# Determinants of retroviral replication in non-native hosts for modeling HIV infection

> **NIH NIH R01** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2024 · $746,254

## Abstract

PROJECT SUMMARY/ABSTRACT
 HIV-1 does not persistently infect macaques due to restriction by several species-specific host factors
necessitating the use of chimeric SIV/HIV-1 viruses (SHIVs) as surrogates to model HIV-1 infection in macaques.
Infection of macaques with SHIVs is the most preferred model system for vaccine and prevention studies
because SHIVs encode HIV-1 Envelope glycoprotein (Env) – the sole target of HIV-1 neutralizing antibodies.
Because the goal of vaccines is to prevent new infection, SHIVs based on circulating, transmitted forms of Env
variants are desired as challenge viruses. Existing SHIV/macaque models typically employ SHIVs that encode
HIV-1 Env from laboratory-adapted viruses, whose neutralization sensitivities differ from circulating Env variants.
This significantly limits the ability of the existing SHIV/macaque models to predict efficacious intervention(s) in
humans. Development of SHIVs encoding circulating Env variants has been extremely challenging, mainly
because such SHIVs replicate poorly in macaques, if at all. To increase their replication and pathogenicity, SHIVs
require extensive adaptation in vivo via serial passage in macaques. The process of serial macaque passage
results in accumulation of adaptive mutations in Env that facilitates robust replication.
 Serial passage is typically performed within the first two weeks of infection, a time during which macaques
mount a robust type-I interferon (IFN) response to infection. The host IFN response presents an early barrier
against infection because production of IFNs upregulates expression of several IFN-stimulated genes (ISGs),
which results in induction of an ‘antiviral state’. Proteins encoded by certain ISGs, referred to as restriction
factors, act as potent barriers against cross-species lentiviral transmission. Thus, macaque restriction factors
have the potential to block SHIV infection as they can antagonize HIV-1 Env. We recently identified macaque
interferon-induced transmembrane proteins (IFITMs) as ISGs that selectively restrict replication of SHIVs
encoding circulating HIV-1 Env variants.
 Our preliminary results suggest that unpassaged SHIV is potently inhibited by IFN in macaque lymphocytes.
In contrast, serial passaged SHIVs are resistant to IFN. We found that the loss to two N-linked glycans in Env
upon serial passage is sufficient to increase replication and confer resistance to IFN. This research proposal will:
1) characterize the adaptive changes in Env of serial passaged SHIVs that increase replication and IFN
resistance; 2) determine the role of N-linked Env glycans in SHIV infection of primary macaque immune cell
subsets ex vivo, and mucosal transmission and pathogenicity of SHIVs in vivo; and 3) evaluate the contribution
of five macaque IFITM homologs, which are upregulated by IFN, in restriction of unpassaged, IFN-sensitive
SHIVs. Upon completion, this study will provide mechanistic insights at the host-viral interface that drive
select...

## Key facts

- **NIH application ID:** 11088644
- **Project number:** 7R01AI172615-02
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Amit Sharma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $746,254
- **Award type:** 7
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11088644

## Citation

> US National Institutes of Health, RePORTER application 11088644, Determinants of retroviral replication in non-native hosts for modeling HIV infection (7R01AI172615-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11088644. Licensed CC0.

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