Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Abstract

cBroadly neutralizing monoclonal antibodies (nAbs) specific for HIV are being investigated for use in HIV prevention. Due to their ability to inhibit HIV attachment to and entry into target cells, nAbs may be suitable for use as topical HIV microbicides. As such, they would present an alternative intervention for individuals who may not benefit from using antiretroviral-based products for HIV prevention. We theorize that nAbs can inhibit viral transmission through mucosal tissue, thus reducing the incidence of HIV infection. The efficacy of the PG9, PG16, VRC01, and 4E10 antibodies was evaluated in an ex vivo human model of mucosal HIV transmission. nAbs reduced HIV transmission, causing 1.5-to 2-log 10 reductions in HIV replication in ectocervical tissues and Ϸ3-log 10 reductions in HIV replication in colonic tissues over 21 days. These antibodies demonstrated greater potency in colonic tissues, with a 50-fold higher dose being required to reduce transmission in ectocervical tissues. Importantly, nAbs retained their potency and reduced viral transmission in the presence of whole semen. No changes in tissue viability or immune activation were observed in colonic or ectocervical tissue after nAb exposure. Our data suggest that topically applied nAbs are safe and effective against HIV infection of mucosal tissue and support further development of nAbs as a topical microbicide that could be used for anal as well as vaginal protection.

Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies

“…The weak activity of 4E10 against onward dissemination of virus reflects earlier reports of poor activity against cell-to-cell spread of HIV-1 (49). The lack of activity in the cervical and penile glans tissues is in concordance with similar observations in an alternative cervical tissue model (40). The predictive nature of these observations is unclear given that 4E10, as a single monoclonal antibody, has not been tested against vaginal challenge in the SHIV model.…”

“…Differences across tissues may reflect potential reactivity with mammalian carbohydrates where PG16 binds complex-type glycans more tightly than Man5GlcNAc2, while PG9 prefers Man5GlcNAc2 (37); alternatively, this may reflect known differences in trimer dependence (38, 39): PG9 is able to weakly bind monomeric gp120 in addition to trimeric Env, but PG16 is able to bind only the latter. An alternative ex vivo study using colorectal and ectocervical tissue explants demonstrated sustained inhibition of viral replication by PG9 and PG16 in an ectocervical tissue model but loss of viral control within the colorectal tissue after 21 days in culture (40). Significant differences in methodology are likely to explain the variance in the observed levels of inhibition; nevertheless, viral rebound in colorectal tissue reflects the lack of inhibition observed in our study.…”

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

“…28,29 Part of this uncertainty is due to the fact that the NHP work employed high dose intra-rectal challenges and included two challenge viruses, representing less diversity than the challenges in human trials. Moreover, the two challenge viruses used had higher transmission probabilities than those common in human trials.…”

“…demonstrated that a 5.1-fold higher concentration of VRC01 was required to protect human inner foreskin compared to outer foreskin explant tissue against ex vivo HIV challenge 28 and Scott et al. reported that a higher concentration of VRC01 was required to reduce transmission in ectocervical tissue compared to colonic tissue 29 . For (2), assuming independence of S and V such that P ( s , v ) = P ( s ) × P ( v ), where P ( s ) and P ( v ) are the probability distributions for S and V , respectively, pharmacokinetics (PK) data from earlier phase 1 trials of VRC01 15–17 are used to estimate P ( s ) for each of the mAb dose groups, and TZM-bl 18 IC80 data for VRC01 against a panel of 177 HIV-1 Env pseudoviruses across multiple genetic subtypes of the virus are used to estimate P ( v ) that is common across the two mAb groups and the placebo group.…”

“…For (1), estimated from NHP high dose intra-rectal challenge data for VRC01 11,30 is used as the basis for a range of per-exposure PE models, indexed by the “NHP model” that assumes the per-exposure efficacy derived from NHP is applicable to humans. Based loosely on human explant experiments that suggest that some human genital tissues require greater concentrations of VRC01 for protection against HIV challenge than others, 28,29 we also use a “5-fold model” that assumes that 5-fold greater mAb concentration would be needed to provide the same level of PE as seen in the NHP challenge data. For example, Lemos et al.…”