From: bigoldberg@igc.apc.org (Billi Goldberg)
Newsgroups: sci.med.aids
Subject: The Case of the Missing CD4s
Date: 5 Sep 92 04:17:23 GMT
Organization: unspecified
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6069

The following is excerpted from Current Biology 1992, Volume 2, Number 7.
Author is Charles A. Janeway Jr., Section of Immunobiology, Yale University 
School of Medicine and Howard Hughes Medical Institute, New Haven, Connecticut 
06510, USA.

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THE CASE OF THE MISSING CD4s.

HIV-1 infection leads to early loss of the T cells responsible for 
immunological memory. Recent results suggest why this might occur, even though 
relatively few T cells are infected with virus.

When a person is infected with the human immunodeficiency virus 1 (HIV-1) 
there is a period of acute viremia followed by an apparently effective immune 
response. However, virus elimination is not achieved, and the persistence of 
HIV-1 is associated with the gradual loss of T cells expressing the cell 
surface marker CD4. CD4 T cells have a central role in virtually all adaptive 
immune responses: in adults, they are particularly important for defense 
against pathogens that can survive within macrophage vesicles, such as 
mycobacteria. Eventually, sufficient CD4 T cells are lost by HIV-1 infected 
individuals to cripple the adaptive immune response, leading to acquired 
immune deficiency syndrome (AIDS). Early studies of HIV-1 demonstrated that 
the virus could infect CD4 T cells directly through binding of its envelope 
glycoprotein gp120 to the CD4 co-receptor on CD4 T cells. It was therefore 
thought that CD4 T-cell depletion might be the result of direct cytopathic 
effect of the virus on the target tissue. However, it has been very difficult 
to demonstrate that this is so, and many aspects of HIV-1 infection are not 
compatible with this simple interpretation. Thus, a central question in AIDS 
research has become the pathogenesis of CD4 T-cell depletion. Recent studies 
in several laboratories suggest a novel interpretation of the data. Critical 
testing of these findings is now required to determine the precise 
pathogenesis of CD4 T-cell depletion.

When a person has been immunized with a protein antigen, a state of 
immunological memory is established. One manifestation of immunological memory 
is the ability of the immunizing antigen to elicit a CD4 T-cell proliferative 
response upon exposure to the antigen in tissue culture. A startling feature 
of HIV-1 infection is that such memory T-cell responses are lost early in 
infection, long before significant reduction in CD4 T cells can be detected. 
Indeed, memory CD4 T cells appear to be particularly vulnerable to direct 
infection with HIV-1. This does not account, however, for complete loss of 
memory responses, and it is difficult to detect HIV-1 virions in CD4 T cells 
during this phase of the disease. Estimates are that fewer than one cell in 
100 is actually infected. Recent studies by Groux et al. have placed these 
findings in a new context. These authors demonstrate that stimulation of CD4 T 
cells in asymptomatic HIV-1 infected individuals leads to rapid programmed 
cell death. Although initially documented using polyclonal stimulators or 
molecules known as superantigens, Groux and colleagues have shown that protein 
antigens also can induce specific CD4 T cells to undergo programmed cell death 
in tissue culture. Thus, it appears that one consequence of early phase of 
HIV-1 infection is a susceptibility of CD4 T cells to activation-induced 
programmed cell death.

Why might this occur? A possible clue came from earlier studies by Liu and 
myself, in which it was shown that ligation of the T-cell receptor on a class 
of murine cloned T-cell lines caused a similar activation-induced cell death. 
Moreover, cell death could be prevented by exposure of the T-cell clone to 
potent antigen-presenting cells. Antigen-presenting cells are defined as cells 
able to activate a T cell to proliferate in response to antigen. To do so, 
they must carry out two distinct processes. First, they must take up the 
antigen, degrade it into peptide fragments, and deliver these peptide 
fragments to the cell surface complexed to the major histocompatibility 
complex (MHC) class II molecule. This complex is recognized by the T cellUs 
antigen-specific receptor. However, this signal can be interpreted in 
different ways by the T cell. How the signal is interpreted is determined by 
other signals delivered by the same antigen-presenting cell. T-cell receptor 
signals by themselves lead to T-cell anergy--the inability to respond to an 
effective stimulus--or to programmed cell death. If at the same time, however, 
the antigen-presenting cell expresses the cells surface molecule B7, it can 
deliver a signal through the T cellUs CD28 molecule. These two signals, 
delivered together, induce the T cell to synthesize and secrete interleukin-2 
and to proliferate. Moreover, both programmed cell death and anergy are 
blocked by simultaneous delivery of the CD28 signal.

