Antibodies and Antibody Derivatives: New Partners in HIV Eradication Strategies

Abstract

Promptly after primoinfection, HIV generates a pool of infected cells carrying transcriptionally silent integrated proviral DNA, the HIV-1 reservoir. These cells are not cleared by combined antiretroviral therapy (cART), and persist lifelong in treated HIV-infected individuals. Defining clinical strategies to eradicate the HIV reservoir and cure HIV-infected individuals is a major research field that requires a deep understanding of the mechanisms of seeding, maintenance and destruction of latently infected cells. Although CTL responses have been classically associated with the control of HIV replication, and hence with the size of HIV reservoir, broadly neutralizing antibodies (bNAbs) have emerged as new players in HIV cure strategies. Several reasons support this potential role: (i) over the last years a number of bNAbs with high potency and ability to cope with the extreme variability of HIV have been identified; (ii) antibodies not only block HIV replication but mediate effector functions that may contribute to the removal of infected cells and to boost immune responses against HIV; (iii) a series of new technologies have allowed for the in vitro design of improved antibodies with increased antiviral and effector functions. Recent studies in non-human primate models and in HIV-infected individuals have shown that treatment with recombinant bNAbs isolated from HIV-infected individuals is safe and may have a beneficial effect both on the seeding of the HIV reservoir and on the inhibition of HIV replication. These promising data and the development of antibody technology have paved the way for treating HIV infection with engineered monoclonal antibodies with high potency of neutralization, wide coverage of HIV diversity, extended plasma half-life in vivo and improved effector functions. The exciting effects of these newly designed antibodies in vivo, either alone or in combination with other cure strategies (latency reversing agents or therapeutic vaccines), open a new hope in HIV eradication.

Keywords: ADCC; HIV persistence; HIV reservoir; NK cells; broadly neutralizing antibodies; effector functions.

Figure 1

Mechanisms controlling HIV reservoir in treated HIV-infected individuals. The HIV reservoir, the pool of HIV latently infected cells, is drained by continuous stochastic activation leading to transient or stable transcription of HIV provirus. Transient reactivation may allow a return to latent infection, while stable reactivation will allow for presentation of viral peptides to HIV specific CD8 T cells, exposure of HIV Env on the surface of cells allowing NK mediated ADCC. Both mechanisms will lead to the lysis of infected cells. Reinfection of target cells by virions produced by reactivated cells is blocked by cART. On the other hand, stimuli that promote cell proliferation in the absence of viral transcription will increase the size of the reservoir (bottom right).

Figure 2

Main antibody features. Antibodies are glycosylated heterodimeric molecules showing a variable region in both light and heavy chains that determine antigen binding. For bNAbs, antigen binding is located on the indicated vulnerability sites of the HIV Env glycoprotein formed by heterotrimers of gp120 (yellow) and gp41 (red in the upper right panel). The crystallizable fragment of the antibodies (Fc) encompasses all constant regions and is responsible for the effector functions. Different antibody subtypes show selective effector functions (color coded displayed in the middle right panel). Furthermore, the Fc region also regulates plasma half-life of antibodies, as they are continuously recycled, degraded or transcytosed by endothelial cells through neonatal Fc receptors (FcRn, lower right panel). HIV Env picture (http://www.rcsb.org/pdb/101/motm.do?momID=169) is from David S. Goodsell and the RCSB PDB under Creative Commons.