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Review
. 2017 Mar 15;215(suppl_3):S152-S159.
doi: 10.1093/infdis/jiw555.

Humoral and Innate Antiviral Immunity as Tools to Clear Persistent HIV Infection

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Free PMC article
Review

Humoral and Innate Antiviral Immunity as Tools to Clear Persistent HIV Infection

Guido Ferrari et al. J Infect Dis. .
Free PMC article

Abstract

Human immunodeficiency virus (HIV) type 1 uses the CD4 molecule as its principal receptor to infect T cells. HIV-1 integrates its viral genome into the host cell, leading to persistent infection wherein HIV-1 can remain transcriptionally silent in latently infected CD4+ T cells. On reactivation of replication-competent provirus, HIV-1 envelope glycoproteins (Env) are expressed and accumulate on the cell surface, allowing infected cells to be detected and targeted by endogenous immune responses or immune interventions. HIV-1 Env-specific antibodies have the potential to bind HIV-1 cell surface Env and promote elimination of infected CD4+ T cells by recruiting cytotoxic effector cells, such as natural killer cells, monocytes, and polymorphonuclear cells. Harnessing humoral and innate cellular responses has become one focus of research to develop innovative strategies to recruit and redirect cytotoxic effector cells to eliminate the HIV-1 latently infected CD4+ T-cell reservoir.

Keywords: ADCC; Antibodies; HIV-1; bispecific antibodies; cure.; innate immunity; latency.

Figures

Figure 1.
Figure 1.
Sites of vulnerability on the human immunodeficiency virus (HIV) type 1 envelope glycoprotein (Env) spike. The structure of a HIV-1 prefusion trimer is displayed and the 6 major sites of vulnerability targeted by broadly neutralizing antibodies discussed in this review are indicated: the variable regions 1 and 2 (V1/V2) loop (green), the base of the variable region 3 (V3) loop (maroon), the CD4-binding site (lavender), the interface between gp120 and gp41 proteins (magenta), the fusion peptide region (orange), and the membrane proximal external region (MPER). Because of the limited structural information, the MPER near the base of the Env trimer is represented by a red cylinder.
Figure 2.
Figure 2.
Anti–human immunodeficiency virus (HIV) type 1 envelope (Env) antibody-derived molecules. A, Bispecific antibodies combine 2 antigen (Ag)–binding site variable fragments (Fvs) into a single immunoglobulin. The 2 Fvs (Fv1 and Fv2) can recognize 2 different antigenic regions of the HIV-1 Env [*], or the HIV-1 Env and cellular receptors involved in virus entry [*, *] or in cytotoxic functions [*]. B, Bispecific T-cell engagers (BiTEs), which are generated by using a single polypeptide linker to join 2 single-chain Fvs (scFvs) with different antigen specificities. The first-generation HIV BiTE was designed to bind the HIV-1 envelope CD4-binding site and recruit cytotoxic T cells by engaging CD3 [47]. C, D, Dual-affinity retargeting (DART) molecules. The variable domains of the 2 scFvs are not only linked by a polypeptide linker to create a “diabody”-type structure but also stabilized into a disulfide-linked heterodimer with different antigen specificity. One arm can bind the HIV-1 envelope, and the other can bind cytotoxic effector cells [45]. DART molecules can also be designed to include the antibody Fc region to improve the half-life of the molecules [46].

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