Antiretroviral therapy-based pre-exposure prophylaxis (PrEP) is a highly effective biomedical HIV prevention
strategy. However, many individuals at high risk of HIV acquisition are not receiving PrEP due to multiple issues,
including potential drug toxicity, adherence and cost. As such, there is a need to develop additional safe and
effective biomedical HIV prevention strategies. Major prevention strategies currently in development include the
provision or induction of anti-viral neutralizing antibodies by passive immunization or vaccination, respectively.
The utility of neutralizing antibodies for preventing HIV infection has been validated in nonhuman primates.
Passively transferred antibodies protect nonhuman primates from oral, vaginal, rectal and intravenous
challenges with simian human immunodeficiency virus (SHIV). Antibody conferred protection is primarily due to
blockade of the viral entry process but can also involve the elimination of infected cells or virions via antibody Fc
dependent functions. An often overlooked issue in preclinical nonhuman primate studies of neutralizing antibody
conferred protection from SHIV challenge is that human HIV infections are a consequence of exposure to
infectious bodily fluids containing both cell-free and cell-associated virus. The viruses that initiate new HIV
infections are termed transmitted founder (TF) viruses. Preliminary data assessed in vitro neutralization of cell-
free and cell-to-cell spread of a panel of SHIVs with envelopes from TF HIVs using the PGT121 anti-HIV
neutralizing antibody. For several of these viruses, PGT121 fully neutralized cell-free spread but did not
neutralize cell-to-cell spread. The proposed research will assess if distinct neutralization of cell-free and cell-to-
cell viral spread impacts the ability of a neutralizing antibody to prevent infection following in vivo viral exposure.
This work will use one of the TF SHIVs, SHIVBG505, to perform cell-free or cell-associated challenges in rhesus
macaques infused with PGT121, an isotype control or a version of PGT121 with abrogated/diminished Fc
dependent functions. The central hypotheses are: (I) PGT121 will prevent infection following cell-free SHIVBG505
challenge; (II) PGT121 will not prevent infection following cell-associated SHIVBG505 challenge; and (III) Fc
dependent functions will contribute to the outcomes of cell-free or cell-associated SHIVBG505 challenges. These
hypotheses will be evaluated across three specific aims: (I) assess if PGT121 protects rhesus macaques from
challenge with cell-free SHIVBG505; (II) assess if PGT121 protects rhesus macaques from challenge with cell-
associated SHIVBG505; and (III) determine the impact of Fc dependent functions on the outcome of cell-free or
cell-associated SHIVBG505 challenges in PGT121 infused rhesus macaques. Generated data will contribute to the
development of antibody-based HIV prevention tools, by providing a refined definition of the characteristics of
neutralizing antibodies required to achieve protection. This work will be done at the Yerkes National Primate
Research Center and is a key piece of the candidate's career development plan. The candidate's long-term goal
is to fully transition into an independent investigator.