Blood, 1 March 2002, Vol. 99, No. 5, pp. 1876-1878
CORRESPONDENCE
To the editor:
Why antiviral CD8 T lymphocytes fail to prevent progressive
immunodeficiency in HIV-1 infection
We would like to comment on the recent review by
Lieberman et al1 by offering an additional interpretation
on the mechanisms that contribute to lack of protection by antiviral
CD8 T cells in HIV infection. In the last few years we have been able
to demonstrate that, since the early phases of HIV infection, the
pulmonary microenvironment can be infected by the etiologic agent of
AIDS and that the intra-alveolar presence of HIV evokes a discrete
immune response mediated by antiviral CD8+ cytotoxic T
lymphocytes (CTLs).2 In asymptomatic patients the
appearance of pulmonary CD8 T cells is associated with the clearance of
the virus from the lung microenvironment. But with the progression of
HIV disease, the cytotoxic activity of pulmonary CTLs declines. Our
data published in 1995 emphasize the role of HIV infection in the
progressive functional impairment of CD8 T cells.3
Although lymphocytes expressing the CD4 receptor are the principal cell
target for HIV, lung CD8+ T cells of most patients with
AIDS show an unexpected in vivo HIV infectivity.3 When
proviral load on pulmonary T-cell subsets is assessed using the
DNA-polymerase chain reaction (PCR) technique, most of the
bronchoalveolar lavage (BAL) proviral DNA can be found in the
underrepresented CD4 T-cell subset, but PCR analysis directly performed
on highly enriched CD8+ T cells shows that this population
also carries detectable amounts of HIV DNA. Circumstantial evidence
obtained evaluating peripheral blood CD8 also supports the hypothesis
that retroviral infection of CD8 cells may contribute to the functional
decline of this subset upon disease progression in HIV-infected
individuals.4 Interestingly, the proviral load of
pulmonary CD8+ T cells usually shows an upward trend with
respect to the corresponding samples isolated from the peripheral blood
of the same patient.5 Because we demonstrated
that CD8+ T cells accumulating in the lungs of HIV-infected
patients are preactivated Tc1 cells prone to spontaneous and
activation-induced apoptosis,6 it is tempting to relate
the productive infection to the increased apoptosis rate of
CD8+ T cells.
Concerning the mechanisms that account for the infection of
CD8+ CTL, at least 2 hypotheses can be proposed.
The repeated contacts occurring in the lung microenvironment between
activated HIV-specific CTLs and relevant targets might lead to the
infection of CD8 cells. This hypothesis is supported by in vitro
studies showing that HIV may be transmitted through cell-to-cell
contact between persistently infected CD4 cells and CD8
CTLs.7 An additional, though not necessarily alternative,
hypothesis is that lung CD8+ CTLs derive from T-cell
precursors that transiently coexpress both CD4 and CD8 determinants in
secondary follicles where trapped extracellular virions are present in
the dendritic network.
In conclusion, on the basis of these data we believe that the
retroviral infection of CD8 T cells should be considered as an
additional mechanism contributing to the fall of antiviral CD8 T-cell
activity during HIV infection. Because it is known that highly active
antiretroviral therapy (HAART) leads to a reduction of HIV load,
additional studies should be performed to evaluate the ultimate effects
of HAART on CD8 T-cell infectivity in relation to their functional
activities. On clinical grounds, this information could have an impact
on strategies for designing therapeutic intervention in HIV infected patients.
Carlo Agostini and Gianpietro Semenzato
Correspondence: Gianpietro Semenzato, Università degli
Studi di Padova, Dipartimento di Medicina Clinica e Sperimentale,
Immunologia Clinica, Via Giustiniani 2, 35128 Padova, Italy
References
1.
Lieberman J, Shankar P, Manjunath N, Andersson J.
Dressed to kill? a review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection.
Blood.
2001;98:1667-1677[Abstract/Free Full Text].
2.
Agostini C, Zambello R, Trentin L, Semenzato G.
HIV and pulmonary immune responses.
Immunol Today.
1996;17:359-364[CrossRef][Medline]
[Order article via Infotrieve].
3.
Semenzato G, Agostini C, Ometto L, et al.
CD8+ T lymphocytes in the lung of acquired immunodeficiency syndrome patients harbor human immunodeficiency virus type 1.
Blood.
1995;85:2308-2314[Abstract/Free Full Text].
4.
Livingstone WJ, Moore M, Innes D, Bell JE, Simmonds P.
Frequent infection of peripheral blood CD8-positive T-lymphocytes with HIV-1: Edinburgh Heterosexual Transmission Study Group.
Lancet.
1996;348:649-654[CrossRef][Medline]
[Order article via Infotrieve].
5.
Semenzato G, Agostini C, Chieco-Bianchi L, De Rossi A.
HIV load in highly purified CD8+ T cells retrieved from pulmonary and blood compartments.
J Leukoc Biol.
1998;64:298-301[Abstract].
6.
Agostini C, Siviero M, Facco M, et al.
Antiapoptotic effects of IL-15 on pulmonary Tc1 cells of patients with human immunodeficiency virus infection.
