Journal
JOURNAL OF VIROLOGY
Volume 94, Issue 21, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00793-20
Keywords
7B2; A32; AZD5582; DART; PGT145; rhesus macaques; SHIV; SMACm; human immunodeficiency virus; simian immunodeficiency virus
Categories
Funding
- Qura Therapeutics
- CARE, a Martin Delaney Collaboratory of the NIAID [1UM1AI126619-01]
- Emory Consortium for Innovative AIDS Research in Nonhuman Primates [UM1 AI124436]
- Yerkes National Primate Research Center [P51 OD011132]
- Translational Virology and Reservoir Cores of the Center for AIDS Research at Emory University [P30 AI050409]
- CARE, a Martin Delaney Collaboratory of the NINDS [1UM1AI126619-01]
- CARE, a Martin Delaney Collaboratory of the NIDA [1UM1AI126619-01]
- CARE, a Martin Delaney Collaboratory of the NIMH [1UM1AI126619-01]
Ask authors/readers for more resources
The shock-and-kill human immunodeficiency virus type 1 (HIV-1) cure strategy involves latency reversal followed by immune-mediated clearance of infected cells. We have previously shown that activation of the noncanonical NF-kappa B pathway using an inhibitor of apoptosis (IAP), AZD5582, reverses HIV/simian immunodeficiency virus (SIV) latency. Here, we combined AZD5582 with bispecific HIVxCD3 DART molecules to determine the impact of this approach on persistence. Rhesus macaques (RMs) (n = 13) were infected with simian/human immunodeficiency virus SHIV.C.CH505.375H.dCT, and triple antiretroviral therapy (ART) was initiated after 16 weeks. After 42 weeks of ART, 8 RMs received a cocktail of 3 HIVxCD3 DART molecules having human A32, 7B2, or PGT145 anti-HIV-1 envelope (Env) specificities paired with a human anti-CD3 specificity that is rhesus cross-reactive. The remaining 5 ART-suppressed RMs served as controls. For 10 weeks, a DART molecule cocktail was administered weekly (each molecule at 1 mg/kg of body weight), followed 2 days later by AZD5582 (0.1 mg/kg). DART molecule serum concentrations were well above those considered adequate for redirected killing activity against Env-expressing target cells but began to decline after 3 to 6 weekly doses, coincident with the development of antidrug antibodies (ADAs) against each of the DART molecules. The combination of AZD5582 and the DART molecule cocktail did not increase on-ART viremia or cell-associated SHIV RNA in CD4(+) T cells and did not reduce the viral reservoir size in animals on ART. The lack of latency reversal in the model used in this study may be related to low pre-ART viral loads (median, <10(5) copies/ml) and low preintervention reservoir sizes (median, <10(2) SHIV DNA copies/million blood CD4(+) T cells). Future studies to assess the efficacy of Env-targeting DART molecules or other clearance agents to reduce viral reservoirs after latency reversal may be more suited to models that better minimize immunogenicity and have a greater viral burden. IMPORTANCE The most significant barrier to an HIV-1 cure is the existence of the latently infected viral reservoir that gives rise to rebound viremia upon cessation of ART. Here, we tested a novel combination approach of latency reversal with AZD5582 and clearance with bispecific HIVxCD3 DART molecules in SHIV.C.CH505-infected, ART-suppressed rhesus macaques. We demonstrate that the DART molecules were not capable of clearing infected cells in vivo, attributed to the lack of quantifiable latency reversal in this model with low levels of persistent SHIV DNA prior to intervention as well as DART molecule immunogenicity.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available