# Lentivirus Replication Strategy and Pathogenesis

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $461,675

## Abstract

Project Summary – Kim
Lentiviruses infect both activated/dividing CD4+ T cells and terminally differentiated/nondividing myeloid cells
during the course of their pathogenesis. As we previously reported, host SAMHD1 dNTPase restricts viral
reverse transcription step specifically in nondividing myeloid cells by depleting cellular dNTPs whereas HIV-2
and some SIVs counteract SAMHD1 by proteosomal degradation through their accessary proteins (e.g. Vpx).
In this renewal, we aim to reveal noble mechanistic strategies that lentiviruses employ for their myeloid cell
infection and rapid evolution/escape. First, lentiviruses encode an additional polypurine track (PPT) sequence,
called central PPT (cPPT), that locates at the center of the viral genome and is used for the additional initiation
of the (+) strand DNA synthesis. We previously reported that the concomitant initiation of the (+) strand DNA
synthesis from both PPT and cPPT compensates the kinetically delayed HIV-1 reverse transcription in
nondividing cells with limited dNTP pools by cutting the size of the (+) strand DNA synthesis from PPT by half.
In Aim 1, we will test our hypothesize that the additional cPPT of HIV-1 allows HIV-1 to overcome the
SAMHD1-mediated dNTP depletion and complete the (+) strand DNA synthesis even in nondividing myeloid
cells without accessary proteins counteracting SAMHD1. Second, we previously reported that the uniquely
tight dNTP binding affinity of HIV-1 RT mechanistically contributes to its catalytic capability to execute DNA
synthesis even at low dNTP concentrations, which enables HIV-1 to replicate in myeloid cells with very low
dNTP pools. Importantly, we also reported that this tight dNTP binding affinity enables HIV-1 RT to efficiently
extend mismatch primer post misinsertion, compared to other retroviral RTs, which is responsible for the highly
error prone DNA synthesis of HIV-1 RT. Based on these observations, we propose to solve the X-ray structure
of HIV-1 RT ternary complex with mismatch primer, which will elucidate the structural nature of the highly error
prone HIV-1 replication machinery which is important for viral evolution and escape. Third, while lethal
mutagenesis has been observed in other RNA viruses, it remains unclear that the lethal mutagenesis of HIV-1
and lentiviruses can be achieved by pharmacological means. Triphosphate (TP) of Molnupiravir, b-d-N4
hydroxycytidine (NHC) prodrug, is a ribonucleotide substrate and an RNA mutagen for RNA-dependent RNA
polymerases of multiple RNA viruses including SARS-CoV-2, which induces viral lethal mutagenesis. Excitingly,
our biochemical data demonstrate that host cellular RNA polymerase II also incorporates NHC-TP during RNA
synthesis, supporting the likelihood of the NHC-TP incorporation into cellular RNAs by host RNA polymerases.
Since lentivirus RNA genomes are synthesized by host DNA-dependent RNA polymerase II, we hypothesize
that NHC may be able to induce lethal mutagenesis in lentiviruses. Overal...

## Key facts

- **NIH application ID:** 10700321
- **Project number:** 2R01AI136581-06A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Baek Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $461,675
- **Award type:** 2
- **Project period:** 2018-01-19 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10700321

## Citation

> US National Institutes of Health, RePORTER application 10700321, Lentivirus Replication Strategy and Pathogenesis (2R01AI136581-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10700321. Licensed CC0.

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