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Phenotypic and mechanistic analysis of the in vivo HIV latent reservoir by single-cell technologies

Award Number: R01AI147777
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Combination antiretroviral therapy (ART) can suppress HIV replication and lead to decreased mortality in HIV-infected individuals. However, ART does not eliminate the latent HIV reservoir, so effective viral suppression requires lifelong ART administration. Therefore, developing a way to eliminate or achieve ART-free control of the reservoir is a top research priority. One challenge to accomplishing this is that we still have limited understanding of the phenotypic and functional properties of the latently-infected cells that persist in people living with HIV. One challenge to characterizing in vivo latently-infected cells is the inability to directly phenotype these cells, due to the lack of a universal biomarker distinguishing them from uninfected cells. As a result, the only way to directly phenotype latent cells has been to stimulate a bulk population of patient-derived cells ex vivo in order to induce expression of viral proteins by the latent cells. Although this allows identification and therefore phenotyping of the reactivated cells by FACS, the measured phenotypes are different from the original phenotypes of the latently-infected cells since ex vivo stimulation alters gene expression. Here, by applying a pseudotime-based bioinformatics approach called PP-SLIDE on paired sets of unstimulated and stimulated patient cells deep-phenotyped by high-dimensional single-cell analytical approaches (CyTOF, single-cell RNAseq), we infer the phenotypes of latently-infected cells in their original pre-stimulation state, and use this approach to chart the in vivo latent reservoir. In Aim 1, we will use PP-SLIDE on CyTOF-phenotyped cells to compare the latently-infected cells present in the blood and tissues of clinically-matched men and women. In Aim 2, we will characterize the extent to which markers identified in Aim 1, as well as markers identified from an unbiased approach implementing PP-SLIDE on cells analyzed by single-cell RNAseq, enrich for reservoir cells harboring HIV with genetically-intact replication-competent HIV, for these are the cells that are likely the most important to control or eliminate for ART-free viral control. In Aim 3, we will characterize the mechanisms that allow the latently-infected cells to persist, focusing on the role of antigen- and homeostasis-driven clonal expansion of CD4+ T cells. By combining cutting-edge single-cell analysis tools with high-dimensional data analysis methods to map the “atlas” of in vivo latent cells, our studies will provide an unprecedented definition of the features of reservoir cells that persist, reveal whether any reservoir cell traits associate with anatomy (blood vs. tissues) or biological sex (men vs. women), and inform on the mechanisms driving reservoir maintenance. This knowledge that will be important for designing targeted methods to achieve a universal HIV cure.


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: 2022 ( Subtotal = $843,541 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	7/28/2022	NON-COMPETING CONTINUATION	$843,541
														Subtotal = $843,541

Issue Date FY: 2021 ( Subtotal = $1,866,886 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	004	4	7/9/2021	NON-COMPETING CONTINUATION	$827,575
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	005	4	7/30/2021	NON-COMPETING CONTINUATION	$733,178
2021	2020	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	003	3	6/28/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$177,211
2021	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	2	3/16/2021	NON-COMPETING CONTINUATION	-$549,305
2021	2020	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	3	3/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$855,438
2021	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	1	6/28/2021	NEW	-$177,211
														Subtotal = $1,866,886

Issue Date FY: 2020 ( Subtotal = $549,305 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	2	7/16/2020	NON-COMPETING CONTINUATION	$549,305
														Subtotal = $549,305

Issue Date FY: 2019 ( Subtotal = $540,392 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	7/30/2019	NEW	$540,392
														Subtotal = $540,392

Grand Total All Awards = $3,800,124

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Phenotypic and mechanistic analysis of the in vivo HIV latent reservoir by single-cell technologies

Award Number: R01AI147777

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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