virus during cART, and the contribution of persisting CNS (and peripheral tissues) virus to viral
rebound after therapy interruption. Two specific aims are proposed: Specific Aim 1 – Determine the impact of
early cART on viral evolutionary patterns, as well as viral and host gene expression patterns, associated with
viral entry and replication in the CNS of SIV-infected rhesus macaques; Specific Aim 2 – Determine relative
contribution of SIV-infected macrophage subsets in the CNS and peripheral tissues to low-level viremia during
cART and viral rebound following cART interruption. The elucidation of viral evolutionary patterns and the
contribution of specific infected tissues/cell populations to CNS infection, in the presence or subsequent
absence of cART, would be highly beneficial to future studies designed to adjust current therapeutic strategies
toward the prevention and elimination of neuroAIDS, and formation of the CNS reservoir, which is a necessary
step for the development of an HIV cure.

## Key facts

- **NIH application ID:** 9948021
- **Project number:** 5R01NS063897-09
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** MARCO SALEMI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $720,652
- **Award type:** 5
- **Project period:** 2009-02-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948021

## Citation

> US National Institutes of Health, RePORTER application 9948021, Viral evolution in peripheral macrophages and brain during progression to AIDS (5R01NS063897-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9948021. Licensed CC0.

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