Dataset Information

Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission.

ABSTRACT: In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIV_SF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.

SUBMITTER: Chang XL

PROVIDER: S-EPMC8184841 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission.

Chang Xiao L XL Webb Gabriela M GM Wu Helen L HL Greene Justin M JM Abdulhaqq Shaheed S Bateman Katherine B KB Reed Jason S JS Pessoa Cleiton C Weber Whitney C WC Maier Nicholas N Chew Glen M GM Gilbride Roxanne M RM Gao Lina L Agnor Rebecca R Giobbi Travis T Torgerson Jeffrey J Siess Don D Burnett Nicole N Fischer Miranda M Shiel Oriene O Moats Cassandra C Patterson Bruce B Dhody Kush K Kelly Scott S Pourhassan Nader N Magnani Diogo M DM Smedley Jeremy J Bimber Benjamin N BN Haigwood Nancy L NL Hansen Scott G SG Brown Timothy R TR Ndhlovu Lishomwa C LC Sacha Jonah B JB

Nature communications 20210607 1

In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challeng ...[more]

PMID: 34099693

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Project description:BackgroundPassive transfer of antibodies can be protective in the simian human immunodeficiency virus (SHIV)--rhesus macaque challenge model. The human monoclonal antibody IgG1 b12 neutralizes human immunodeficiency type 1 (HIV-1) in vitro and protects against challenge by SHIV. Our hypothesis is that neutralizing antibodies can only completely inactivate a relatively small number of infectious virus.Methods and findingsWe have used GHOST cell assays to quantify individual infectious events with HIV-1SF162 and its SHIV derivatives: the relatively neutralization sensitive SHIV(SF162P4) isolate and the more resistant SHIV(SF162P3). A plot of the number of fluorescent GHOST cells with increasing HIV-1SF162 dose is not linear. It is likely that with high-dose inocula, infection with multiple virus produces additive fluorescence in individual cells. In studies of the neutralization kinetics of IgG1 b12 against these isolates, events during the absorption phase of the assay, as well as the incubation phase, determine the level of neutralization. It is possible that complete inactivation of a virus is limited to the time it is exposed on the cell surface. Assays can be modified so that neutralization of these very low doses of virus can be quantified. A higher concentration of antibody is required to neutralize the same dose of resistant SHIV(SF162P3) than the sensitive SHIV(SF162P4). In the absence of selection during passage, the density of the CCR5 co-receptor on the GHOST cell surface is reduced. Changes in the CD4 : CCR5 density ratio influence neutralization.ConclusionsLow concentrations of IgG1 b12 completely inactivate small doses of the neutralization resistant SHIV(SF162P3). Assays need to be modified to quantify this effect. Results from modified assays may predict protection following repeated low-dose shiv challenges in rhesus macaques. It should be possible to induce this level of antibody by vaccination so that modified assays could predict the outcome of human trials.

Dataset Information

Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission.

Publications

Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission.

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