DEFECTIVE HIV-1 PROVIRAL ABUNDANCE AND THEIR IMMUNE EFFECTS IN CHILDREN AND ADOLESCENTS LIVING WITH PERINAT…

Assistance award details

Assistance award identifier

ASST_NON_R37AI198053_075

FAIN

R37AI198053

Recipient

THE JOHNS HOPKINS UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$779,616

Period

Apr 10, 2026 – Mar 31, 2031

Fiscal year

2026

Place of performance state

MD

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

DEFECTIVE HIV-1 PROVIRAL ABUNDANCE AND THEIR IMMUNE EFFECTS IN CHILDREN AND ADOLESCENTS LIVING WITH PERINATAL HIV-1 - DURING SUPPRESSIVE ANTIRETROVIRAL THERAPY (ART), HIV-1 PERSISTS IN LONG-LIVED RESTING MEMORY CD4+ T CELLS OF CHILDREN AND YOUNG ADULTS WITH PERINATAL HIV-1 AS BOTH INTACT AND DEFECTIVE PROVIRAL GENOMES. THE INTACT, REPLICATION-COMPETENT PROVIRUSES CONTRIBUTE TO THE LATENT RESERVOIR AND ARE A LIFELONG BARRIER TO CURE. IN PERINATAL HIV-1, THE RESERVOIR IS ESTABLISHED EARLY AND SHAPED BY UNIQUE IMMUNOLOGIC FACTORS. A GROWING BODY OF EVIDENCE SUGGESTS THAT WHILE DEFECTIVE PROVIRUSES CANNOT CONTRIBUTE TO REBOUND IN THE ABSENCE OF ART, THESE PROVIRUSES ARE TRANSCRIPTIONALLY AND TRANSLATIONALLY ACTIVE, POTENTIALLY LEADING TO ADVERSE IMMUNE EFFECTS. HOWEVER, THE FREQUENCY, COMPOSITION, AND POTENTIAL IMMUNOLOGIC EFFECTS OF DEFECTIVE PROVIRUSES ACROSS PEDIATRIC AGE GROUPS REMAIN POORLY UNDERSTOOD. IN THIS PROPOSAL, WE AIM TO CHARACTERIZE THE DEFECTIVE PROVIRAL RESERVOIR IN CHILDREN AND YOUNG ADULTS LIVING WITH PERINATAL HIV-1 BY DETERMINING THE ABUNDANCE AND SEQUENCES OF PROVIRUSES THAT ARE MAINTAINED FOR YEARS DESPITE ART AND ASSESSING THEIR ABILITY TO PRODUCE VIRAL MRNA AND PROTEINS. THIS PROJECT LEVERAGES WELL-CHARACTERIZED, BIO-BANKED PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) AND PLASMA SPECIMENS FROM PEDIATRIC HIV-1 COHORTS TO SYSTEMATICALLY CHARACTERIZE THE LANDSCAPE OF DEFECTIVE PROVIRUSES IN PERINATAL INFECTION FROM INFANCY THROUGH ADOLESCENCE. OUR HYPOTHESIS IS THAT IN LONGSTANDING TREATED PERINATAL HIV-1, DEFECTIVE PROVIRUSES ARE TRANSCRIPTIONALLY AND TRANSLATIONALLY ACTIVE AND DRIVE PERSISTENT RESIDUAL HIV-1 VIREMIA DURING ART, PROMOTING IMMUNE ACTIVATION AND EXHAUSTION DESPITE REPLICATION INCOMPETENCE. DEFECTIVE PROVIRUSES MAY ALSO SERVE TO PRODUCE DECOY VIRAL PROTEINS THAT ELICIT AUTOLOGOUS NEUTRALIZING ANTIBODIES, THEREBY REDUCING THE EFFICACY OF AUTOLOGOUS NEUTRALIZATION OF THE LATENT RESERVOIR. WE PROPOSE THREE SPECIFIC AIMS. IN AIM 1, WE WILL Q