Knowing these facts, Groux et al. exposed the T cells of HIV-1 infected 
asymptomatic individuals to specific protein antigens in the presence of 
antibody to CD28. This antibody can substitute for B7 in delivering the 
necessary signal to the CD4 T-cell. Groux et al. showed that the programmed 
cell death induced in CD4 T cells of HIV-1 infected individuals could be 
reversed by anti-CD28 antibodies, which instead cause the cells to 
proliferate. Thus, memory cells are not lost in HIV-1 infected patients, they 
are merely unable to respond by proliferation when exposed to antigen; instead 
they die. These data suggest that an early effect of HIV-1 infection is 
interference with B7-CD28 interaction.

This raises two questions. First, what cells normally express B7 and serve as 
professional antigen-presenting cells? And second, are such cells likely to be 
infected by HIV-1? The answer to the first question is that B7 is expressed 
constitutively on only a small population of cells, known as dendritic cells, 
found in lymphoid organs. Dendritic cells have been demonstrated to be the 
most potent cells for stimulating T-cell proliferative responses. However, 
they have no obvious means for taking up; and processing antigens delivered 
from the exterior of the cell. Because of this, it has been hypothesized that 
the primary function of dendritic cells might be to present viral antigens to 
the immune system. For the dendritic cell to be effective at doing so, it 
would need to be highly susceptible to viral infection. It is not known if 
this is correct, but two groups have shown that the dendritic cell readily 
infectable with HIV-1. Moreover, HIV-1 does not become latent in dendritic 
cells. Rather, infected dendritic cells produce HIV-1 virions in large 
numbers.

Could the infection of dendritic cells by HIV-1 account for the findings of 
Groux and colleagues? It is worth noting that restoration of normal dendritic 
cells allows purified CD4 T cells from HIV-1 infected individuals to respond 
normally to stimulation. There are several possible mechanisms by which HIV-1 
might alter dendritic cell function. First, HIV-1 appears to deplete dendritic 
cells. Second, HIV-1 may be able to subvert the expression of B7 on dendritic 
cells. This might happen either through binding of gp120 to the B7 molecule, 
or through some action of a gene in the HIV-1 genome on B7 synthesis. Either 
mechanism could account for the results of Groux et al. It is also possible 
that CD4 T cells require intermittent contact with dendritic cells to survive; 
as HIV-1 depletes dendritic cells, this loss may lead to the depletion of CD4 
T cells that occurs late in disease. Alternatively, if dendritic cells are 
producing large amounts of virus, they can be expected to display high levels 
of surface gp120. This gp120 may ligate CD4 molecules on T cells that come 
into contact with the dendritic cell. Cross-linking of CD4 has long been known 
to suppress T-cell proliferation. However, this negative-signaling effect 
would not account for the cell death observed by Groux et al. A few years ago, 
it was reported that heavy cross-linking of CD4 prior to ligation of the 
T-cells receptor could lead to activation-induced cell death CD4 T cells. 
Thus, it is possible that dendritic cells expressing high levels of gp120 
could drive the activation-induced cell death of CD4 T cells observed by Groux 
et al. It is not known whether ligation of CD28 can inhibit programmed cell 
death induced by CD4 cross-linking. If it cannot, then it is unlikely that CD4 
cross-linking by gp120 on infected dendritic cells can account for the results 
obtained by Groux et al. I personally favor some effect of HIV-1 on B7 
expression or dendritic cell function as the mechanism underlying the finding 
of Groux et al.

Several other mechanisms have been proposed to account for the depletion of 
CD4 T cells seen during HIV-1 infection. Few, if any, of these account for the 
surprising absence of recall responses to antigen observed by many workers. 
However, the finding that one mechanism operates does not mean that other 
mechanisms cannot also contribute to the mysterious disappearance of CD4 T 
cells in HIV-1 infected individuals. Thus, direct cytopathic effects, syncytia 
formation, or T cell-mediated cytotoxicity of cells that have passively 
acquired gp120 from serum are all possible mechanism of CD4 T cell depletion 
in patients with HIV-1 infection. Moreover, a great deal of excitement has 
been aroused by the possibility that HIV-1 encodes a superantigen. The current 
proposal in no way negates that earlier proposition, as Groux et al. show that 
superantigens induced programmed cell death of CD4 T cells in HIV-1 infected 
individuals, but not in normal individuals. Thus, superantigens encoded either 
by HIV-1 itself or by bacteria to which HIV-1-infected individuals are exposed 
could have an important role in deletion of mature CD4 T cells in HIV-1 
infected individuals. Perhaps all these mechanism, acting together, are what 
lead eventually to AIDS. The documentation that asymptomatic HIV-1-infected 
individuals have memory T cells, but that these cells die upon exposure to 
antigen, adds a new element to the story of CD4 T cell disappearance in HIV-1 
infected individuals. It also suggest new targets for therapy and new places 
to look for culprits. It will be interesting to examine this mechanism in 
detail, as it might allow novel therapeutic approaches to the treatment of 
this perplexing and devastating illness.
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Newsgroups: sci.med.aids