Novel Transmitted/Founder Simian-Human Immunodeficiency Viruses for Human Immunodeficiency Virus Latency and Cure Research

Abstract

A robust simian-human immunodeficiency virus (SHIV)-macaque model of latency is critical to investigate eradicative and suppressive strategies that target HIV-1 Env. To this end, we previously reported a novel strategy for constructing SHIVs that bear primary or transmitted/founder (TF) Envs with modifications at Env residue 375 that enable efficient replication in Indian rhesus macaques (RM). Such TF SHIVs, however, have not been examined for their suitability for HIV-1 latency and cure research. Here, we evaluate two promising TF SHIVs, SHIV.D.191859 and SHIV.C.CH848, which encode TF subtype D and C HIV-1 Envs, respectively, for their viral kinetics and persistence during suppressive combination antiretroviral therapy (cART) and treatment interruption in RM. Our results suggest that the viral kinetics of these SHIVs in RM during acute, early, and chronic infection, and upon cART initiation, maintenance and discontinuation, mirror those of HIV-1 infection. We demonstrate consistent early peak and set point viremia, rapid declines in viremia to undetectable plasma titers following cART initiation, infection of long-lived cellular subsets and establishment of viral latency, and viral rebound with return to pretreatment set point viremia following treatment interruption. The viral dynamics and reservoir biology of SHIV.D.191859, and to a lesser extent SHIV.C.CH848, during chronic infection, cART administration, and upon treatment interruption suggest that these TF SHIVs are promising reagents for a SHIV model of HIV-1 latency and cure. IMPORTANCE Simian-human immunodeficiency viruses (SHIVs) have been successfully used for over 2 decades to study virus-host interactions, transmission, and pathogenesis in rhesus macaques. The majority of Env trimers of most previously studied SHIVs, however, do not recapitulate key properties of transmitted/founder (TF) or primary HIV-1 isolates, such as CCR5 tropism, tier 2 neutralization resistance, and native trimer conformation. Here, we test two recently generated TF SHIVs, SHIV.D.191859 and SHIV.C.CH848, which were designed to address these issues as components of a nonhuman primate model of HIV-1 latency. We conclude that the TF SHIV-macaque model reflects several hallmarks of HIV and SIV infection and latency. Results suggest that this model has broad applications for evaluating eradicative and suppressive strategies against the HIV reservoir, including Env-specific interventions, therapeutic vaccines, and engineered T cells.

New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention and Cure

“…This resulted in productive clinical infection in both animals, as indicated by plasma viremia one week later. Plasma viral load kinetics through 13 weeks of followup were comparable to SHIV.D.191859 plasma virus loads resulting from other routes of transmission reported earlier (35, 101) and similar to plasma viremia of SHIV.A.BG505.N332.375Y following low-dose intrarectal challenge ( B ).…”

“…These findings again demonstrate reproducibility in AID 50 titers in different primate centers and in monkeys from different breeding colonies as well as a 30-40 fold difference in infectivity between IR versus IVAG challenge routes. Previously, we estimated the AID 50 for SHIV.D.191879 for IVAG inoculation to be approximately 1:3 (1 ml) (101). Here, we could not estimate an AID 50 for penile transmission by the SHIV.D.191879 challenge stock since 2 of 2 animals became infected after a single inoculation ( Fig.…”

New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention, and Cure

“…This resulted in productive clinical infection in both animals, as indicated by plasma viremia 1 week later. Plasma viral load kinetics through 13 weeks of follow-up were comparable to SHIV.D.191859 plasma virus loads resulting from other routes of transmission where data were reported earlier ( 35 , 101 ) and similar to plasma viremia of SHIV.A.BG505.N332.375Y following low-dose intrarectal challenge (B). Of note, none of the 19 RMs depicted in panels A and B had been treated with anti-CD8 MAb, thus demonstrating consistent replication kinetics by different SHIVs administered by different mucosal inoculation routes.…”

Immune Responses and Viral Persistence in Simian/Human Immunodeficiency Virus SHIV.C.CH848-Infected Rhesus Macaques

“…Recently developed CCR5-tropic SHIV.C.CH848 and CH505 strains, encoding Env from a transmitted founder HIV-1 subtype C, with an increased affinity for rhesus CD4 have shown promise for viral replication kinetics more closely resembling HIV infection in humans (16,17,48). Here we analyzed neutralizing antibody responses and cellular reservoirs in systemic and lymphoid tissues of rhesus macaques infected with T/F SHIV.C.CH848, before and after cART treatment and interruption.…”

“…), which exclusively utilize CCR5. The new CCR5-tropic clade C SHIV (SHIV.C.CH848) clone (12)(13)(14) encodes for a clade C Env isolated from an acutely-infected Malawian man in 2008 (15), and was developed by a single amino acid substitution at Env residue 375 to increase the affinity of CH848 Env for rhesus CD4 (16,17). Here, we investigate immunological and virological events in SHIV.C.CH848-infected animals in acute infection and on antiretroviral therapy including CD4+ T cells, neutralizing antibody responses, and Env viral evolution.…”