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  • Review Article
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Envelope-specific antibodies and antibody-derived molecules for treating and curing HIV infection

Nature Reviews Drug Discovery volume 15, pages 823–834 (2016)Cite this article

Subjects

Key Points

  • HIV-1 infection is characterized by a chronic phase during which the virus persists as integrated provirus in the genome of latently infected CD4+ T cells.

  • Cells latently infected with HIV-1 are not commonly recognized by the immune system owing to the absence of virus antigen expression on their cellular membrane and selection of escape mutants by natural infection-induced immune responses.

  • HIV-1 neutralizing antibodies are capable of reducing the level of virus replication and decreasing the pool of latently infected cells.

  • Antibodies with broadly neutralizing activity have been exploited to generate bispecific and trispecific molecules with multiple anti-HIV-1 envelope (HIV-1 Env) specificities to augment the breadth of recognition of diverse HIV-1 isolates.

  • Bispecific and trispecific molecules, such as dual-affinity re-targeting (DART) proteins, have been generated that combine broadly reactive anti-Env and anti-CD3 specificities to recruit cytotoxic T cells to eliminate latently infected cells that express HIV-1 Env upon provirus reactivation.

  • Preclinical and clinical studies are planned to evaluate the safety and activity of antibody-derived therapeutics (as single agents or combinations) that may be co-administered with agents capable of reversing HIV-1 latency.

Abstract

HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4+ T cells and thus limit the spread of progeny virus. Recent innovations in antibody engineering have resulted in novel immunotherapeutics such as bispecific dual-affinity re-targeting (DART) molecules and other bi- and trispecific antibody designs that can recognize HIV-1 Env and recruit cytotoxic effector cells to kill CD4+ T cells latently infected with HIV-1. Here, we review these immunotherapies, which are designed with the goal of curing HIV-1 infection.

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Figure 1: Dynamics of virus replication and therapeutic interventions.
Figure 2: HIV-1 envelope epitopes, monoclonal antibodies and engineered antibody-based proteins.
Figure 3: Recruitment of effector cell subsets.

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Acknowledgements

This Review was supported by US National Institutes of Health grants to the Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (UM1 AI100645), the Duke Center for AIDS Research (P30 AI64518), the Collaboratory of AIDS Researchers for Eradication (CARE) based at the University of North Carolina (U19 AI096113), and the University of North Carolina Center for AIDS Research (P30 AI50410). The authors thank J. Pollara, C.-H. Chen and E. Boritz for their comments on the manuscript.

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Authors and Affiliations

  1. Department of Surgery, Duke University, Durham, 27710, North Carolina, USA

    Guido Ferrari & Georgia D. Tomaras

  2. Department of Molecular Genetics and Microbiology, Duke University, Durham, 27710, North Carolina, USA

    Guido Ferrari & Georgia D. Tomaras

  3. Duke Human Vaccine Institute, Duke University, Durham, 27710, North Carolina, USA

    Guido Ferrari, Barton F. Haynes & Georgia D. Tomaras

  4. Department of Medicine, Duke University, Durham, 27710, North Carolina, USA

    Barton F. Haynes

  5. Department of Immunology, Duke University, Durham, 27710, North Carolina, USA

    Barton F. Haynes & Georgia D. Tomaras

  6. MacroGenics, Rockville, 20850, Maryland, USA

    Scott Koenig & Jeffrey L. Nordstrom

  7. University of North Carolina at Chapel Hill HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    David M. Margolis

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  2. Barton F. Haynes
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Corresponding authors

Correspondence to Guido Ferrari or Georgia D. Tomaras.

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Competing interests

B.F.H., S.K. and J.L.N. have patents submitted on HIV antibodies for use as DARTS and as antibody therapeutics. G.F. and G.D.T. declare no competing interests.

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Glossary

Combined antiretroviral therapy

(cART). A HIV treatment regimen that uses a combination of drugs from two different classes of antiretrovirals that can act as inhibitors of at least two enzymes essential for the replicative cycle of HIV-1. The four major classes of antiretrovirals are nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors.

Virus set point

The level of viraemia reported as viral RNA copies per ml of plasma in a person infected with HIV. The viraemia level becomes relatively stable after the period of acute HIV infection, and usually remains stable until the onset of late-stage AIDS. The set point is thought to reflect the balance between the replicative capacity of the virus and partial control by the immune system.

Elite controllers

Elite controllers are canonically defined as people in whom viraemia is below the limit of 50 copies per ml of plasma for three consecutive measurements performed over a period of 1 year while not on antiretroviral therapy. The ability of these individuals to control virus replication in the absence of therapeutic intervention is related to unique aspects of their humoral and/or cellular immune responses.

Neutralizing antibody

An antibody that defends a cell from infectious pathogens or toxins by neutralizing their biological effects. In the case of HIV-1, neutralizing antibodies prevent the virus from entering target cells expressing the CD4 receptor and the co-receptor CC-chemokine receptor 5 (CCR5) or CXC-chemokine receptor 4 (CXCR4).

Quantitative viral outgrowth assay

(QVOA). A standard assay used to estimate the frequency of latently infected cells in an HIV-infected individual. The assay requires isolation of resting memory CD4 T cells from the infected patient on antiretroviral therapy. The cells are stimulated and co-cultured with allogeneic CD4 T cells in multiple wells in a limiting dilution manner for a minimum period of 2 weeks. The frequency of replication-competent virus, or as infectious units per million (IUPM), is assessed by measuring the frequency of cultures expressing HIV-1 p24 antigen in the supernatant.

CD4+ follicular helper T (TFH) cells

A subset of the CD4 T cell population specialized in providing help to B cells within secondary lymphoid tissues. TFH cells are identified according to the cell surface expression of several different molecules, including CXC-chemokine receptor 5 (CXCR5), programmed cell death protein 1 (PD1), SLAM-associated protein (SAP) and inducible T cell co-stimulator (ICOS). These cells can also produce interleukin-21 and express the transcription factor B cell lymphoma 6 (BCL-6). TFH cells are important for the formation of the germinal centre where they regulate the differentiation of B cells into plasma cells and memory B cells, thus regulating the antibody responses against pathogens.

Viral latency

The ability to remain dormant within the host cell to establish a persistent occult infection. In the case of HIV-1, the viral genome is integrated into the DNA of the host cell as a provirus. Latency can be reversed, allowing viral RNA, protein and even virion production from the latently infected cell upon viral genome reactivation as a consequence of cellular signals. This latent HIV DNA genome can also be expanded during cellular replication in the absence of viral gene expression.

Escape mutations

Mutations in the virus genome that encode modified gene products that will retain their function and preserve replication and assembly of infectious particles, but prevent recognition by immune responses directed against the parental gene product.

Latency reversing agents

(LRAs). A relatively new class of agents used to selectively activate the provirus by interfering with the mechanisms reportedly identified to prevent HIV-1 expression in the latently infected cells or by promoting transcription of the provirus. Ideally, these agents should specifically stimulate virus reactivation but induce minimal activation of cellular subsets of the immune system.

Epitopes

Portions of a molecule that are recognized by the immune system as non-self antigens and therefore capable of inducing antibody and/or cellular immune responses.

Transmitted/founder

The transmitted/founder virus is a molecular definition of the virus whose genomic sequence is identified following acute infection as the earliest virus transmitted and is responsible for the productive clinical infection.

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Ferrari, G., Haynes, B., Koenig, S. et al. Envelope-specific antibodies and antibody-derived molecules for treating and curing HIV infection. Nat Rev Drug Discov 15, 823–834 (2016). https://doi.org/10.1038/nrd.2016.173

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