Despite the major success of combination antiretroviral therapy (ART) in suppressing viral replication and preventing disease progression, HIV-1 infection persists in a latent reservoir, composed primarily of a long- lived population of resting memory CD4+ T cells. These latently infected cells harbor replication competent HIV-1 DNA, therefore the elimination of the latent viral reservoir is essential to eradicating HIV-1 infection. Several eradication strategies are currently being evaluated, and broadly neutralizing antibodies (bNAbs) represent a promising new modality, particularly if coupled with latency reversing agents. BNAbs differ from standard ART in that they can engage the host immune system by virtue of their Fc effector domains. Most importantly, recent data shows that bNAbs interfere with the establishment and maintenance of the reservoir in humanized mice. 3BNC117 is one of such highly potent and broad NAbs and is being developed as a clinical candidate for HIV-1 prevention and therapy. It has been shown to lead to viral suppression in HIV-1 infected humanized mice and in SHIV-infected non-human primates. We are currently testing 3BNC117 in a phase 1 dose-escalation study in HIV-infected and uninfected individuals. The available clinical data shows that 3BNC117 is generally safe and well tolerated, and has a favorable pharmacokinetic profile in both HIV- uninfected and HIV-infected subjects. We now propose to study the effects of 3BNC117 on established HIV-1 reservoirs in humans. The envisioned clinical trial is a phase I, open label study to evaluate the antiretroviral activity of three infuions of 3BNC117 in HIV-infected subjects who have achieved viral suppression with ART alone. We propose to evaluate the reservoir by quantitative PCR-based assays to measure cell-associated HIV-1 DNA and RNA and by functional viral outgrowth assays that measure infectious units per million CD4+ resting T cells. Given the limitations of these assays, the study includes an analytical treatment interruption which is a more stringent tool to evaluate HIV-1 persistence and the ability of new therapeutic modalities to alter the reservoir. In addition we will evaluate if 3BNC117 will modulate HIV-specific immune responses and modify the state of chronic inflammation characteristic of HIV-1 infection.
Transmission of HIV-1 continues at staggering rates in many areas of the world. Combination antiretroviral therapy (ART) is highly successful in suppressing viral replication and preventing disease progression, however, HIV-1 infection persists. Standard ART does not fully restore health or a normal immune status in HIV-infected individuals and co-morbidities such as cardiovascular disease and cognitive impairment may occur. Efforts to identify strategies to eradicate HIV-1 infection are critical.
|Lorenzi, Julio C C; Cohen, Yehuda Z; Cohn, Lillian B et al. (2016) Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. Proc Natl Acad Sci U S A 113:E7908-E7916|