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  • Review Article
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Control of HIV-1 infection by soluble factors of the immune response

Nature Reviews Microbiology volume 2, pages 401–413 (2004)Cite this article

Key Points

  • Immune responses against viral infections can be supplemented by soluble factors that suppress viral replication without killing infected cells. This non-cytolytic effector mechanism contrasts with the viral clearance mediated by cytotoxic T lymphocytes (CTLs), which involves the targeted destruction of cells that harbour replicating viruses.

  • Many soluble suppressor factors have immunomodulatory as well as antiviral functions. In some cases, these different functions involve the same receptor-mediated pathways.

  • HIV-1 infection is a model case in which soluble non-cytolytic suppressor activity might have an important role in antiviral immunity.

  • Soluble and non-cytolytic HIV suppressor activity was originally identified in cultures of activated CD8+ T cells and was called CD8 antiviral factor (CAF). However, it is now known that soluble HIV-1 suppressor activity is produced by several cell types and is mediated by combinations of diverse factors.

  • Studies of HIV-1 infection show that the composition of soluble virus suppressor activities can vary according to the producer cell type and the mode of cellular activation. Furthermore, the arrays of factors that comprise the activity may change over time.

  • Only a few HIV suppressor factors have been identified. These factors target a range of viral replication steps. In many cases, the chemokines RANTES, MIP-1α and MIP-1β are responsible for suppressing R5 strains of HIV-1. Interferons, eosinophil-derived neutrophils and macrophage-derived chemokines also contribute to the bulk suppressor activity in certain systems. The element of CAF that suppresses HIV-1 gene transcription remains unidentified.

  • Clinical studies have correlated the natural ability to produce high concentrations of soluble suppressor factors with the control or prevention of HIV-1 infection. Other studies indicate that secondary infections by other microorganisms might suppress HIV-1 infection by stimulating the release of soluble suppressor factors. Collectively, these studies indicate that soluble non-cytolytic suppressor factors might provide a valuable basis for developing new ways to treat or prevent viral infections.

Abstract

An increasing body of evidence indicates that the immune system uses a range of soluble molecules to suppress certain viral infections without killing infected host cells. Recent studies indicate that such factors might have an especially important role in the immune response to HIV-1. Accordingly, this review uses HIV-1 as a model to explore the diversity of non-cytolytic antiviral factors and considers how these molecules might be used to develop new therapeutic and prophylactic strategies to fight viral infections.

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Figure 1: A working model of an antiviral immune response that uses cytolytic cell killing, antibodies and soluble non-cytolytic factors as a means to suppress infection.
Figure 2: RANTES, MIP-1α and MIP-1β are primarily responsible for the suppression of macrophage-tropic (R5) HIV-1 replication by CD8+ T-cell-culture supernatants.
Figure 3: A schematic representation of the multipartite nature of the soluble HIV-1 suppressor activity produced by CD8+ T cells.
Figure 4: A variety of primary cell subsets secrete soluble HIV-1 suppressor activities in response to various stimuli.
Figure 5: Soluble factors might suppress HIV-1 at multiple replication steps through several mechanisms.

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Authors and Affiliations

  1. Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, 21202, Maryland, USA

    Anthony L. DeVico & Robert C. Gallo

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DATABASES

Entrez

hepatitis A virus

hepatitis B virus

HIV-1

human T lymphotrophic virus

simian immunodeficiency virus

vaccinia virus

vesicular stomatitis virus

LocusLink

CCR5

CXCR4

IFNs

TNF

SwissProt

eosinophil-derived neurotoxin

MIP-1α

MIP-1β

Glossary

NATURAL KILLER CELLS

(NK cells). Lymphocytes that do not express the T-cell receptor (TCR) or B-cell receptor (BCR) and which mediate natural killing against prototypical NK-cell-sensitive targets.

