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SHIV-OPT4: A new model of rapid and consistent V2 apex bNAb elicitation

Award Number: R01AI200472
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: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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SHIV-OPT4: A new model of rapid and consistent V2 apex bNAb elicitation - PROJECT SUMMARY It is widely believed that broadly neutralizing antibodies (bNAbs) can contribute importantly to HIV-1 prevention and cure. One major roadblock to these efforts is the lack of an outbred animal model in which bNAbs can be reliably induced and the molecular, biological and immunological mechanisms required for their elicitation can be deciphered. Recently, we demonstrated that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses (SHIVs) in rhesus macaques (RMs), elicited patterns of Env-antibody coevolution strikingly similar to those observed in humans infected by the same virus, leading to neutralization breadth in approximately 20% of monkeys 1-3 yrs post infection (1, 2). These similarities in bNAb induction between humans and RMs included conserved immunogenetic, structural and biochemical solutions to epitope recognition and common Env amino acid substitutions, insertions and deletions selecting for antibody affinity maturation (2, 3). However, to be useful as a model of bNAb elicitation, a much higher proportion of animals must develop bNAbs in a shorter period of time. For V2 apex bNAbs, we recently showed that this can only be achieved by substantially increasing the efficiency of bNAb precursor priming (2). In the Preliminary Results section of this application, we now present evidence that this critical milestone has been reached. Using a design strategy exclusively based on neutralization signatures (4), we developed novel germline-targeting Envs, termed OPT4 and OPT4-S, that uniquely focus germline B cell responses to the canonical V2 apex bNAb epitope. When expressed as SHIVs, these Envs expand numerous V2 apex bNAb precursors and induce neutralization breadth in virtually all infected animals within 20 weeks, in some cases generating plasma titers of > 1:1000 against several heterologous tier 2 viruses. In this application, we propose to dissect the bNAb induction pathways in this new SHIV model to design optimal priming and boosting immunogens, which will then be tested in a proof-of-concept preclinical trial in RMs. The results are expected to define essential virus-antibody interactions responsible for consistent bNAb induction, which will provide a molecular guide for the design of novel immunogens that can reliably elicit V2 apex bNAbs in monkeys and be adapted for human use in HIV prevention and immunotherapy. If successful, this study has the potential for a paradigm shift in the fields of HIV/AIDS cure and prevention research.


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: 2026 ( Subtotal = $1,337,794 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	6/26/2026	NEW	$1,337,794
														Subtotal = $1,337,794

Grand Total All Awards = $1,337,794

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SHIV-OPT4: A new model of rapid and consistent V2 apex bNAb elicitation

Award Number: R01AI200472

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: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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