The search for the CD8+ cell anti-HIV factor (CAF)

doi:10.1016/j.it.2003.10.005

Trends in Immunology

Volume 24, Issue 12, December 2003, Pages 628-632

https://doi.org/10.1016/j.it.2003.10.005 Get rights and content

Abstract

Efforts to control HIV infection have led to the development of several antiretroviral drugs that can limit virus replication, however, these therapies do not offer a long-term solution to the infection. We can learn a great deal from HIV-infected individuals who have lived for more than ten years and remain healthy without receiving antiviral drugs. These long-term survivors or long-term non-progressors have an immune system that can control HIV infection. A major component of this immune response is innate immunity, particularly the CD8⁺ cell antiviral non-cytotoxic response (CNAR), mediated by a novel CD8⁺ cell antiviral factor (CAF). The characteristics of CNAR and CAF will be described and progress made toward identifying CAF will be reviewed. These studies have uncovered several potentially important natural anti-HIV factors and their relationship to the originally described CAF is considered.

Section snippets

CD8⁺ cell non-cytotoxic anti-HIV response

CNAR occurs early in HIV infection before antibodies are produced [15] and thus appears to have a role with CTLs in controlling the virus soon after infection [16]. It can also be observed in high-risk HIV-exposed uninfected individuals [17], suggesting its importance in preventing HIV infection. CNAR and CAF activity is not specific for a particular retrovirus; this antiviral response inhibits all HIV-1, HIV-2 and simian immunodeficiency virus (SIV) isolates tested 3, 18. It can also affect

CD8⁺ cell antiviral factor

The soluble anti-HIV activity found in fluids of cultured CD8⁺ cells (referred to as CAF) is produced at low levels (4 units ml⁻¹ in culture fluids; 1 unit=50% suppression of HIV replication in cell culture) [3] and thus has been difficult to identify. Nevertheless, using non-cytotoxic anti-HIV activity in cell culture fluids as a marker, CAF was shown to be a protein produced only by activated [human leukocyte antigen-DR (HLA-DR)] CD8⁺ cells (primarily CD28⁺) 3, 26, 27 with distinct

Other natural anti-HIV factors

During the search for CAF, other new distinct anti-HIV factors were found (Box 2) but they also lacked the characteristics of the initially described CD8⁺ cell antiviral protein (Box 1), such as, the factor should be made exclusively by CD8⁺ cells, particularly cells coming from infected individuals who are healthy and not those progressing to disease. Moreover, the factor should block HIV transcription and be resistant to heat and low pH.

In 1995, Cocchi et al. [31] reported that the β

CD8⁺ cell anti-HIV factors: recent observations

In other studies directed at identifying CAF, Zhang et al. [44] co-cultivated CD8⁺ cells on allogeneic irradiated peripheral blood mononuclear cells and found antiviral activity in some of the cell culture fluids. By mass spectrometry and with purified defensins and anti-defensin neutralizing antibodies, they showed that this activity was associated with the presence of α-defensins 1, 2 and 3. The anti-HIV activity of α-defensins had been reported previously [45]. Zhang and co-workers concluded

Conclusions

These past and recent studies indicate that several groups are directing efforts at finding natural anti-HIV factors that could explain the mechanism for CD8⁺ cell non-cytotoxic antiviral activity and, in particular, the identity of CAF. Whereas CNAR might reflect the presence of several antiviral factors, I believe that one major protein is involved that leads to an arrest in HIV transcription. Whether a proteolytic step is needed to activate a CD8⁺ cell product or it affects the infected CD4⁺

Acknowledgements

The research cited from my laboratory was supported by grants from the National Institutes of Health (RO1-AI-30350), the American Foundation for AIDS Research (amfAR), the California State Universitywide Task Force on AIDS and the Pendleton Charitable Trust. Because of limited space for references, I regret that several citations could not be included. I thank Ann Murai and Kaylynn Peter for their assistance in the preparation of the manuscript. I also thank Alan Landay, Leyla Diaz and Kyle

References (64)