γδ-T CELLS

T lymphocytes express a T-cell receptor (TCR) that is composed of either α- and β-subunits (αβTCR) or a TCR that is composed of γ- and δ-subunits (γδTCR). Most (>90%) T cells have an αβTCR that recognizes conventional MHC class I or II ligands. T cells expressing γδTCR are less common and the ligands of this type of receptor are less well characterized.

CYTOKINES

Originally used to describe a group of immunomodulatory growth factors, the term cytokine is now used to describe a diverse group of soluble proteins that modulate the many activities of cells and tissues.

CHEMOKINES

Chemotactic cytokines involved in specific inflammatory responses. They are differentiated into CC or CXC chemokines on the basis of their primary amino acid sequence.

INNATE IMMUNE RESPONSE

The first line of defence against microbial infections. Innate responses do not require the induction of MHC gene products or antigen presentation in the context of MHC molecules.

CD8+ T CELLS

One of the two main classes of T lymphocytes (the other being CD4+ T cells). CD8+ T cells exert cytolytic activity in an antigen-specific manner. They also produce various cytokines to regulate the immune system.

CD4+ HELPER T CELLS

T helper cells that collaborate with antigen-presenting cells in the initiation of an immune response.

CELLULAR IMMUNE RESPONSE

An adaptive immune response that is mediated by CD8+ cytotoxic T lymphocytes that have been primed by dendritic cells and other cell subsets that present viral antigens in conjunction with Class I MHC molecules. Cellular responses help clear viral infections by killing infected cells.

HUMORAL IMMUNE RESPONSE

An adaptive immune response that is mediated by antibodies directed against specific epitopes on viral antigens. These antibodies prevent the intercellular transmission of virions and the reinfection of the host.

NON-CYTOLYTIC SOLUBLE SUPPRESSOR FACTORS

Diffusible molecules that are released during an innate and/or adaptive immune response and which suppress viral replication without killing host cells.

INTERFERONS

(IFNs). Interferons are proteins with potent antiviral activity that are of particular importance during the early response to pathogens. Type I IFNs (α, β and ω) are homologous proteins that interact with a common two-chain receptor (IFNAR1 and IFNAR2). Type II or immune IFN is represented by a single protein (IFN-γ) that interacts with different two-chain receptors (IFN-γR1 and IFN-γR2).

CD8 ANTIVIRAL FACTOR

(CAF). The first reported soluble HIV-1 suppressor activity; CAF is released by primary CD8+ T cells upon activation in vitro.

RANTES

A CC-chemokine that binds to and activates the chemokine receptor CCR5.

MIP-1α AND MIP-1β

Like Rantes, MIP-1α and MIP-1β are CC-chemokines that bind to and activate the chemokine receptor CCR5. All these chemokines block the entry of HIV-1 strains that use CCR5 as a co-receptor.

MACROPHAGE-TROPIC

Also known as R5. A viral phenotype that is defined by the use of CCR5 as the co-receptor for viral entry. These isolates are selectively sensitive to suppression by the soluble suppressor factors RANTES, MIP-1α and MIP-1β, which are natural ligands for CCR5.

T-TROPIC

Also known as X4. A viral phenotype that is defined by the use of CXCR4 as a co-receptor for viral entry. These isolates are not inhibited by RANTES, MIP-1α and MIP-1β, but are sensitive to suppression by other soluble suppressor factors.

DUAL-TROPIC

Also known as R5X4. An HIV-1 phenotype that is defined by the use of either CCR5 or CXCR4 co-receptors for viral entry. These isolates are suppressed by RANTES, MIP-1α and MIP-1β in CCR5-dependent infection systems.

LONG TERMINAL REPEAT

A repeated sequence, several hundred base-pairs long, found at the two ends of the retroviral genome.

LONG-TERM NON-PROGRESSORS

HIV-infected persons who remain clinically healthy for long periods of time in the absence of antiretroviral therapy. These persons seem to have a natural capacity to effectively control HIV-1 infection.

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DeVico, A., Gallo, R. Control of HIV-1 infection by soluble factors of the immune response. Nat Rev Microbiol 2, 401–413 (2004). https://doi.org/10.1038/nrmicro878

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