The primary research focus of the Sharma laboratory is to study how pathogens like retroviruses regulate multiple steps of their replication cycle by interfacing with host cell biology. Ongoing research in our lab is characterizing the retrovirus-host interactions in the non-human primate models of HIV-1 infection. In particular, we study the replication of chimeric HIV/SIV viruses (SHIVs) in the macaque model of HIV-1 infection.
Description of the research projects
The host type-1 interferon (IFN) response is the first line of defense against viral infections. IFN upregulates expression of a number of IFN-stimulated genes (ISGs) and the proteins encoded by certain ISGs, referred to as restriction factors, potently block HIV-1 and SIV replication. HIV-1 infection in humans and SIV infection in macaques induces a robust IFN response in vivo. Despite the induction of the IFN response, HIV-1 and SIV replication persists in their respective natural hosts. This is because restriction factors are less active against wild-type viruses replicating in their natural host due to virally encoded evasion/escape mechanisms but act as potent barriers against cross-species transmission.
HIV-1 does not persistently infect macaques due to restriction by several macaque-specific restriction factors. To overcome these restrictions chimeric SIV/HIV-1 viruses (SHIVs), which encode the SIV antagonists of the known restriction factors and HIV-1 Envelope glycoprotein (Env) to permit viral entry, are used to infect macaques to model HIV-1 infection. Existing SHIV/macaque models typically employ SHIVs that encode HIV-1 variants isolated from chronic stages of infection that were further adapted by viral passage in cell culture (lab-adapted viruses). Moreover, these SHIVs require further adaptation in vitro in macaque cells and/or in vivo by serial macaque-passage. The adaptation of env sequences in macaques increases replication and pathogenicity of SHIVs but also leads to antigenic changes in Env that limit their utility for vaccine and therapeutic approaches. Thus, SHIVs encoding HIV-1 variants isolated directly from infected humans near the time of transmission without any adaptation (unadapted SHIVs) that maintain the antigenic properties of the transmitted variants are desired as challenge viruses for vaccine and therapeutic studies. However, most attempts at generating these SHIVs have failed as unadapted SHIVs replicate poorly in macaque cells and do not establish persistent infection.
The research in our lab is characterizing the viral and host determinants that restrict replication of unadapted SHIVs in macaque cells. Thus, our lab is tackling a fundamental weakness in the HIV-1/AIDS field that affects all downstream aspects of HIV-1 pathogenesis, vaccine, and prevention research by developing more relevant SHIV/macaque models of HIV-1 infection.
Projects in the Sharma lab are focused on answering the following questions:
- What are the viral and host factors that drive selection, adaptation, and pathogenicity of SHIVs in macaque cells?
- What is the molecular and mechanistic basis of adaptation of SHIVs to the macaque immune responses?
- Can the molecular mechanisms of SHIV replication in macaque cells be exploited to rationally engineer SHIVs for HIV-1 vaccine and prevention research?
- Can the genetic repertoire of non-human primate species be explored to identify novel innate immune factors that limit the cross-species transmission of lentiviruses?