J.A. Levy
The importance of the innate immune system in controlling HIV infection and disease
Trends Immunol.
(2001)
J.A. Levy
Controlling HIV pathogenesis: the role of noncytotoxic anti-HIV activity of CD8⁺ cells
Immunol. Today
(1996)
S. Rowland-Jones et al.
Cytotoxic T lymphocytes in HIV infection
Semin. Virol.
(1993)
C.M. Walker
CD8⁺ T cells from HIV-1-infected individuals inhibit acute infection by human and primate immunodeficiency viruses
Cell. Immunol.
(1991)
B.A. Castro
Suppression of human immunodeficiency virus replication by CD8⁺ cells from infected and uninfected chimpanzees
Cell. Immunol.
(1991)
A.L. Landay
An activated CD8⁺ T cell phenotype correlates with anti-HIV activity and asymptomatic clinical status
Clin. Immunol. Immunopathol.
(1993)
C.E. Mackewicz
Effect of cytokines on HIV replication in CD4⁺ lymphocytes: lack of identity with the CD8⁺ cell antiviral factor
Cell. Immunol.
(1994)
C.E. Mackewicz
Lack of the CD8⁺ cell anti-HIV factor in CD8⁺ cell granules
Blood
(2003)
R.I. Lehrer et al.
Defensins of vertebrate animals
Curr. Opin. Immunol.
(2002)
R. Geiben-Lynn
Purification of a modified form of bovine antithrombin III as an HIV-1 CD8⁺ T-cell antiviral factor
J. Biol. Chem.
(2002)

T. Vu

Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation

Cell

(1991)

R. Geiben-Lynn

HIV-1 antiviral activity of recombinant natural killer cell enhancing factors NKEF-A and NKEF-B, Members of the peroxiredoxin family

J. Biol. Chem.

(2003)

L.A. Pinto

Alloantigen-induced anti-HIV activity occurs prior to reverse transcription and can be generated by leukocytes from HIV-infected individuals

Blood

(2000)

T.B. McNeely

Inhibition of human immunodeficiency virus type 1 infectivity by secretory leukocyte protease inhibitor occurs prior to viral reverse transcriptase

Blood

(1997)

C.M. Walker

CD8⁺ lymphocytes can control HIV infection in vitro by suppressing virus replication

Science

(1986)

C.M. Walker

Inhibition of human immunodeficiency virus replication in acutely infected CD4⁺ cells by CD8⁺ cells involves a noncytotoxic mechanism

J. Virol.

(1991)

C. Mackewicz et al.

CD8⁺ cell anti-HIV activity: nonlytic suppression of virus replication

AIDS Res. Hum. Retroviruses

(1992)

D.J. Blackbourn

Suppression of HIV replication by lymphoid tissue CD8⁺ cells correlates with the clinical state of HIV-infected individuals

Proc. Natl. Acad. Sci. U. S. A.

(1996)

M. Kannagi

Suppression of simian immunodeficiency virus replication in vitro by CD8⁺ lymphocytes

J. Immunol.

(1988)

J.E. Brinchmann

CD8⁺ T cells inhibit HIV replication in naturally infected CD4⁺ T cells: Evidence for a soluble inhibitor

J. Immunol.

(1990)

A.M. Gomez

Inhibition of HIV replication by CD8⁺ T cells correlates with CD4 counts and clinical stage of disease

Clin. Exp. Immunol.

(1994)

C.M. Walker et al.

A diffusible lymphokine produced by CD8⁺ T lymphocytes suppresses HIV replication

Immunology

(1989)

C.H. Chen

CD8⁺ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism

AIDS Res. Hum. Retroviruses

(1993)

C.E. Mackewicz

CD8⁺ cells suppress human immunodeficiency virus replication by inhibiting viral transcription

Proc. Natl. Acad. Sci. U. S. A.

(1995)

C.E. Mackewicz

CD8⁺ cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration

J. Gen. Virol.

(2000)

C.E. Mackewicz

Non-cytolytic CD8 T-cell anti-HIV responses in primary infection

Lancet

(1994)

R.A. Koup

Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome

J. Virol.

(1994)

S. Stranford

Lack of infection in HIV-exposed individuals is associated with a strong CD8⁺ cell noncytotoxic anti-HIV response

Proc. Natl. Acad. Sci. U. S. A.