Am J Respir Crit Care Med.
2001;163:484-489[Abstract/Free Full Text].
7.
De Maria A, Colombini S, Schnittman SM, Moretta L.
CD8+ cytolytic T lymphocytes become infected in vitro in the process of killing HIV-1-infected target cells.
Eur J Immunol.
1994;24:531-536[Medline]
[Order article via Infotrieve].
Response:
HIV infection of CD8 T cells: a factor in progressive
immunodeficiency?
Agostini and Semenzato suggest that an important factor in the
lack of protection by antiviral CD8 T cells in HIV infection is
infection of CD8 T cells by HIV. A number of studies have indicated that, when naïve CD8 T cells are activated via the T-cell
receptor (TCR), they express CD4, although at reduced levels compared
to that on CD4 T cells.1,2 Moreover, in vitro CD8 T cells
can be productively infected with HIV.3-8 The real
question is how significant HIV infection of CD8 T cells is in vivo,
whether it is productive, and whether it contributes to the
lack of CD8 T cell function. The studies of HIV infection in vivo have
relied on polymerase chain reaction (PCR) amplification of proviral DNA from immunomagnetically separated or sorted cell populations. The
majority have studied advanced patient samples. Although it is unlikely
that the PCR results are all due to contaminating CD4-expressing T
cells or monocytes, none of the published studies use quantitative or
even semiquantitative assays to give an accurate assessment of the
rates of infection of CD8 T cells in vivo. There is also little
evidence that the infection is productive in vivo. Moreover, in early
and moderately advanced disease the number of CD8 T cells is expanded
above normal levels, and HIV-specific CD8 T cells represent a sizable
proportion of the expanded population (see references in Lieberman et
al9). Therefore, because HIV infection of CD8 T
cells would be expected to deplete CD8 T cells, as it does CD4 T cells,
it is unlikely that HIV infection of CD8 T cells contributes in any
substantial way to CD8 T cell dysfunction in less advanced stages of
disease. In more advanced patients with AIDS, however, HIV infection
might well contribute to the late decline in CD8 T cells and loss of
HIV-specific immunity.10 This merits further study.
Quantitative assessment of HIV proviral DNA and mRNA in highly purified
CD8 T cells or simultaneous measurement of CD8 and CD3 with
intracellular HIV p24 protein or in situ hybridization of HIV RNA would
help establish that this is an important contributing factor to
antiviral CD8 T cell dysfunction. In vitro studies that demonstrate
functional effects of selected in vitro infected HIV-specific CD8 T
cells would also help build a case.
Judy Lieberman, Premlata Shankar, M. Swamy, and Jan Andersson
Correspondence: Judy Lieberman, Center for Blood Research, 800 Huntington Avenue, Boston, MA 02115
References
1.
Flamand L, Crowley RW, Lusso P, et al.
Activation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: implications for HIV pathogenesis.
Proc Natl Acad Sci U S A.
1998;95:3111-3116[Abstract/Free Full Text].
2.
Kitchen SG, Korin YD, Roth MD, Landay A, Zack JA.
Costimulation of naive CD8(+) lymphocytes induces CD4 expression and allows human immunodeficiency virus type 1 infection.
J Virol.
1998;72:9054-9060[Abstract/Free Full Text].
3.
De Maria A, Colombini S, Schnittman SM, Moretta L.
CD8+ cytolytic T lymphocytes become infected in vitro in the process of killing HIV-1-infected target cells.
Eur J Immunol.
1994;24:531-536.
4.
Semenzato G, Agostini C, Ometto L, et al.
CD8+ T lymphocytes in the lung of acquired immunodeficiency syndrome patients harbor human immunodeficiency virus type 1.
Blood.
1995;85:2308-2314.
5.
Livingstone WJ, Moore M, Innes D, Bell JE, Simmonds P.
Frequent infection of peripheral blood CD8-positive T-lymphocytes with HIV-1: Edinburgh Heterosexual Transmission Study Group.
Lancet.
1996;348:649-654.
6.
Semenzato G, Agostini C, Chieco-Bianchi L, De Rossi A.
HIV load in highly purified CD8+ T cells retrieved from pulmonary and blood compartments.
J Leukoc Biol.
1998;64:298-301.
7.
Yang LP, Riley JL, Carroll RG, et al.
Productive infection of neonatal CD8+ T lymphocytes by HIV-1.
J Exp Med.
1998;187:1139-1144[Abstract/Free Full Text].
8.
Saha K, Zhang J, Gupta A, et al.
Isolation of primary HIV-1 that target CD8+ T lymphocytes using CD8 as a receptor.
Nat Med.
2001;7:65-72[CrossRef][Medline]
[Order article via Infotrieve].
9.
Lieberman J, Shankar P, Manjunath N, Andersson J.
Dressed to kill? a review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV infection.
Blood.
2001;98:1667-1677.
10.
Saha K, Zhang J, Zerhouni B.
Evidence of productively infected CD8+ T cells in patients with AIDS: implications for HIV-1 pathogenesis.
J Acquir Immune Defic Syndr.
2001;26:199-207.
