Intersection of HIV-1 Tat and SARS-CoV-2 S1 on neuroinflammation

Project Abstract
COVID-19, caused by the infection of SARS-CoV-2, is associated with significant long-term neurological
complications. Even mild COVID-19 can lead to such lasting neurological symptoms. Because only low or
undetectable levels of SARS-CoV-2 viral RNA are detected in the brain, neurological complications of COVID-
19 may not result from direct SARS-CoV-2 infection in the brain; Rather, released SARS-CoV-2 viral factors-
and/or virus-induced vascular dysfunction and aberrant neuroimmune responses may drive the development of
neurological complications. COVID-19 outcomes are further complicated by HIV-1; Advanced HIV disease
leads to delayed clearance of SARS-CoV-2, and people living with HIV-1 (PLWH) have an increased risk for
adverse outcomes and mortality of COVID-19. However, it is not known how HIV-1 and SARS-CoV-2 may
interact to affect the development of neurological complications. Our cell biology studies are aimed to
determine early and upstream mechanisms governing interactions between HIV-1 and SARS-CoV-2 that could
provide novel insights into the development of COVID-19-associated neurological complications in the general
population and PLWH. The objective here is to determine the extent to which and mechanisms by which
SARS-CoV-2 S1 and HIV-1 Tat intersect at endolysosomes to affect viral clearance and neuroinflammation.
Based on our own findings, we will test the hypothesis that SLC38A9 functions as a sensor on endolysosome
that mediates SARS-CoV-2 S1- and HIV-1 Tat-induced endolysosome de-acidification and dysfunction,
impaired viral clearance, and neuroinflammation. Our hypothesis will be tested with three Specific Aims. (1)
Determine the extent to which and mechanisms by which SARS-CoV-2 S1 and HIV-1 Tat induce
endolysosome de-acidification and dysfunction. (2) Determine the extent to which endolysosome de-
acidification induced by HIV-1 Tat affects SARS-CoV-2 clearance and the extent to which endolysosome de-
acidification induced by SARS-CoV-2 S1 affects Tat-mediated HIV-1 LTR transactivation. (3) Determine the
extent to which and mechanisms by which SARS-CoV-2 S1 and HIV-1 Tat affect astrocyte-dependent immune
responses and neuronal injury. We expect to identify SLC38A9 as a sensor protein that mediates SARS-CoV-2
S1- and HIV-1 Tat-induced endolysosome de-acidification and dysfunction. Such an effect not only impairs the
complete degradation of internalized SARS-CoV-2 but also lead to neuroinflammation and neuronal injury. The
proposed mechanistic studies will not only lead to novel insights into the development of COVID-19-associated
neurological complications in the general population and PLWH but also provide a rationale for developing
novel therapeutic strategies such as blocking SLC38A9 and acidifying endolysosomes. Thus, the proposed
research is responsive for this Urgent Award: COVID-19 Mental Health Research (PAR-22-113).

Grant Number: 1RF1MH134592-01
NIH Institute/Center: NIH
Principal Investigator: Xuesong Chen