Project Details
Description
PROJECT SUMMARY/ABSTRACT
Immunotherapeutic approaches which target the programmed cell death protein (PD)-1 co-inhibitory immune
checkpoint have revolutionized treatment of several types of advanced cancer. However, the susceptibility of
particular cell types remains highly variable and difficult to predict. We have found that both microglial cells
and astrocytes govern the activity of brain-infiltrating antiviral T-cells through upregulation of PD-L1 expression
in an effort to limit damaging encephalitic responses. Likewise, we have found that CD4(+) regulatory T-cells
(Tregs) limit viral encephalitis through restraining expansion and activity of CD8(+) cytotoxic T-lymphocytes.
While these anti-inflammatory responses within the brain are undoubtedly beneficial to the host, preventing
immune-mediated damage to this vital organ, establishment of a prolonged anti-inflammatory milieu may also
lead to deficiencies in viral clearance. Patients undergoing successful cART are viremically suppressed in both
plasma and CSF, but persisting HIV-1 reservoirs are believed to contribute to the inability to completely cure
infection. HIV-specific CD8(+) T-cell responses are critical in suppressing acute viral infection within the brain,
but ultimately fail in their ability to fully eradicate virus. It is currently unknown whether glia are viable cellular
targets for immune checkpoint blockade or Treg modulation. Studies proposed here are intended to fill this
critical void in our understanding of how the immunosuppressive, neuroprotective brain microenvironment
complicates complete clearance of viral infection. Building on our previous studies, we have developed an
innovative experimental murine model in which strong CD8(+) T-cell responses specific for immunodominant
HIV-1 Gag epitopes are generated within the brains of mice via heterologous prime-boost immunization with
recombinant adenovirus vectors expressing the p24 capsid protein (rAd5-p24), followed by a CNS boost using
Pr55Gag/Env virus-like particles (HIVLPs). This novel approach allows us to investigate the effects of
immunotherapy on viral clearance from the brain in a powerful, yet convenient and inexpensive small animal
model. The proposed studies will first determine whether glial cells restrain T-cell-mediated clearance of viral
infection through the PD-1: PD-L1 negative immune checkpoint. Experiments proposed in Aim #2 will go on to
determine whether loss or blockade of the PD-1: PD-L1 axis will facilitate anti-HIV-1 T-cell-mediated viral
clearance from the brain. Finally, in Specific Aim #3 we will determine whether modulation of Treg cell activity
in combination with immune checkpoint blockade will further stimulate anti-HIV-1 T-cells to promote viral
clearance. The potentially synergistic combination of immune checkpoint blockade and Treg modulation is
currently an area of intense investigation for treatment of a variety of immunosuppressive cancers. One of the
highest priorities in contemporary HIV-1 research is to identify strategies to effect a functional cure, in which
viral load is fully suppressed for extended periods in the absence of antiretroviral therapy. These studies will
determine whether immunotherapy can be used to reverse immune exhaustion against the viral brain reservoir.
Status | Finished |
---|---|
Effective start/end date | 2/1/03 → 12/31/23 |
Funding
- National Institute of Mental Health: $234,063.00
- National Institute of Mental Health: $346,500.00
- National Institute of Mental Health: $380,000.00
- National Institute of Mental Health: $346,500.00
- National Institute of Mental Health: $380,000.00
- National Institute of Mental Health: $248,068.00
- National Institute of Mental Health: $232,343.00
- National Institute of Mental Health: $355,039.00
- National Institute of Mental Health: $255,477.00
- National Institute of Mental Health: $385,000.00
- National Institute of Mental Health: $380,000.00
- National Institute of Mental Health: $385,000.00
- National Institute of Mental Health: $377,500.00
- National Institute of Mental Health: $106,220.00
- National Institute of Mental Health: $355,039.00
- National Institute of Mental Health: $385,000.00
- National Institute of Mental Health: $155,654.00
- National Institute of Mental Health: $380,000.00
- National Institute of Mental Health: $358,625.00
- National Institute of Mental Health: $358,625.00
- National Institute of Mental Health: $380,000.00
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