Infection with the AIDS virus has led to an expanding global health crisis, with over 45 million persons currently living with HIV infection. Ineffective immune control and resultant disease progression is a hallmark of this infection, despite the induction of vigorous virus-specific CD8 T cell responses in most infected persons. Although the features of protective immunity in HIV infection remain to be defined, growing evidence points to a critical role for virus-specific CD4 cells. This is consistent with observations in murine models that maintenance of effective antiviral CTL responses in chronic viral infections is critically dependent on virusspecific T helper cells (1–8).

A potentially simple explanation for the lack of effective immune control in chronic HIV infection is that HIV selectively infects activated CD4 cells and thereby destroys the very cells being generated to coordinate the adaptive immune response (9). However, simple deletion of antigen-specific CD4 cells cannot be the reason for immune failure, since it has been shown that large numbers of virus-specific CD4 cells that secrete interferon gamma (IFN-) persist in most persons with uncontrolled viremia (10–12). In contrast, the ability of CD4 cells to proliferate in response to viral antigenic challenge is impaired in persons with progressive infection and high viral loads (13–15). This apparent paradox implies the presence of a functional CD4 defect, the definition of which is of critical importance in understanding the immunologic control of viral replication. A paper published by Younes et al. in this issue (16), and a series of recent publications (17–19), provide new insights into CD4 cells that are associated with lack of HIV immune control and suggest that the presence of antigen-specific CD4 cells able to produce IL-2 is a key component of effective immunity. Younes et al. examined virus-specific CD4 T cell responses in two groups of newly HIV-infected persons (16). One group consisted of persons treated in the earliest stages of acute infection in whom viremia was consistently suppressed by effective antiviral therapy (aviremic subjects),