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Mechanisms of HIV-1 inhibition by the lysosome modulating compound bafilomycin A1

Award Number: R16AI192040
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/11/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Mechanisms of HIV-1 inhibition by the lysosome modulating compound bafilomycin A1 - PROJECT SUMMARY Human immunodeficiency virus (HIV-1) is one of the leading causes of death and a health threat to millions worldwide. Approximately, 630,000 people died of AIDS-related causes and 1.3 million people were newly infected with HIV-1 in 2022. The HIV-1 genome encodes a small number of viral proteins, invariably establishing cooperative interactions between viral proteins and host cell machinery for productive virus replication. Despite the steady progress in our knowledge of HIV-1 biology, there is a significant gap in our understanding of the role of the lysosomal pathway in the HIV-1 life cycle. The major goal of this proposal is to understand the interplay between lysosomal functions and HIV-1 replication. Once known as recycling and degradation centers for dealing with cellular waste, lysosomes have emerged as a central hub for regulating cellular signaling and energy metabolism. There are conflicting reports on the effects of lysosome inhibitors in HIV-1 replication. To clarify the role of lysosomal processes in HIV-1 replication, we tested several lysosome modulating compounds for their ability to inhibit HIV-1. Our preliminary results showed that the vacuolar ATPase inhibitor bafilomycin A1, the lysosomotropic malarial drug chloroquine, and the cholesterol transport inhibitor U18666A inhibit HIV-1 replication. Among these compounds, bafilomycin A1 showed the most potent inhibition of HIV-1. Interestingly, bafilomycin A1 treatment resulted in several lysosomal alterations. The bafilomycin A1-induced changes include the accumulation of cholesterol in lysosomes and the alterations in lysosome positioning. Cholesterol plays a critical role throughout the HIV-1 replication cycle including viral entry, assembly, and budding. Lysosomes are crucial to maintaining cholesterol trafficking and homeostasis in cells. There is increasing evidence that suggests a complex interplay between lysosomal processes and HIV-1 replication. We hypothesize that bafilomycin A1 inhibits HIV-1 replication by impairing lysosomal cholesterol trafficking and lysosome positioning as well as by altering previously unknown cellular functions or mechanisms. To test our hypothesis, we propose the following specific aims. In Aim 1, we will determine the steps of the HIV-1 replication cycle that are modulated by bafilomycin A1. In Aim 2, we will determine the significance of lysosomal cholesterol transport and lysosome positioning in HIV- 1 replication. In Aim 3, we will Identify the cellular determinants of bafilomycin A1 effects on HIV-1. The studies proposed here will enhance our understanding of the virus–host interactions in HIV-1 biology. Our findings from this proposal will contribute to the identification of new therapeutic targets in the lysosomal pathway or in previous unknown cellular processes that can be exploited for combating HIV-1 infections and AIDS epidemic.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $145,500 )
2025	2025	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	8/11/2025	NEW	$145,500
														Subtotal = $145,500

Grand Total All Awards = $145,500

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Mechanisms of HIV-1 inhibition by the lysosome modulating compound bafilomycin A1

Award Number: R16AI192040

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/11/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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