(1999)

K.F.T. Copeland

Suppression of activation of the human immunodeficiency virus long terminal repeat by CD8+ T cells is not lentivirus specific

AIDS Res. Hum. Retroviruses

(1995)

C.E. Mackewicz

HLA compatibility requirements for CD8⁺ T-cell-mediated suppression of human immunodeficiency virus replication

J. Virol.

(1998)

D.J. Blackbourn

CD8⁺ cells from HIV-2-infected baboons control HIV replication

AIDS

(1997)

C.R. Jeng

Evidence for CD8⁺ antiviral activity in cats infected with feline immunodeficiency virus

J. Virol.

(1996)

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Citation Excerpt :
In addition, CD8+ T cell depletion in rhesus macaques did not increase the life-span of SIV-infected cells, indicating that direct killing was unlikely the main mechanism antagonizing viral replication (Klatt et al., 2010; Wong et al., 2010). The suppressive effect is attributed, at least in part, to a still unidentified soluble molecule known as cellular antiviral factor or CAF (Levy, 2003; Walker et al., 1986). In addition to CAF, beta-chemokines produced by CD8+ T cells such as CCL3 (MIP1-α), CCL4 (MIP1-β), and CCL5 (RANTES) have been shown to exert anti-HIV activities as these molecules interfere with viral entry by binding to CCR5, a key co-receptor of HIV (Cocchi et al., 1995).
CD8+ T cells are crucial for immunity against viral infections, including HIV. Several characteristics of CD8+ T cells, such as polyfunctionality and cytotoxicity, have been correlated with effective control of HIV. However, most of these correlates have been established in the peripheral blood. Meanwhile, HIV primarily replicates in lymphoid tissues. Therefore, it is unclear which aspects of CD8+ T cell biology are shared and which are different between blood and lymphoid tissues in the context of HIV infection. In this review, we will recapitulate the latest advancements of our knowledge on lymphoid tissue CD8+ T cells during HIV infection and discuss the insights these advancements might provide for the development of a HIV cure.
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Despite more than three decades of intense research, a prophylactic HIV-1 vaccine remains elusive. Four vaccine modalities have been evaluated in clinical efficacy studies, but only one demonstrated at least modest efficacy, which correlated with polyfunctional antibody responses to the HIV surface protein Env. To be most effective, a HIV-1 vaccine probably has to induce both, functional antibody and CD8⁺ T cell responses. We therefore analyzed DNA/DNA and DNA/virus-like particle (VLP) regimens for their ability to induce humoral and cellular immune responses. Here, DNA vaccination of mice induced strong CD8⁺ responses against Env and Gag. However, the humoral response to Env was dominated by IgG1, a subclass known for its low functionality. In contrast, priming only with the Gag-encoding plasmid followed by a boost with VLPs consisting of Gag and Env improved the quality of the anti-Env antibody response via intrastructural help (ISH) provided by Gag-specific T cells to Env-specific B cells. Furthermore, the Gag-specific CD8⁺ T cells induced by the DNA prime immunization could still protect from a lethal infection with recombinant vaccinia virus encoding HIV Gag. Therefore, this immunization regimen represents a promising approach to combine functional antibody responses toward HIV Env with strong CD8⁺ responses controlling early viral replication.
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Citation Excerpt :
HLA concordance is not needed for CNAR (in contrast to CTL), but a match gives a more robust response [30,41]. CNAR is active at lower CD8+ cell:CD4+ cell input ratios than the CTL response and has other characteristics of innate immune activity [14,30]: the response occurs early and no virus specificity is involved. CNAR is effective against all HIV-1, HIV-2, and Simian immunodeficiency virus (SIV) isolates tested, as well as other retroviruses; no resistant virus has been found (Box 1) [14,17,30].
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CD8<sup>+</sup> T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production
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Trends in Immunology

The search for the CD8+ cell anti-HIV factor (CAF)

Abstract

Section snippets

CD8+ cell non-cytotoxic anti-HIV response

CD8+ cell antiviral factor

Other natural anti-HIV factors

CD8+ cell anti-HIV factors: recent observations

Conclusions

Acknowledgements

Trends Immunol.

