# Overcoming Host Restriction Factors to Develop Better Animal Models for HIV/AIDS

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $708,106

## Abstract

ABSTRACT
HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most non-human species.
Therefore, the most practical animal model of human AIDS consists of infection of macaques with SIVMAC or
chimeras derived from SIVMAC. However, the usefulness of these models is limited by the fact that HIV-1 and
SIVMAC are distinct viruses. Based on an understanding of species-specific restriction factors, we have
generated simian tropic HIV (stHIV) variants that are almost entirely derived from HIV-1 but can replicate in
pigtailed macaques. During the last funding cycle, we have used animal adaptation to develop stHIV isolates
that cause AIDS in pigtail macaques. Additionally, we have studied the effects of known restriction factors on
stHIV replication and unveiled the activity of novel, as yet unidentified, inhibitors that are induced by IFNα and
limit lentiviral replication in a species-specific manner in primary cells. The aims of this proposal are to further
develop stHIV by deriving novel viral clones that are consistently pathogenic in immunologically intact animals.
We will also derive stHIV variants based on HIV-1 strains circulating in humans and ultimately variants for
mucosal transmissions. To achieve these aims our studies will include a detailed characterization of viral RNA
splicing and functional characterization of in vivo-adapted viral proteins. Additionally, we will generate an stHIV
variant where 100% of the sequence is derived from HIV-1 strains by engineering an HIV-1 Vif proteins that
can counteract a major species-specific barrier to virus replication: macaque APOBEC3 proteins. Finally, we
aim to identify novel IFNα-induced inhibitors that limit stHIV replication in macaque cells and generate stHIV
variants that can overcome them. Our preliminary data suggest that these goals are feasible and will lead to
the successful development of stHIV variants with the desired properties, an advance that has the potential to
transform non-human primate models for HIV-1 drug and vaccine development.

## Key facts

- **NIH application ID:** 9956969
- **Project number:** 5R01AI078788-14
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Theodora Hatziioannou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $708,106
- **Award type:** 5
- **Project period:** 2008-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956969

## Citation

> US National Institutes of Health, RePORTER application 9956969, Overcoming Host Restriction Factors to Develop Better Animal Models for HIV/AIDS (5R01AI078788-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9956969. Licensed CC0.

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