Defining the mechanisms of HIV resistance to bNAbs in humans

PROJECT SUMMARY
Combination antiretroviral therapy (ART) revolutionized the treatment and prevention of HIV-1 infection.
However, ART does not eradicate established infection and worldwide HIV-1 incidence rates remain high and
have been declining slowly. Thus, the search for novel preventive and therapeutic interventions remains a high
priority. In recent years, broadly neutralizing antibodies (bNAbs) emerged as a long-acting alternative to daily
ART and as a promising strategy to achieve long-term treatment-free HIV-1 control. bNAbs differ from ART in
that they engage the host immune system by virtue of their Fc effector domains and therefore have the potential
to mediate killing of infected cells and modulate or enhance HIV-specific immune responses. However, bNAbs
are vulnerable to escape by HIV-1 variants. During HIV-1 infection, antibody responses co-evolve with a large
population of rapidly mutating viruses, such that variants that are resistant to individual antibodies are frequently
encountered. Consistent with this high level of diversity, several clinical studies have demonstrated that bNAb
monotherapy leads to transient declines in viremia with rapid selection of bNAb-resistant viral strains. In contrast,
a combination of two bNAbs targeting non-overlapping Env epitopes maintained viral suppression in participants
harboring antibody sensitive viruses who had achieved viral suppression with ART and subsequently received
repeated doses of bNAbs during ART interruption. These early studies demonstrate the potential therapeutic
application of bNAbs but also highlight the need to better understand viral escape pathways leading to bNAb
resistance. Although resistance to some bNAbs (i.e. anti-V3 loop) is predicated on known features of Env, the
determinants of resistance are poorly defined for other bNAbs and for combinations of bNAbs. The overarching
goals of this proposal are to understand the diversity of pathways leading to bNAb escape and use this
information to guide the design of more effective optimized bNAb combinations that prevent emergence of
resistant variants. This proposal has four interrelated aims directed at accomplishing these goals: (1) Determine
the sequence elements that lead to viral resistance to bNAb administration in humans using newly developed
next generation deep sequencing methods; (2) Systematically map all possible viable bNAb resistance mutations
to identify mechanisms of escape across viral strains and subtypes by producing and testing complete libraries
of Env mutants; (3) Determine the nature of clinically relevant bNAb-resistant HIV-1 variants that can be selected
in cell culture in the presence or absence of autologous serum; (4) Develop computational models that define
mechanisms of HIV-1 bNAb resistance by integrating the sequence information obtained from Aims 1-3.

Grant Number: 5U01AI169385-04
NIH Institute/Center: NIH
Principal Investigator: Marina Caskey