Immunol. Today

Semin. Virol.

Cell. Immunol.

Cell. Immunol.

Clin. Immunol. Immunopathol.

Cell. Immunol.

Blood

Curr. Opin. Immunol.

J. Biol. Chem.

Cell

J. Biol. Chem.

Blood

Blood

CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication

Science

Inhibition of human immunodeficiency virus replication in acutely infected CD4+ cells by CD8+ cells involves a noncytotoxic mechanism

J. Virol.

CD8+ cell anti-HIV activity: nonlytic suppression of virus replication

AIDS Res. Hum. Retroviruses

Suppression of HIV replication by lymphoid tissue CD8+ cells correlates with the clinical state of HIV-infected individuals

Proc. Natl. Acad. Sci. U. S. A.

Suppression of simian immunodeficiency virus replication in vitro by CD8+ lymphocytes

J. Immunol.

CD8+ T cells inhibit HIV replication in naturally infected CD4+ T cells: Evidence for a soluble inhibitor

J. Immunol.

Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease

Clin. Exp. Immunol.

A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication

Immunology

CD8+ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism

AIDS Res. Hum. Retroviruses

CD8+ cells suppress human immunodeficiency virus replication by inhibiting viral transcription

Proc. Natl. Acad. Sci. U. S. A.

CD8+ cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration

J. Gen. Virol.

Non-cytolytic CD8 T-cell anti-HIV responses in primary infection

Lancet

Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome

J. Virol.

Lack of infection in HIV-exposed individuals is associated with a strong CD8+ cell noncytotoxic anti-HIV response

Proc. Natl. Acad. Sci. U. S. A.

Suppression of activation of the human immunodeficiency virus long terminal repeat by CD8+ T cells is not lentivirus specific

AIDS Res. Hum. Retroviruses

HLA compatibility requirements for CD8+ T-cell-mediated suppression of human immunodeficiency virus replication

J. Virol.

CD8+ cells from HIV-2-infected baboons control HIV replication

AIDS

Evidence for CD8+ antiviral activity in cats infected with feline immunodeficiency virus

J. Virol.

The search for the CD8⁺ cell anti-HIV factor (CAF)

CD8⁺ cell non-cytotoxic anti-HIV response

CD8⁺ cell antiviral factor

CD8⁺ cell anti-HIV factors: recent observations

CD8⁺ lymphocytes can control HIV infection in vitro by suppressing virus replication

Inhibition of human immunodeficiency virus replication in acutely infected CD4⁺ cells by CD8⁺ cells involves a noncytotoxic mechanism

CD8⁺ cell anti-HIV activity: nonlytic suppression of virus replication

Suppression of HIV replication by lymphoid tissue CD8⁺ cells correlates with the clinical state of HIV-infected individuals

Suppression of simian immunodeficiency virus replication in vitro by CD8⁺ lymphocytes

CD8⁺ T cells inhibit HIV replication in naturally infected CD4⁺ T cells: Evidence for a soluble inhibitor

Inhibition of HIV replication by CD8⁺ T cells correlates with CD4 counts and clinical stage of disease

A diffusible lymphokine produced by CD8⁺ T lymphocytes suppresses HIV replication

CD8⁺ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism

CD8⁺ cells suppress human immunodeficiency virus replication by inhibiting viral transcription

CD8⁺ cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration

Lack of infection in HIV-exposed individuals is associated with a strong CD8⁺ cell noncytotoxic anti-HIV response

HLA compatibility requirements for CD8⁺ T-cell-mediated suppression of human immunodeficiency virus replication

CD8⁺ cells from HIV-2-infected baboons control HIV replication

Evidence for CD8⁺ antiviral activity in cats infected with feline immunodeficiency virus