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Gene Expression-178

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Heart-61

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Viruses-85

Chapter category: Vaccines

Immune Responses to DNA Vaccines: Induction of CD8⁺

Chapter authors:
Jens A. Leifert and J. Lindsay Whitton

The importance of CD8⁺ T cells in the control and eradication of viruses has been demonstrated in mice and men. In the mouse, they are critical in combating infection with lymphocytic choriomeningitis virus (LCMV; ref. 1), and in humans, "experiments of nature" strongly suggest that T cells play a vital role in controlling many virus infections.² For example, children born with hereditary agammaglobulinemia are much more susceptible to suppurative bacterial infections,³ and people with defects in the complement cascade show increased susceptibility to Neisserial diseases;⁴⁶ however, in contrast to their greatly enhanced vulnerability to bacterial infections, these individuals show only mildly elevated susceptibility to most viral diseases, with the exception of rare enteroviral meningitides, caused most often by picornaviruses such as coxsackievirus^7,8 and echovirus type 9 or 11.^9,10 For most virus infections, the incidence of disease, and disease severity, are similar in antibodydeficient and in immunocompetent individuals. These observations suggest that other factorsperhaps CD8⁺ T cellsare capable of resolving (most) virus infections in humans. This suggestion is supported by the finding that the frequency and severity of virus infections are markedly increased in humans with impaired Tcell responses [for example, in patients with Di George's syndrome (congenital thymic aplasia), acquired immunodeficiency syndrome (AIDS), leukemia, or recipients of immunosuppressive therapy].¹¹ In HIV infection, CD8⁺ Tcell activity correlates with clearance of initial viral load, and their absence heralds a return to high viral titers, and eventual AIDS.¹²¹⁴ The importance of T cells in controlling human virus infections is further highlighted by our responses to measles virus. In immunocompetent individuals, the infection is typified by the characteristic (& diagnostic) rash, and complete recovery is the norm. In contrast, in Tcell deficiency, the disease is often fatal.¹⁵¹⁷ The rash itself is Tcellmediated and does not develop in severely immunosuppressed individuals; indeed, the presence of a rash in an immunosuppressed victim (e.g., in a leukemic child with measles) is considered a positive prognostic indicator.¹⁸ In agammaglobulinemic children, the rash develops normally, and the infection is cleared. Furthermore, these children are subsequently immune to measles,² suggesting that T cells can play an important role not only in controlling a primary infection, but also in preventing disease following secondary exposure; this observation was an early (and often overlooked) indication that CD8⁺ memory T cells might be important in vaccineinduced antiviral immunity (see below). In the next section, we shall provide a molecular explanation of why CD8⁺ T cells are important in controlling most virus infections; and why bacterial infections, rather than virus infections, are more severe in the absence of antibodies.

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