HIV infection and AIDS:
HIV infection represents one of the major health
threats in the developing world with millions of infected individuals suffering
from immunosuppression-associated diseases such as opportunistic infections or
infection-associated cancer. Prevention of HIV infection in developed countries
is achievable by rising public awareness of the sexual transmission pattern.
Furthermore, the costly treatment of infected individuals with multiple highly
efficient anti-HIV drugs is - still - only affordable in industrialized
countries. However, under-developed countries, mainly in Africa, require a
cost-effective vaccination strategy to prevent the further spread of the
infection.
From UNAIDS report 2006 (http://data.unaids.org/pub/GlobalReport/2006/2006_GR-ExecutiveSummary_en.pdf)
HIV
infection and immunity
Prevention
of HIV infection
The
thorough knowledge of the biology of HIV that has been generated over the last
two decades has paved the way for a rational vaccine design. Furthermore, the
progress in the understanding of the basic immunological mechanisms underlying
antigen presentation 1, lymphocyte trafficking and
activation 2, and immunological memory 3 has been instrumental for the
identification of the relevant parameters that ensure the induction of
protective antiviral immunity. Accordingly, an efficient HIV vaccine should
induce long-lasting, broad humoral and cellular responses against the
immunodominant HIV antigens. In particular, the vaccine should (i) target and
activate DCs, (ii) contain the immunodominant antigens recognized by CTL and Th
cells, (iii) be able to display antigenic determinants that induce broadly
neutralizing antibody responses, and (iv) be applicable via mucosal surfaces.
HIV-specific CTL and Th cell responses
CTL responses
crucially contribute to control of immunodeficiency virus infection. Broad
virus-specific CTL responses can be found in peripheral blood of HIV-infected
humans 4;5 and the decline of plasma viral RNA during primary
HIV infection is associated with the appearance of HIV-specific CTL 6;7. Furthermore, transient in vivo depletion of
CD8 T cells lead to a massive increase in viral load in SIV-infected monkeys,
whereas extension of the depletion for more than 28 days elicited a progressive
AIDS-like syndrome 8;9. HIV-specific Th cells can be detected in infected
individuals 10. It is, however, not yet clear whether these cells
extert direct antiviral effects. However, the good correlation of functional
CD4-T cell responses against HIV 11 or SIV 12 with the clinical status strongly supports the notion
that intact Th cell responses are instrumental for long-term virus control.
This is most likely mediated indirectly by stimulation of virus-specific CTL. Since most patients develop T cell responses against
the HIV proteins env, gag or nef 4;5, a broadly applicable vaccine should elicit immune
responses (at least) against these three immmunodominant antigens.
Broadly neutralizing antibodies
Non-neutralizing
antibodies directed against viral proteins appear early after HIV infection,
whereas neutralizing antibodies appear usually rather late after primary
infection 13. Furthermore, sera from HIV-infected individuals
usually display only weak neutralizing activity against primary isolates 14. The fact that depletion of B cells in rhesus monkeys
significantly delayed the appearance of neutralizing antibodies but did not
impact on the early viral clearance 15 supports the notion that neutralizing antibodies do
not contribute significantly during initial HIV infection. However, the
presence of neutralizing antibodies may alter the clinical course of SHIV
infection in macaques and prevents peripartal infection 16. Conventional vaccination approaches consistenly
failed to induce broadly neutralizing antibody responses 17. Nevertheless, distinct monoclonal antibodies have
been described that are capable of neutralizing a broad range of different HIV
isolates, suggesting that such antibody responses might be induced once an
adequate vaccination strategy has been developed 18. For example, altering the immunodominance pattern by
using CD4-HIV envelope fusion constructs that expose normally occluded and
conserved antigenic regions represents such an approach for the induction of
broadly neutralizing antibodies 19. An alternative strategy for the induction of
antibodies that inhibit the infection of primary T cells with different primary
HIV-1 isolates has been reported recently. This promising approach takes
advantage of the highly conserved caveolin-1 binding domain of HIV-1
glycoprotein 41. Neutralization of the caveolin-1 binding site in gp41
efficiently blocks HIV-1 entry in a wide range of primary cells 20.
Mucosal vaccination
HIV is predominantly
transmitted via mucosal surfaces 21. For example, SIV rapidly crosses the epithelial
layers in the cervical mucosa and infects predominantly DCs and CD4 T cells 22. Following primary infection, the virus gains access
to lymphoid organs and establishes persistent infection in CD4 T cells and
macrophages. It appears that constant low-level exposure to virus (via mucosal
surfaces?) is associated with resistance to HIV infection 23. Mucosal vaccination may block transmission of
intravaginally or intrarectally applied SIV 24-26 indicating that an HIV vaccine should prevent the
early stage of infection and elicit long-lasting mucosal immunity.
1. R. M. Steinman and M. Pope, J.Clin.Invest 109, 1519-1526 (2002).
2. S. A. Luther and
J. G. Cyster, Nat.Immunol. 2, 102-107
(2001).
3. S. M. Kaech, E.
J. Wherry, R. Ahmed, Nat.Rev.Immunol.
2, 251-262 (2002).
4. M. M. Addo et al., J.Virol.
77, 2081-2092 (2003).
5.
M. R. Betts et al., J.Virol. 75, 11983-11991 (2001).
6. P. Borrow,
H. Lewicki, B. H. Hahn, G. M. Shaw, M. B. Oldstone, J.Virol. 68, 6103-6110 (1994).
7. R. A. Koup et al., J.Virol.
68, 4650-4655 (1994).
8.
X. Jin et al., J.Exp.Med. 189, 991-998 (1999).
9.
J. E. Schmitz et al., Science 283, 857-860 (1999).
10.
C. J. Pitcher et al., Nat.Med. 5, 518-525 (1999).
11.
E. S. Rosenberg et al., Science 278, 1447-1450 (1997).
12.
P. F. McKay et al., J.Virol. 77, 4695-4702 (2003).
13.
A. K. Pilgrim et al., J.Infect.Dis. 176, 924-932 (1997).
14.
J. P. Moore et al., J.Virol. 69, 101-109 (1995).
15.
J. E. Schmitz et al., J.Virol. 77, 2165-2173 (2003).
16.
T. W. Baba et al., Nat.Med. 6, 200-206 (2000).
17. A. J.
McMichael and T. Hanke, Nat.Med. 9,
874-880 (2003).
18. J. P. Moore, P. W.
Parren, D. R. Burton, J.Virol. 75,
5721-5729 (2001).
19. T. R. Fouts et al.,
FEMS Immunol.Med.Microbiol. 37,
129-134 (2003).
20. A. G. Hovanessian
et al., Immunity. 21, 617-627 (2004).
21. M. Pope and A. T.
Haase, Nat.Med. 9, 847-852 (2003).
22. A. I. Spira et al., J.Exp.Med.
183, 215-225 (1996).
23.
T. Zhu et al., J.Virol. 77, 6108-6116 (2003).
24.
R. R. Amara et al., Science 292, 69-74 (2001).
25. R. S.
Veazey et al., Nat.Med. 9, 343-346
(2003).
26. I. M. Belyakov et
al., Nat.Med. 7, 1320-1326 (2001).