Characterizing the viral and host effector mechanisms that govern HIV-1 rebound

PROJECT SUMMARY
A central goal in HIV/AIDS cure research is preventing or delaying viral rebound following analytical treatment
interruption (ATI). It is widely assumed that understanding the viral and host factors involved in in vivo latency
reactivation would lead to new, more rational cure strategies; however, the biology and provenance of the
rebounding virus remains largely unknown. Here, we propose to leverage four recent discoveries from our
groups to gain insight into the mechanisms of HIV-1 recrudescence. Using “gold standard” sampling methods
to characterize the latent reservoir before and after treatment interruption (ATI), we discovered that viral isolates
derived by quantitative virus outgrowth (QVOA) do not represent or predict the viruses that emerge in the plasma
following treatment interruption (1, 2). We also found that rebound viruses, but not QVOA-derived reservoir
viruses, were highly resistant to type 1 interferons (IFN-I), indicating potent host innate responses at the site of
viral recrudescence (3). Surprisingly, some, but not all, rebound
suggesting
isolates replicated to high titers in macrophages,
a greater biological diversity than previously known. Finally, we discovered that IFN-I resistant
rebound viruses have the ability to reseed the reservoir, raising the possibility of long-term clinical consequences
of ATI (2, 3). In this application, we will leverage these discoveries to elucidate the viral and host factors
that govern HIV-1 rebound. Our hypothesis is that by (i) determining the universality, kinetics and clinical
impact of IFN-I resistance during rebound, (ii) defining the viral determinants of IFN-I resistance and the host
interferon stimulated genes (ISGs) that place pressure on the rebounding virus, and (iii) tracing the provenance
of IFN-I resistant rebound viruses, we will uncover key mechanisms that control HIV-1 reactivation from latency.
In Aim 1, we will expand our studies to more diverse ATI trial participants, including women, minorities, acute
and early ART initiators and individuals receiving IFN-I modulating therapies, to assess the generality of the
IFN-I resistant phenotype of rebound viruses. We will also test to what extent IFN-I resistance persists during
prolonged ATI and determine how this influences the rates of IFN-I resistant viruses that reseed the reservoir. In
Aim 2, we will elucidate the biological properties of rebound HIV-1, map the viral determinants of IFN-I resistance,
and identify the host interferon stimulated genes (ISGs) that place pressure on the recrudescing virus. In Aim 3,
we will trace the provenance of rebound virus by testing blood, thoracic duct lymph and lymphatic tissue using
regular and modified QVOAs, examine whether long-lived myeloid cells, including brain macrophages and
microglia, serve as reservoirs of IFN-I resistant viruses, and explore whether SHIV-infected rhesus macaques
recapitulate the IFN-I phenotypes of HIV-1 reservoir and rebound viruses. We expect these studies to improve
our understanding of the clinically relevant, rebound competent HIV-1 reservoir, the mechanisms underlying in
vivo viral reactivation and the host factors that place pressure on the rebounding virus pool, which should lead
to more rational and effective HIV/AIDS cure strategies.
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Grant Number: 5R01AI162646-05
NIH Institute/Center: NIH
Principal Investigator: Katharine Bar