Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

Abstract

Title: 129 characters | Abstract: 250 words | Importance: 120 words | Text: ~48000 characters 24 including figure captions and references | Figures: 6 | References: 58 25 Supplementary text: 1 | Supplementary figures: 11 | Supplementary tables: 10 | Supplementary 26 database: 1 27 42 viremic control. Early bNAb therapy lowered viremia, which also limited CTL exhaustion, and 43 improved CTL stimulation via cross-presentation. Post bNAb therapy, viremia resurged but in 44 the presence of a primed CTL population, which eventually controlled the infection. 45 Antiretroviral therapy suppresses viremia but does not enhance CTL stimulation, which limits 46 its ability to elicit post-treatment control. Our model suggests bNAb-based intervention 47 Importance 49 Antiretroviral therapy (ART) for HIV-1 infection is life-long. Remarkably, a recent study 50 showed that 3 weekly doses of HIV-1 broadly neutralizing antibodies (bNAbs) soon after 51 infection kept viral levels controlled for years in macaques. If translated to humans, this bNAb 52 therapy may elicit a functional cure of HIV-1 infection, eliminating the need for life-long 53 treatment. How early bNAb therapy works in macaques remains unknown. Here, we elucidate 54 the mechanism using mathematical modeling and analysis of in vivo data. Early bNAb therapy 55 suppresses viremia, reduces cytotoxic T lymphocyte (CTL) exhaustion, and enhances antigen 56 uptake and CTL stimulation, which collectively drive infection to lasting control. Model 57 predictions fit the complex in vivo data quantitatively and suggest new avenues to optimize 58 bNAb-based interventions. 59 60 Current antiretroviral therapies (ART) for HIV-1 infection control viremia in infected 61 individuals but are unable to eradicate the virus (1). A reservoir of latently infected cells, which 62 is established soon after infection (2), escapes drugs and the host immune response (3), is long-63 lived (4, 5), and can reignite infection following the cessation of therapy (6), presents the key 64 obstacle to sterilizing cure. Efforts are now aimed at eliciting a "functional cure" of the 65 infection, where the virus can be controlled without life-long treatment even though eradication 66 is not possible (7). That functional cure can be achieved has been demonstrated by the 67 VISCONTI trial, where a subset of patients, following early initiation of ART, maintained 68 undetectable viremia long after the cessation of treatment (8). A limitation, however, is that the 69 subset that achieves post-treatment control with ART is small, 5-15% of the patients treated 70 (9). In a major advance, Nishimura et al. (10) found recently that early, short-term passive 71 immunization with a combination of two HIV-1 broadly neutralizing antibodies (bNAbs) 72 elicited lasting control of viremia in 10 of 13, or nearly 77%, of SHIV-infected macaques 73 treated. This high success rate raises the prospect of achieving functional cure in all HIV-1 74 infected individuals using short-term bNAb therapy. Efforts have been initiated to d...

Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy

“…The work presented here introduced new models for four different possible mechanisms by which a monoclonal antibody against the α4β7 integrin could modulate immune responses. These models, although needing further validation, may prove useful in exploring the mechanism of action of other antibodies, such as broadly neutralizing antibodies [51,52], in generating long-term virologic control of SIV/HIV. PLOS COMPUTATIONAL BIOLOGY S18 Table . The estimate parameters for the eight treated macaques using the increased antigen presentation mechanism with increased viral clearance for the three different effector cell source models.…”

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

“…The virions produced, being bNAb sensitive, would get neutralized and cleared by the bNAbs. Previous studies have argued that in the process bNAbs can stimulate CD8 T cells 20,87 , improving the overall immune activation status, possibly explaining the higher latency reactivation rate we required to describe VRC01 failure than previously used to describe historical controls. Our parameters would thus tend to underpredict the remission times in the historical controls.…”

“…bNAbs are known to engage the immune system via multiple mechanisms 20,84–87 . The result could be heightened activation, which for HIV-1 infection, could mean greater susceptibility of target CD4 T cells.…”

Estimation of the in vivo neutralization potency of eCD4Ig and conditions for AAV-mediated production for SHIV long-term remission

“…In the second group, the viral load measurements were less frequent (biweekly) during the primary infection measured; however, after eCD4Ig infusion, they were measured frequently at days 0, 3,7,8,14,17,21,24,28,31,35,38,41,45,49,52,56,59, 63, 70, 84, and 98. Similarly, eCD4Ig was measured at days 1, 3, 7, 8, 10, 14,17,21,24,28,31,38,41,43,45,49,52,56, and 59 after the first infusion.…”