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Principal Investigator: Felipe Diaz-Griffero
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $528,657
Funding agency: National Institute of Allergy and Infectious Diseases
Despite of a great deal of effort by public and private institutions, we don't have a prophylactic vaccine
against HIV-1 or an eradication protocol to treat infected patients. Recently, laboratories all over the word have
reported an increase in the transmission of HIV-1 strains that are resistant to one or more components of the
antiretroviral (ART) cocktail. In order to find novel therapeutic targets, basic understanding of HIV-1 replication
is urgently needed. Early steps in the replication of human immunodeficiency virus (HIV-1) involve delivery of
the viral core into the cytoplasm of the host cell. The viral core is a conical structure composed of ~1500
monomers of the HIV-1 capsid protein, which houses the viral RNA genome. We studied HIV-1 uncoating,
reverse transcription, and nuclear import by exploiting the ability of different cellular factors to affect early
events of HIV-1 replication. “Uncoating” is the dissociation of monomeric capsids from the HIV-1 core. Proteins
and drugs that destabilize the HIV-1 core and accelerate uncoating in the cytosol prevent reverse transcription.
Consistent with the concept that reverse transcription is linked to uncoating, we have shown that genetic or
pharmacologic inhibition of reverse transcription prevents uncoating. During the previous funding period, we
found that cellular proteins that stabilize the HIV-1 core allow reverse transcription but not nuclear import.
These results support a model in which the HIV-1 core is a “container” that holds the elements required for
reverse transcription. Opening the “container” disrupts reverse transcription. Keeping the “container” closed
allows completion of reverse transcription but prevents nuclear import. These results suggest that core stability
is tightly modulated during infection. Cyclophilin A (CypA) accounts for up to 0.4% of cellular protein and
interacts with the HIV-1 capsid and core. However, the role that CypA plays in HIV-1 infection is not known.
Our preliminary data indicate that CypA depletion inhibits HIV-1 infection in primary CD4+ T cells by 100 fold,
supporting the use of this model to understand the role of CypA in HIV-1 infection. We hypothesize that CypA
functions as a central modulator of HIV-1 infection by controlling interactions between cellular factors
and the HIV-1 core during the early steps of HIV-1 infection. With the expert support of Dr. Hultquist, Dr.
Campbell, Dr. Luban and Dr. KewalRamani, the following specific aims will test this hypothesis. Aim 1 will
determine the mechanisms through which CypA modulates HIV-1 infection in human primary CD4+ T cells. Aim
2 will determine the effects of CypA on the HIV-1 capsid in the nucleus. Aim 3 will examine the roles of other
cyclophilins in HIV-1 replication. Aim 4 will determine the effects of the Nup358 cyclophilin domain (Cyp358) on
HIV-1 nuclear import. This proposal will address two important questions on the HIV-1 field: 1) The role of
CypA in HIV-1 replication, which has been elusive for 25 years, and 2) the role of nuclear capsid in HIV-1
productive infection.
Terms: <AIDS><AIDS Virus><Acceleration><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Affect><Anti-Retroviral Agents><Binding><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Capsid><Capsid Proteins><Cell Body><Cell Nucleus><Cells><Coat Proteins><Complex><Cyclophilin A><Cyclophilins><Cyclosporin-Binding Proteins><Cytoplasm><Cytosol><Data><Dissociation><Drugs><Elements><Event><Funding><Genetic><Genome><HIV><Human><Human Immunodeficiency Viruses><Infection><Infection Control><Institution><LAV-HTLV-III><Laboratories><Life Cycle><Life Cycle Stages><Link><Lymphadenopathy-Associated Virus><Medication><Modeling><Modern Man><Molecular Interaction><Nuclear><Nuclear Import><Nuclear Pore Complex Proteins><Nucleoporin Gene><Nucleoporins><Nucleus><Nup Protein><Patients><Pharmaceutical Preparations><Play><Preventative vaccine><Preventive vaccine><Privatization><Productivity><Prophylactic vaccine><Proteins><Protocol><Protocols documentation><Reporting><Reverse Transcription><Reverse Transcription Inhibition><Role><Structure><T4 Cells><T4 Lymphocytes><Testing><Transmission><Viral><Viral Coat Proteins><Viral Diseases><Viral Outer Coat Protein><Virus Diseases><Virus Replication><Virus-HIV><anti-retroviral><drug/agent><life course><monomer><mutant><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pharmacologic><prevent><preventing><recruit><resistance strain><resistant strain><social role><therapeutic target><therapeutically effective><transmission process><viral RNA><viral infection><viral multiplication><viral replication><virus RNA><virus core><virus infection><virus multiplication><virus-induced disease>